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Guideline Summary
Guideline Title
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype.
Bibliographic Source(s)
Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC, Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012 Feb;91(2):321-6. [40 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Pain

Guideline Category
Prevention
Risk Assessment
Treatment
Clinical Specialty
Medical Genetics
Pharmacology
Preventive Medicine
Intended Users
Advanced Practice Nurses
Pharmacists
Physician Assistants
Physicians
Guideline Objective(s)

To provide information relating to the interpretation of cytochrome P450 2D6 (CYP2D6) genotype test results to guide the dosing of codeine

Target Population

Patients with pain requiring analgesics

Interventions and Practices Considered

Codeine therapy and codeine dosing adjustments based on cytochrome P450 2D6 (CYP2D6) genotype

Major Outcomes Considered
  • Level of codeine analgesia
  • Rate of morphine formation
  • Risk of toxicity

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

The guideline authors searched the PubMed® database (1966 to February 2011) and Ovid MEDLINE (1950 to February 2011) for keywords (cytochrome P450 2D6) OR (CYP2D6) AND (codeine OR morphine) for the association between CYP2D6 genotype and codeine metabolism or codeine-related adverse drug event (ADE) or outcome. For additional reviews, see references 1 and 2 in the online supplemental material (see the "Availability of Companion Documents" field).

To construct a CYP2D6 minor allele frequency table based on ethnicity, the PubMed® database (1966 to February 2011) and Ovid MEDLINE (1950 to February 2011) were searched using the following criteria: ((CYP2D6 or 2D6) AND (genotype OR allele OR frequency OR minor allele OR variant OR ethnic OR race OR racial OR ethnicity)). Studies were considered for inclusion if: (1) the ethnicity of the population was clearly indicated, (2) either allele frequencies or minor allele percentages for CYP2D6 genotypes were reported, (3) the method by which CYP2D6 was genotyped was reliable and proven (no proof-of-principle experiments), (4) the sample population consisted of at least 50 patients, and (5) the study represented an original publication (no reviews or meta-analyses).

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Levels of Evidence

High: Evidence includes consistent results from well-designed, well-conducted studies.

Moderate: Evidence is sufficient to determine effects, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence.

Weak: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information.

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

The Clinical Pharmacogenetics Implementation Consortium's therapeutic recommendations are based on weighting the evidence from a combination of preclinical functional and clinical data. Some of the factors that are taken into account in evaluating the evidence supporting therapeutic recommendations include: in vivo pharmacokinetic and pharmacodynamic data for codeine, in vitro enzyme activity of tissues expressing wild-type or variant-containing cytochrome P450 2D6 (CYP2D6), in vitro CYP2D6 enzyme activity from tissues isolated from individuals of known CYP2D6 genotypes, and in vivo pre-clinical and clinical pharmacokinetic and pharmacodynamic studies.

Evidence was summarized into tables (see the "Availability of Companion Documents" field) and graded (see the "Rating Scheme for the Strength of the Evidence" field).

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Multiple rating schemes for strength of recommendations in a number of clinical guidelines were evaluated. Ultimately, the guideline authors chose to use a slight modification of a transparent and simple system for just three categories for recommendations: strong, moderate, and optional (see the "Rating Scheme for the Strength of the Recommendations" field).

Overall, the dosing recommendations are simplified to allow rapid interpretation by clinicians. They have been adopted from the Department of Health and Human Services rating scale for evidence-based therapeutic recommendations on the use of retroviral agents. (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf External Web Site Policy)

Rating Scheme for the Strength of the Recommendations

Strength of Therapeutic Recommendations

Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

Not stated

Recommendations

Major Recommendations

The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the "Major Recommendations" field.

Interpretation of Genetic Test Results

The combination of alleles is used to determine a patient's diplotype. Cytochrome P450 2D6 (CYP2D6) alleles are characterized as wild-type (normal function), reduced-function, or nonfunctional based on the expected activity level of the enzyme for which they encode. Each functional group is assigned an activity value ranging from 0 to 1.0 (e.g., 0 for nonfunctional, 0.5 for reduced function, and 1.0 for fully functional). Supplementary Table S4 (see the "Availability of Companion Documents" field) describes the activity score values assigned to selected alleles. If multiple copies of the CYP2D6 gene are detected, the activity score is multiplied by the number of copies of each allele present. The total CYP2D6 activity score is the sum of the values assigned to each allele, which typically ranges from 0 to 3.0 but may exceed 3.0 in rare cases.

The CYP2D6 activity score relates to the phenotype classification system (see Table 1 below).

