Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism

Gasche, Yvan; Daali, Youssef; Fathi, Marc; Chiappe, Alberto; Cottini, Silvia R; Dayer, P.; Desmeules, Jules Alexandre

doi:10.1056/nejmoa041888

Cited by 607 publications

(380 citation statements)

References 14 publications

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“…It is well established that variability in CYP2D6 enzyme activity can affect the efficacy and toxicity of codeine in patients. [15][16][17][18][19][20] Notably, CYP2D6 ultra-rapid metabolizers are at risk for toxic systemic concentrations of morphine with label-recommended dosages of codeine, and CYP2D6 poor metabolizers are unable to achieve adequate systemic concentrations of morphine to experience a therapeutic benefit from codeine. CYP2D6 genotyping options are available from several clinical laboratories.…”

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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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confidence: 99%

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

et al. 2016

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“…Because of codeine's genetic variability in its rate of metabolism, its use should be individualized. 51 Tramadol is a synthetic analog of codeine that has shown efcacy in neuropathic pain, 52 but has no anti-infammatory activity. It can increase the risk of seizures and serotonin syndrome because it is also a monoamine reuptake inhibitor.…”

Section: Reviewmentioning

confidence: 99%

Cancer-related pain management in clinical oncology

Cipta¹,

Pietras²,

Weiss³

et al. 2015

J Community Support Oncol

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Uncontrolled pain is one of the most feared and debilitating symptoms among cancer patients, and many suffer unnecessarily from suboptimal pain control. Cancer-related pain is often multidimensional and can affect all aspects of a patient's life. Hence, achieving adequate pain relief among cancer patients involves a proper assessment of psychosocial, spiritual, and physical pain issues, matched with an individualized treatment plan involving pharmacologic, nonpharmacologic, and procedural therapies when appropriate. Providing effective pain relief can help ease the overall burden of disease among oncology patients while helping them tolerate cancer-directed therapies and achieve the most optimal quality of life throughout all phases of the disease continuum. In this review, the authors will discuss the syndromes, assessment of, and treatment for cancer-related pain in the outpatient setting.

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“…hPpM traits are primarily determined by a single gene with redundancy within the biologic output leading to preservation of the phenotype when a deficiency of one enzyme occurs. Clinical examples of this phenomenon are toxicity associated with HLA polymorphisms in patients given carbamazepine [35,36], CYP2D6 deficiency leading to ineffective analgesia with codeine [37,38], or increased CYP2D6 activity leading to opioid toxicity [39][40][41]. In these cases, genotypic characterization allowed for prediction of drug efficacy or toxicity at the extremes of the phenotypic distribution.…”

Section: Monogenetic Versus Polygenetic Diseasesmentioning

confidence: 99%

Prediction of Drug Response and Safety in Clinical Practice

2011

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Many clinicians hoped that the completion of the Human Genome Project would result in "individualized drug therapy," i.e., determining the right medication at the right dose 100% of the time based upon the individual's genetics. The pharmacogenomic prediction of drug efficacy and safety has not become a reality due to continuing realization of the complexity dictating the human-drug interaction. New methods of metabolomics, proteomics, and transcriptomics that account for this complexity hold promise for translational researchers hoping to increase drug efficacy and decrease drug toxicity.

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Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism

Cited by 607 publications

References 14 publications

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

Cancer-related pain management in clinical oncology

Prediction of Drug Response and Safety in Clinical Practice

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