PEDIATRICS Vol. 121 No. 4 April 2008, pp. e782-e786 (doi:10.1542/peds.2007-1774)
ARTICLE |
Toxicity of Buprenorphine Overdoses in Children
Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, Maryland
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. There are few reports in children of overdoses of buprenorphine, a partial opioid agonist used in the treatment of opioid dependence and pain. The purpose of this study was to analyze buprenorphine overdoses in young children reported by US poison centers to the Researched Abuse, Diversion, and Addiction-Related Surveillance System.
METHODS. A retrospective review of buprenorphine overdoses in children <6 years of age reported to the Researched Abuse, Diversion, and Addiction-Related Surveillance System from November 2002 through December 2005 was performed. Patients lost to follow-up and those ingesting multiple substances were excluded.
RESULTS. Eighty-six cases met inclusion criteria. In the 54 children who developed toxicity, the clinical effects included drowsiness or lethargy (55%), vomiting (21%), miosis (21%), respiratory depression (7%), agitation or irritability (5%), pallor (3%), and coma (2%). There were no fatalities. The mean time to onset of effects was 64.2 minutes, with a range of 20 minutes to 3 hours. Duration of clinical effects was under 2 hours in 11%, 2 to 8 hours in 59%, 8 to 24 hours in 26%, and >24 hours in 4%. Children who ingested 
2 mg of buprenorphine were more likely to experience clinical effects, and all of the children who ingested >4 mg experienced some effect. No child ingesting <4 mg experienced a severe effect. Of the 22 children administered naloxone, 67% had at least a partial response.
CONCLUSIONS. Buprenorphine overdoses are generally well tolerated in children, with significant central nervous system and respiratory depression occurring in only 7%. Any child ingesting >2 mg and children <2 years of age ingesting more than a lick or taste should be referred to the emergency department for a minimum of 6 hours of observation. Naloxone can be used to reverse respiratory depression.
Key Words: buprenorphine • toxicity • overdose • children
Abbreviations: RADARS—Researched Abuse, Diversion, and Addiction-Related Surveillance • CNS—central nervous system
Buprenorphine is a semisynthetic, highly lipophilic opioid derived from thebaine. It is a partial µ-receptor agonist and 
-receptor antagonist and is 25 to 50 times more potent than morphine.1 Buprenorphine was approved by the Food and Drug Administration in 2002 for the treatment of opioid dependence, although it has been available for many years to treat pain. Three buprenorphine products are commercially available in the United States. Suboxone combines buprenorphine and naloxone in a 4:1 ratio (2.0 mg of buprenorphine to 0.5 mg of naloxone or 8.0 mg of buprenorphine to 2.0 mg of naloxone). The naloxone component is included to help discourage diversion and misuse. Naloxone has very limited oral and sublingual bioavailability.2 However, if Suboxone is crushed and injected, the naloxone will precipitate opioid withdrawal.3 Subutex contains either 2 mg of buprenorphine or 8 mg of buprenorphine, without naloxone. Both Suboxone and Subutex are sublingual tablets indicated for the management of opioid dependence. Buprenex is the injectable form of buprenorphine and is indicated for pain relief.
Buprenorphine has high affinity for and slow association and dissociation from the µ-receptor, which results in a long duration of action.4 The partial agonist properties translate into low intrinsic activity, which was thought to cause its effects to plateau at higher doses. Recent data demonstrated that buprenorphine does in fact induce a ceiling effect in respiratory depression but not in analgesia.5 These unique qualities may confer a high safety profile compared with other opioids and cause less toxicity in children after unintentional overdoses.
A paucity of literature exists regarding the effects of buprenorphine in pediatric patients. Ceiling effects suggest that minimal toxicity would be expected in overdoses.6,7 Some authors, however, have reported serious effects in this population with clinical courses characterized by a need for antidotal therapy and ventilatory support.8 The purpose of this retrospective study was to identify and analyze all of the pediatric exposure calls regarding buprenorphine reported to the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System for clinical effects, dose response, and treatment.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Unintentional buprenorphine overdoses in children reported by poison centers to RADARS from November 2002 through December 2005 were examined. For inclusion, children had to be <6 years of age and have a history of ingestion of buprenorphine. Children lost to follow-up or ingesting multiple substances were excluded. This study was reviewed by the University of Maryland at Baltimore Institutional Review Board and determined to be exempt from the institutional review board approval process.