Table 1. Assignment of Likely Codeine Metabolism Phenotypes Based on CYP2D6 Diplotypes

Likely Phenotypea Activity Score Genotypes Examples of Diplotypes
Ultrarapid metabolizer (~1–2% of patients) >2.0 An individual carrying more than two copies of functional alleles *1/*1xN, *1/*2xN
Extensive metabolizer (~77–92% of patients) 1.0–2.0b An individual carrying two alleles encoding full or reduced function or one full function allele together with either one nonfunctional or one reduced-function allele *1/*1, *1/*2, *2/*2, *1/*41,*1/*4,*2/*5, *10/*10
Intermediate metabolizer (~2–11% of patients) 0.5b An individual carrying one reduced and one nonfunctional allele *4/*10, *5/*41
Poor metabolizer (~5–10% of patients) 0 An individual carrying no functional alleles *4/*4, *4/*5, *5/*5, *4/*6

a The frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See Supplementary Data in the "Availability of Companion Documents" field for estimates of phenotype frequencies among different ethnic/geographic groups.

b Note that some investigators define patients with an activity score of 0.5 and 1.0 as intermediate metabolizers and define patients with an activity score of 1.5 and 2.0 as extensive metabolizers. Classifying patients with an activity score of 1.0 as extensive metabolizers in this guideline is based on data specific for formation of morphine from codeine in these patients.

Linking Genetic Variability To Variability in Drug-Related Phenotypes

There is substantial evidence linking CYP2D6 genotype to variability in codeine efficacy and toxicity (see Supplementary Table S6 online in the "Availability of Companion Documents" field). Decreased codeine analgesia has been observed in poor metabolizers, whereas severe or life-threatening toxicity after normal doses of codeine has been documented in ultrarapid metabolizers. This body of evidence, rather than randomized clinical trials involving pharmacogenetic testing, provides the basis of the therapeutic recommendations in Table 2 below.

Table 2. Codeine Therapy Recommendations Based on CYP2D6 Phenotype

Phenotype Implications for Codeine Metabolism Recommendations for Codeine Therapy Classification of Recommendation for Codeine Therapy
Ultrarapid metabolizer Increased formation of morphine following codeine administration, leading to higher risk of toxicity Avoid codeine use due to potential for toxicity. Consider alternative analgesics such as morphine or a nonopioid. Consider avoiding tramadol.a Strong
Extensive metabolizer Normal morphine formation 15–60 mg every 4 h as needed for pain (label recommendation)b Strong
Intermediate metabolizer Reduced morphine formation Begin with 15–60 mg every 4 h as needed for pain.b If no response, consider alternative analgesics such as morphine or a nonopioid. Monitor tramadol use for response. Moderate
Poor metabolizer Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief Avoid codeine use due to lack of efficacy. Consider alternative analgesics such as morphine or a nonopioid. Consider avoiding tramadol.a Strong

CYP2D6, cytochrome P450 2D6

aAlthough detailed recommendations for using CYP2D6 phenotype in tramadol therapy are beyond the scope of this guideline, there is strong evidence for decreased efficacy of tramadol in poor metabolizers and a single case report of toxicity in an ultrarapid metabolizer with renal impairment following tramadol postsurgery. Use of other analgesics in CYP2D6 poor metabolizers and ultrarapid metabolizers may therefore be preferable.

bFor pediatric patients who are extensive or intermediate metabolizers, use label recommended age- or weight-specific dosing.

CYP2D6 Genetic Test Interpretation and Suggested Clinical Action

Table 2 summarizes the therapeutic recommendations for codeine based on CYP2D6 phenotype. A standard starting dose of codeine, as recommended in the product label, is warranted in patients with an extensive metabolizer phenotype (i.e., a CYP2D6 activity score of 1.0 to 2.0). Likewise, a standard starting dose of codeine is warranted in patients with an intermediate metabolizer phenotype (i.e., a CYP2D6 activity score of 0.5); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if required. If the CYP2D6 substrate tramadol is selected as alternative therapy in intermediate metabolizers, close monitoring should be carried out because of the possibility of low response.

If clinical genotyping identifies a patient as a CYP2D6 poor metabolizer (i.e., a CYP2D6 activity score of 0), current evidence suggests that the use of codeine be avoided because of the possibility of lack of effect, and that an alternative analgesic should be used. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in poor metabolizers. There is insufficient evidence in the literature to recommend a higher dose of codeine in poor metabolizers, especially given that adverse effects do not differ between poor metabolizers and extensive metabolizers.

In a patient identified as a CYP2D6 ultrarapid metabolizer (i.e., a CYP2D6 activity score of >2.0), the choice of an alternative analgesic should be made to avoid the risk of severe toxicity associated with a "normal" dose of codeine. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in ultrarapid metabolizers.

