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Considerations for the utility of the CPIC guideline for CYP2D6 genotype and codeine therapy.

To the Editor:

We appreciate the recent Perspective from Nicholson and Formea (1) because it allows us to clarify the role of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for clinicians. CPIC publishes genotype-based drug therapy guidelines to help clinicians understand how genetic test results could be used to optimize drug therapy. The underlying assumption for CPIC guidelines is that clinical high-throughput and preemptive genotyping will become common practice and clinicians will increasingly have patients' genotypes, such as a cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) genotype test result, available before a prescription is written (2,3). Therefore, CPIC guidelines provide guidance on how to interpret available genetic test results to improve drug therapy. For example, patients carrying 2 nonfunctional alleles that give rise to CYP2D6 poor metabolizer status derive little or no pain relief from codeine and tramadol. Thus the CPIC guideline recommends avoiding their use in these patients due to lack of efficacy and to use alternative pain medications. The guideline discusses that although alternatives might include hydrocodone or oxycodone, both have limitations. The guideline states that "there is insufficient evidence to conclude whether poor metabolizers can be expected to have decreased analgesia or whether ultrarapid metabolizers have an increased risk of toxicity with normal doses of hydrocodone," and that "it is difficult to conclude whether CYP2D6 metabolizer phenotype affects oxycodone analgesia or risk of toxicity" (4). However, we acknowledge that a quick read of Table 2 of the guidelines, rather than the text, might be taken as strong advice against the use of hydrocodone and oxycodone in patients with high-risk CYP2D6 genotypes. Nonetheless, for the reasons stated in the text, and with the evidence provided in the supplement, we think it wise to alert prescribers to possible problems with hydrocodone and oxycodone in poor and ultrarapid metabolizers of CYP2D6.

Nicholson and Formea comment that "many healthcare providers follow a WHO ladder 'type' approach for the treatment of pain." They express valid concern that the entire second step includes opioids "commonly used for moderate pain (e.g., tramadol, codeine, hydrocodone, and possibly oxycodone)" that overlap with medicines that the CPIC guideline recommends avoiding (codeine and tramadol) or for which concerns are noted (oxycodone and hydrocodone). We agree with Nicholson and Formea that this creates a problem for prescribers, in that the third step includes opioids "usually reserved for severe pain presentation (e.g., morphine, oxymorphone, fentanyl, methadone, and hydromorphone)" and may be less familiar to practitioners.

However, the fact that these step 3 agents may be more difficult to use and prescribe does not negate the fact that they are alternatives to codeine and tramadol, and are not subject to concerns about CYP2D6 genotype. Although we agree with Nicholson and Formea that for "moderate pain where an opioid might be required (e.g., musculoskeletal pain, toothache), it is unlikely that the provided alternatives would be an appropriate opioid choice for routine use," the CPIC guideline is recommending these alternatives for the minority of the population with a pharmacogenetic profile that poses them at risk of therapeutic failure or adverse effects. It is exactly these patients who may require step 3 analgesics. The fact that prescribing these agents is more difficult should not deter physicians from choosing more appropriate treatment to achieve pain relief in patients with at-risk CYP2D6 genotypes.

Finally, Nicholson and Formea suggest that CPIC guideline recommendations for analgesic alternatives may be readily accepted without consideration of the complex interplay between clinical care and the proper application of pharmacogenomics. The guideline includes the caveat that "like all diagnostic tests, that for CYP2D6 genotype is one of multiple pieces of information that clinicians should consider in guiding their therapeutic choice for each patient" (4). The CYP2D6 and codeine guideline, like all published CPIC guidelines, includes the statement that "Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for all individual variations among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient" (4).

We thank Nicholson and Formea for their valuable feedback about the applicability of the CPIC guideline for CYP2D6 and codeine. When choosing analgesic therapy, healthcare providers must keep the whole patient in mind. We conclude that the goal of this CPIC guideline is to allow pharmacogenetic test results to serve as a tool to individualize analgesic prescribing for acute or chronic pain and thereby enable the clinician to make more rational treatment decisions.

Author Contributions: Allauthors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared. Consultant orAdvisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared.

Research Funding: K.E. Caudle, NIH U01 GM92666 (CPIC), U01 HL0105918 (CPIC), and R24 GM61374 (PharmGKB); T.C. Skaar, R01 GM088076.

Expert Testimony: K.R. Crews received compensation for services as an expert witness on a legal case involving codeine.

Patents: None declared.

Acknowledgments: We acknowledge the critical input of members of the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network, specifically Andrea Gaedigk, J. Steve Leeder, Teri E. Klein, Cyrine E. Haidar, Danny D. Shen, John T. Callaghan, Cynthia A. Prows, Evan D. Kharasch, and Mary V. Relling.


(1.) Nicholson WT, Formea CM. Clinical Perspective onthe Clinical Pharmacogenetics Implementation Consortium Updated 2014 Guidelines for CYP2D6 and Codeine. Clin Chem 2015;61:319-21.

(2.) Crews KR, Cross SJ, McCormick JN, Baker DK, Molinelli AR, MuMullins R, et al. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm 2011;68:143-50.

(3.) Schildcrout JS, DennyJC, Bowton E, Gregg W, Pulley JM, Basford MA, et al. Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping. Clin Pharmacol Ther 2012;92:235-42.

(4.) Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 2014;95:376-82.

Kristine R. Crews [1] * Kelly E. Caudle [1] Henry M. Dunnenberger [2] Senthilkumar Sadhasivam [3,4] Todd C. Skaar [5]

[1] Department of Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis, TN

[2] Center for Molecular Medicine North Shore University Health System Evanston, IL

[3] Department of Pediatrics and

[4] Department of Anesthesia Cincinnati Children's Hospital Medical Center Cincinnati, OH

[5] Division of Clinical Pharmacology Department of Medicine Indiana University School of Medicine Indianapolis, IN

* Address correspondence to this author at:

Pharmaceutical Sciences Department St. Jude Children's Research Hospital Mail Stop 313, 262 Danny Thomas Place

Memphis, TN 38105-3678

Fax 901-595-8869


Previously published online at DOI: 10.1373/clinchem.2014.237412
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Title Annotation:Letters to the Editor
Author:Crews, Kristine R.; Caudle, Kelly E.; Dunnenberger, Henry M.; Sadhasivam, Senthilkumar; Skaar, Todd
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:May 1, 2015
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