The RADARS System was developed in response to increasing concerns of anticipated rates of prescription opioid abuse in several areas of the United States. Its mission is "to provide timely and geographic-specific data to the pharmaceutical industry, regulatory agencies, policy makers and medical/public health officials to aid in understanding trends in the abuse, misuse, and diversion of prescription drugs in the United States."9 The RADARS System is composed of 4 signal detection systems that each report to a central location for analysis and storage. Records from the poison center network arm of the RADARS System were obtained. Currently the poison center network includes 43 poison centers and serves a population of 200 million people in urban, suburban, and rural areas of the United States. Each poison center and the network as a whole possess a standardized data collection tool with quality control measures. Data fields include: age, gender, product or substance, call type, reason for exposure, exposure duration and route, dates, clinical effects, therapies, and free text fields. The free text fields, which describe clinical effects and management in detail and resemble a hospital medical chart, allow for a more accurate and in-depth investigation of each case and represent a definite advantage over other population-based data collection systems.10
Data in the RADARS records were analyzed for age, gender, product ingested, dose, site of exposure, reason for exposure, acuity, clinical effects, duration of effect, management site, therapy, and medical outcome. Dose reported as a "taste or lick" was included as a dose of one tenth of the dosage form involved.11 Dose per kilogram of body weight was calculated for each case. If missing, children's weights were imputed by using previously described methods.11
Medical outcomes were classified according to severity. A minor effect was defined as evidence of clinical toxicity without respiratory depression or significant central nervous system (CNS) depression. For example, drowsiness or lethargy, vomiting, and miosis were considered minor effects. Patients with a severe effect developed coma and/or respiratory depression. Respiratory depression was defined as a decreased rate of respirations, decreased depth of respirations, decreased oxygen saturation, or evidence of cyanosis.
Data were analyzed by using Microsoft Excel 2003 (Redmond, WA) and SigmaStat 3.1 (Sigma, Point Richmond, CA), and summary statistics were generated. Age and dose (in milligrams) were evaluated as categorical data by using 
2 statistical analyses to examine whether there was a relationship between dose or age and medical outcome. Nonparametric analysis was performed using Kruskal-Wallis 1-way analysis of variance on ranks with posthoc multiple comparison analysis using Dunn's method to investigate the relationship between median dosage (milligrams per kilogram) and symptom severity, because variances were unequal and data were not normally distributed. Statistical significance was defined as a P value of <.05.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Ninety-six patients were evaluated. Seven patients were excluded because they were lost to follow-up, and 3 were excluded for ingesting multiple substances. Eighty-six patients met inclusion criteria, of which 45 (52%) were boys and 41 (48%) were girls. The mean age was 2.06 years ± 0.86 years, with a range of 9 months to 5 years. Eighty-three exposures (96%) occurred at the child's own residence. All of the ingestions were unintentional and acute in nature. There were 34 cases involving ingestion of 2 mg of Suboxone (40%), 32 with 8 mg of Suboxone (37%), 8 with 0.3 mg/mL of Buprenex (9%), 2 with 2 mg of Subutex (2%), 1 with 8 mg of Subutex (1%), and 10 with unspecified formulations of buprenorphine (12%).
Sixty-four patients (74%) were treated at a health care facility, whereas 22 (26%) were managed at home. Thirty-two patients (37%) remained asymptomatic, 48 patients (56%) had a minor effect, and 6 patients (7%) developed severe effects. There were no fatalities. Of the 22 children managed at home, 15 (68%) had no effect, and 7 (32%) developed a minor effect. Seventeen patients (27%) treated at a health care facility had no effect, 41 (64%) developed minor effects, and 6 (9%) developed severe effects.
The most common clinical effects were drowsiness or lethargy (55%), vomiting (21%), and miosis (21%). Severe toxicity including respiratory depression and coma occurred less frequently. Table 1 provides a complete list of reported clinical effects. The time to onset of clinical effects was reported in 25 children. The mean time to onset of effects was 64.2 minutes (± 39.4 minutes) with a median of 60 minutes and a range of 20 minutes to 3 hours. Time to onset of respiratory depression was reported in 2 of the 6 patients with a severe effect. Respiratory depression was noted 2 hours into the clinical course in a 4-year-old girl and at 3 hours postingestion in a 16-month-old boy. In children experiencing toxicity, the duration of clinical effects was <2 hours in 6 (11%), 2 to 8 hours in 32 (59%), 8 to 24 hours in 14 (26%), and >24 hours in 2 (4%) children.