Definitions:

Strength of Therapeutic Recommendations

Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Clinical Algorithm(s)

A codeine and morphine pathway is available from the Pharmacogenomics Knowledgebase Web site External Web Site Policy.

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The evidence summarized in Supplemental Table S6 (see the "Availability of Companion Documents" field) is graded using a scale based on previously published criteria and applied to other Clinical Pharmacogenetics Implementation Consortium guidelines (see the "Rating Scheme for the Strength of the Evidence" field). Every effort was made to present evidence from high-quality studies, which provided the framework for the strength of therapeutic recommendations.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

The potential benefit of cytochrome P450 2D6 (CYP2D6) genotype testing is that patients with genotypes that are associated with a higher risk of ineffective analgesia or of an adverse event may be identified, and alternative analgesics may be administered to these patients.

Potential Harms
  • Cytochrome P450 2D6 (CYP2D6) genotyping is reliable when performed in qualified laboratories. However, as with any laboratory test, a possible area of risk is an error in genotyping, which could have long-term adverse health implications for the patient.
  • Codeine and its metabolites, including morphine, are secreted in human breast milk, but the amount is typically low and dose dependent. However, breastfeeding women with an ultrarapid metabolizer phenotype may achieve high serum levels of morphine on standard codeine therapy. This may lead to high concentrations of morphine in breast milk and dangerously high serum morphine levels in their breastfed infants. Notably, there was a reported case of fatal opioid poisoning in a breastfed neonate as a result of the codeine treatment taken by the mother, an ultrarapid metabolizer. Case reports such as this prompted the US Food and Drug Administration to change the codeine product label to include information on the increased risk of morphine overdose in breastfed infants whose mothers are taking codeine and are ultrarapid metabolizers. Additional information about codeine use in breastfeeding mothers can be found elsewhere. Codeine is not recommended in children less than 2 years of age and presumably would carry similar dangers in other neonates and young children who are themselves ultrarapid metabolizers.
  • The most common adverse reactions to codeine include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. Serious adverse reactions include respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Pharmacokinetic studies show increased conversion of codeine to morphine in ultrarapid metabolizers as compared with extensive metabolizers. Case reports detail the occurrence of severe or life-threatening side effects following standard doses of codeine in ultrarapid metabolizers.

Qualifying Statements

Qualifying Statements

Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests

One of the challenges with using clinical pharmacogenetic testing for codeine dosing is the need for results at the time an analgesic regimen is chosen. The ideal situation is to preemptively genotype patients who may need pain control in the future. For instance, preemptive cytochrome P450 2D6 (CYP2D6) genotyping has been implemented in patients treated for acute lymphoblastic leukemia, who often require pain control medication during their therapy. Like all diagnostic tests, the CYP2D6 genotype test is one of multiple pieces of information that clinicians should consider in guiding their therapeutic choice for each patient.

Disclaimer

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making and to identify questions for further research. New evidence may have emerged since the time a guideline was submitted for publication. 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. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. CPIC assumes no responsibility for any injury to persons or damage to persons or property arising out of or related to any use of CPIC's guidelines, or for any errors or omissions.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Clinical Algorithm
Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
Staying Healthy
IOM Domain
Effectiveness
Safety

Identifying Information and Availability

Bibliographic Source(s)
Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC, Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012 Feb;91(2):321-6. [40 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2012 Feb
Guideline Developer(s)
Clinical Pharmacogenetics Implementation Consortium - Independent Expert Panel
Source(s) of Funding

This work was supported by NIH U01 GM061373, R01 GM088076, K24DA00417, PharmGKB (R24-GM61374), ALSAC, and the Agency for Healthcare Research and Quality R01 HS19818-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.

Guideline Committee

Not stated

Composition of Group That Authored the Guideline

Authors: KR Crews, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA; A Gaedigk, Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospital & Clinics, Kansas City, Missouri, USA; HM Dunnenberger, University of Tennessee College of Pharmacy, Memphis, Tennessee, USA; TE Klein, Department of Genetics, Stanford University, Stanford, California, USA; DD Shen, Department of Pharmaceutics and Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, USA; JT Callaghan, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Department of Veterans Affairs, RLR VA Medical Center, Indianapolis, Indiana, USA; ED Kharasch, Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA; TC Skaar, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

Financial Disclosures/Conflicts of Interest

The authors declared no conflict of interest.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the Pharmacogenomics Knowledge Base Web site External Web Site Policy.

Availability of Companion Documents

The following are available:

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on May 15, 2013. The information was verified by the guideline developer on June 25, 2013.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Disclaimer

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The National Guideline Clearinghouseâ„¢ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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