More Codeine Fatalities After Tonsillectomy in North American Children

Kelly, Lauren; Rieder, Michael J.; Anker, John van den; Malkin, Becky; Ross, Colin J.D.; Neely, Michael; Carleton, Bruce; Hayden, Michael R.; Madadi, Parvaz; Koren, Gideon

doi:10.1542/peds.2011-2538

Cited by 348 publications

(257 citation statements)

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“…1 Many of the deaths have been in children who possess forms of the liver microenzyme CYP2D6 that make them extensive or ultrarapid metabolizers of codeine. 2 The current concerns regarding rapid metabolism of codeine products in children following tonsillectomy 3 have led to widespread reconsideration of posttonsillectomy pain management regimens for the pediatric population. Nonsteroidal anti-inflammatory drugs (NSAID), specifically ibuprofen, have gained favor as an alternative to narcotics for postoperative pain control.…”

Section: Introductionmentioning

confidence: 99%

Postoperative nonsteroidal anti-inflammatory drugs and risk of bleeding in pediatric intracapsular tonsillectomy

D'Souza¹,

Schmidt²,

Xie³

et al. 2015

International Journal of Pediatric Otorhinolaryngology

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Section: Introductionmentioning

confidence: 99%

Postoperative nonsteroidal anti-inflammatory drugs and risk of bleeding in pediatric intracapsular tonsillectomy

D'Souza¹,

Schmidt²,

Xie³

et al. 2015

International Journal of Pediatric Otorhinolaryngology

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“…21 In environments without the routine use of CYP2D6 genotyping, several cases of fatal and severe, nonfatal respiratory depression were reported in children receiving seemingly appropriate weight-based dosing of codeine for postoperative pain management after elective adenotonsillectomies. 22,23 The common thread that emerged from these reports was clear; children with functional CYP2D6 gene duplications are at high risk for codeine toxicity because of its excessive conversion to morphine. Given these reports, the FDA issued a Drug Safety Communication in 2012 that warned clinicians to exercise caution when prescribing codeine to children after tonsillectomy and/ or adenoidectomy and alerting parents/caregivers to the signs of morphine toxicity.…”

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confidence: 99%

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

et al. 2016

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After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. abstractDepartments of a Pharmaceutical Sciences, b Hematology, and c Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee; and d Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin Dr Gammal collected data, carried out the initial analyses, and drafted the initial manuscript; Drs Crews, Haidar, and Hoffman are coinvestigators on the PG4KDS study; they supervised the collection and analysis of data and critically reviewed and revised the manuscript; Dr Baker created the clinical decision support alerts, collected data, and critically reviewed the manuscript; Drs Barker, Estepp, Wang, and Weiss critically reviewed and revised the manuscript; Ms Pei designed and conducted the statistical analysis; Dr Broeckel supervises all PG4KDS-related genotyping; Dr Relling conceptualized and designed the PG4KDS study, supervised the collection and analysis of data, and critically reviewed and revised the manuscript; Dr Hankins conceptualized and designed the study and critically reviewed and revised the manuscript; and all authors approved the fi nal manuscript as submitted. The use of codeine in pediatric medicine has been questioned following reports of postoperative deaths in children who were prescribed codeine and the subsequent US Food and Drug Admin...

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“…1 In April 2012, a case series was published reporting two deaths and one case of respiratory depression in children 3 to 5 years of age who had received typical doses of codeine after tonsillectomy, adenoidectomy, or both performed because of obstructive sleep apnea. 2 The two deaths occurred in children who had evidence of being ultrarapid metabolizers, and the postmortem morphine levels in these children were substantially high- er than the therapeutic range. The third child was an extensive metabolizer.…”

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confidence: 97%