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Doses were documented for 70 patients. The mean dose of buprenorphine was 3.02 ± 3.80 mg, with a median of 2 mg and a range of 0.03 to 24.00 mg. Children who ingested
2 mg of buprenorphine were more likely to experience clinical effects (2 = 4.667; P = .031). No child ingesting <4 mg experienced a severe effect. Similarly, all of the children who ingested >4 mg experienced some effect. Table 2 contains a more detailed description of the dose-effect relationship.
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The dose was known in 3 of the 6 patients who developed a severe effect. One half of an 8-mg tablet (4 mg, 0.215 mg/kg) caused respiratory depression and drowsiness or lethargy in a 20-month-old boy. A 2-year-old boy developed coma and respiratory depression after ingesting
24 mg (1.789 mg/kg). Finally, 12 mg (0.970 mg/kg) caused cyanosis, respiratory depression, and drowsiness or lethargy in a 20-month-old boy. The preceding case has been reported previously.8
The exact age was reported for 85 children. Children <2 years of age were more likely to experience clinical effects (2 = 4.811; P = .028). Five (83%) of the 6 patients who experienced severe effects were 2 years of age.
Decontamination modalities included dilution, food, or snack (20%); single-dose activated charcoal (16%); and ipecac or another emetic (3%). Intubation and mechanical ventilation were needed in 1 patient.
Naloxone was administered in 21 patients (24%). Nine patients (43%) had a complete response, 5 (24%) had a partial response, 2 (9%) had no response, and response was not documented in 5 children (24%). Doses of naloxone were not recorded in more than three fourths of these patients; however, of the 2 patients who had no response, 1 received 0.1 mg and the other was administered 5.0 mg. A third patient required 0.8 mg before responding, whereas a fourth patient did not respond to an initial 1 mg dose but responded to higher doses. Six patients required multiple doses of naloxone to elicit a response. Two patients required a continuous intravenous naloxone infusion in addition to boluses.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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To our knowledge this study represents the largest pediatric population with buprenorphine overdoses examined to date. Buprenorphine produces similar effects in children as other opioids, including CNS and respiratory depression, miosis, and vomiting. Previous reports have indicated a lack of significant toxicity in pediatric patients.12,13 An analysis of 33 buprenorphine ingestions in children and adults reported to poison centers nationally over a 1-year period found that 87.9% experienced clinical effects, but the majority did not experience serious toxicity.12 This study did not provide a breakdown of clinical effects for the 10 children
2 years of age. Gaulier et al13 reported on a 4-year-old girl who ingested 4 mg of buprenorphine and experienced only miosis. More recent reports have suggested that buprenorphine can have serious effects in this population.8,14 In a case series by Geib et al,8 5 children <2 years of age ingested buprenorphine doses estimated between 4 and 10 mg. All of them developed respiratory and CNS depression. Naloxone was administered in 4 patients, and the fifth patient required intubation with mechanical ventilation. In our study, the most common products ingested were the Suboxone (buprenorphine/naloxone) preparations. Interestingly, there were 8 exposures to the injectable form of buprenorphine. In each of the 8 patients, the reason that this formulation was available in the home was because a family pet was prescribed the drug for pain. None of the patients developed any adverse clinical effects from the exposure. One explanation for the lack of clinical effects is that the liquid was swallowed quickly so that it was not in the oral cavity long enough to be absorbed sublingually.
Eighty-nine percent of patients who experienced clinical effects had minor CNS depression, miosis, and/or vomiting. There were, however, 6 children who developed some degree of respiratory depression; 1 required intubation with mechanical ventilation and 2 required continuous naloxone infusions. Four mg (0.215 mg/kg) was the lowest dose associated with a severe effect. Geib et al8 speculated that toddlers may suck on or chew tablets, which can lead to buccal absorption of the drug. Although buprenorphine has poor oral bioavailability,2 chewing or sucking on the tablets by young children may result in increased bioavailability, comparable to bioavailability in adults after sublingual administration. Children who are naive to opioids may also have greater µ-receptor sensitivity than a dependent adult, which may account for the observed clinical effects.8 It is noteworthy that 7% of children who ingested buprenorphine developed a severe effect. It is also important to note that, with proper management, pediatric fatalities secondary to buprenorphine can be prevented.
Dose response data may have implications for triage and management. Children ingesting <4 mg of buprenorphine are not likely to have a severe effect. Therefore, a lick or taste of a tablet of either strength (2 or 8 mg), may be observed at home in a properly monitored environment. Likewise, confirmed ingestion of a full 2-mg tablet may also be considered for home monitoring with proper supervision by a reliable caregiver. The low oral bioavailability of buprenorphine may explain the lack of severe toxicity associated with an ingestion <4 mg. Sublingual bioavailability of buprenorphine has been measured from 13% to 51%.15–17 Oral bioavailability is thought to be much lower. Brewster et al15 showed intraduodenal bioavailability to be 9.7%. Area under the curve analysis of buprenorphine concentrations in blood showed that gut and liver extraction ratios are 0.5, which would reduce oral bioavailability to <10%.15 Children <2 years of age were more likely to experience a severe effect than older children. Consequently, any child ingesting >2 mg and children <2 years of age ingesting more than a lick or taste should be referred to the emergency department. Any child in whom the dose cannot be determined with certainty or who may have ingested multiple substances should also be referred to an emergency department.
Although the elimination half-life of oral buprenorphine is 37 hours,6 the duration of effect from a single acute ingestion may vary. More than half of the patients had clinical effects lasting between 2 and 8 hours, and about a quarter had effects from 8 to 24 hours. This is consistent with the pharmacology of the drug in that it has a high affinity for the µ-receptor and slow dissociation.18 Several reports have documented the potential for delayed onset of CNS and respiratory depression.8,14,19 We observed a mean onset of effects at 
1 hour postingestion, with respiratory depression developing 2 to 3 hours postingestion. Buprenorphine is metabolized almost exclusively by the cytochrome CYP 3A4 isozyme system, which is largely developed in children by 1 year of age and should not extend the duration of action.20 We recommend that children with a suspected buprenorphine exposure be observed for a minimum of 6 hours. Patients without any clinical effects at this point may be discharged from the hospital.
The unique pharmacodynamic profile of buprenorphine has led to the belief that higher doses of naloxone, a µ-receptor antagonist, may be required to reverse the respiratory depressant effects of buprenorphine.21 Naloxone successfully reversed, at least partially, the opioid effects in two thirds of the patients to whom it was administered. Although several of these patients required multiple doses to elicit an initial response, it is promising that naloxone is able to overcome the high binding affinity of buprenorphine. The reporting of naloxone doses was limited in our study, and, therefore, we are unable to speculate whether increased naloxone dosing is needed to reverse buprenorphine-related toxicity. Both patients whose clinical effects lasted >24 hours had received naloxone. In addition, 8 of the 14 patients who had effect lasting 8 to 24 hours received naloxone. The duration of action of buprenorphine is much longer than the 40-minute reversal effect of naloxone. Therefore, pediatric patients ingesting buprenorphine may require intermittent doses of naloxone or a continuous infusion. The antidote will not shorten the clinical course for the patient but can reverse respiratory depression and help avoid intubation.
Buprenorphine is becoming increasingly prescribed to manage opioid dependence. For the first time in 2006, Suboxone appeared in the top 200 drug list with $140 000 000 in US sales.22 Increased prescription sales translate into increased availability for children to unintentionally overdose. Patients who have, or are around, children should be properly counseled at the onset of therapy of the possibility of an accidental overdose in their child and the effects that children can experience if buprenorphine is ingested. Pediatricians also have an important role in teaching parents safe storage of medications. Finally, veterinarians should counsel pet owners about proper storage of injectable buprenorphine to avoid accidental ingestions.
Limitations of this retrospective study include the fact that poison centers serve as consultants and as a result do not have complete access to patient medical charts. Although RADARS data allowed access to the text fields of the poison center patient record, it is still limited compared with the hospital chart. Inherent in reviewing poison center data are that some data may be underdocumented (ie, dose of toxicant and dose and timing of treatment modalities, such as doses of naloxone, are poorly documented). Because measuring or observing for respiratory depression can be difficult, this effect may have been underreported. Although laboratory confirmation of exposure was not available in any of the cases, testing for buprenorphine is not commonly done in clinical practice. Finally, because reporting to poison centers is voluntary, there may be a reporting bias.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Unintentional buprenorphine ingestions are generally well tolerated in pediatric patients, with respiratory depression and significant CNS depression occurring in only 7% of patients. Any child ingesting >2 mg and children <2 years of age ingesting more than a lick or taste should be referred to the emergency department. Children in whom the dose cannot be determined with certainty should also be referred to an emergency department. Pediatric patients with a suspected buprenorphine exposure should be monitored in an emergency department setting for a minimum of 6 hours. Naloxone can be used to reverse respiratory depression.
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FOOTNOTES |
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Accepted Aug 31, 2007.
Address correspondence Bryan D. Hayes, PharmD, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch St, Office Level 1, Baltimore, MD 21201. E-mail: bryan_d_hayes{at}yahoo.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Two reports show a lack of significant toxicity from buprenorphine in pediatric patients. Two more recent reports have suggested that buprenorphine can have serious effects in this population. Overall, a paucity of literature exists on this subject.
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| What This Study Adds To our knowledge this study represents the largest pediatric population with buprenorphine overdoses examined to date. With increasing availability of buprenorphine, it is important for clinicians to understand clinical effects and treatment should a child accidentally ingest it.
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REFERENCES |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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- Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70 (2 suppl):S13 –S27[Web of Science][Medline]
- Mendelson J, Fernandez E, Welm S, et al. Bioavailability of oral and sublingual buprenorphine and naloxone tablets (abstract PI-113). Clin Pharmacol Ther. 2001;69 (2):29
- Suboxone. About suboxone. Available at: www.suboxone.com/hcp/suboxone. Accessed June 5, 2007
- Yassen A, Olofsen E, Romberg R, et al. A mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007;81 (1):50 –58[CrossRef][Web of Science][Medline]
- Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia.
Br J Anaesth. 2006;96
(5):627
–632
[Abstract/Free Full Text] - Food and Drug Administration. Suboxone and subutex official labeling. Available at: www.fda.gov/cder/foi/label/2002/20732,20733lbl.pdf. Accessed May 15, 2007
- Yassen A, Olofsen E, Romberg R, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers. Anesthesiology. 2006;104 (6):1232 –1242[CrossRef][Web of Science][Medline]
- Geib AJ, Babu K, Ewald MB, Boyer EW. Adverse effects in children after unintentional buprenorphine exposure.
Pediatrics. 2006;118
(4):1746
–1751
[Abstract/Free Full Text] - Researched Abuse, Diversion, and Addiction-Related Surveillance System. Available at: www.radars.org. Accessed May 15, 2007
- Cicero TJ, Dart RC, Inciardi JA, Woody GE, Schnoll S, Munoz A. The development of a comprehensive risk-management program for prescription opioid analgesics: researched abuse, diversion and addiction-related surveillance (RADARS). Pain Med. 2007;8 (2):157 –170[CrossRef][Web of Science][Medline]
- Benson BE, Spyker DA, Troutman WG, Watson WA. TESS-based dose-response using pediatric clonidine exposures. Toxicol Appl Pharmacol. 2006;213 (2):145 –151[CrossRef][Web of Science][Medline]
- Doyon S, Klein-Schwartz W, Welsh C. Toxicity following buprenorphine ingestions. Clin Toxicol. 2005;43 (6):640
- 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 (7):993 –995[Web of Science][Medline]
- Spadari M, Arditti J, Affaton MF, David JM, Valli M. Accidental narcotic and buprenorphine poisoning in children notified at the Marseille Poison Center between 1993 and 1999 [in French] [published correction appears in Therapie. 2001;56(1):73]. Therapie. 2000;55 (6):705 –708[Web of Science][Medline]
- Brewster D, Humphrey MJ, Mcleavy MA. The systemic bioavailability of buprenorphine by various routes of administration. J Pharm Pharmacol. 1981;33 (8):500 –506[Web of Science][Medline]
- Mendelson J, Upton RA, Everhart ET, Jacob P 3rd, Jones RT. Bioavailability of sublingual buprenorphine.
J Clin Pharmacol. 1997;37
(1):31
–37
[Free Full Text] - Kuhlman JJ, Lalani S, Magluilo J, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20 (6):369 –378[Web of Science][Medline]
- Huang P, Kehner GB, Cowan A, et al. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist.
J Pharmacol Exp Ther. 2001;297
(2):688
–695
[Abstract/Free Full Text] - McQuay HJ, Bullingham RE, Bennett MR, Moore RA. Delayed respiratory depression: a case report and a new hypothesis. Acta Anaesthesiol Belg. 1979;30 (suppl):245S –247S
- de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37 (6):485 –505[CrossRef][Web of Science][Medline]
- van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006;105 (1):51 –57[CrossRef][Web of Science][Medline]
- Drugs.com. Top 200 drugs for 2006 by sales. Available at: www.drugs.com/top200.html. Accessed August 10, 2007
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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