last updated 01/24/2014

CPIC Dosing Guideline for codeine and CYP2D6

Summary

Alternate analgesics are recommended for CYP2D6 ultrarapid and poor metabolizers. A label recommended age- or weight-specific codeine dose is warranted for CYP2D6 extensive and intermediate metabolizers.

Annotation

Please see below for full details of these guidelines, with supporting evidence and disclaimers.

Guidelines regarding the use of pharmacogenomic tests in dosing for codeine have been published in 2012 in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and have been updated in 2014.

Download updated guideline: article (update) and supplement (update)
Download original guideline: article and supplement

Excerpt from the codeine dosing guidelines:

The table below 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 alternative analgesics that are not affected by this CYP2D6 phenotype, including morphine and non-opioid analgesics, 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 alternative analgesics that are not affected by this CYP2D6 phenotype, including morphine and non-opioid analgesics, in ultrarapid metabolizers.

Recommended dosing of codeine by CYP2D6 Phenotype

CYP2D6 genotype is expected to be equally reliable for inferring phenotype status from genotype in children as in adults. Codeine is not recommended in children less than 2 years of age, but presumably would carry additional dangers in neonates and young children who are ultrarapid metabolizers. The codeine drug label includes a black box warning against codeine use to manage post-operative pain in children following tonsillectomy with or without adenoidectomy.

Please see below for full details of these guidelines, with supporting evidence and disclaimers.

Likely phenotype* Activity score Genotypes Examples of diplotypes Implications for codeine metabolism Recommendations for codeine therapy Classification of recommendation for codeine therapy Considerations for alternative opioids
Ultrarapid metabolizer (~1-2% of patients) >2.0 An individual carrying more than two copies of functional alleles *1/*1xN, *1/*2xN Increased formation of morphine following codeine administration, leading to higher risk of toxicity Avoid codeine use due to potential for toxicity. Strong Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics. Tramadol, and to a lesser extent hydrocodone and oxycodone, are not good alternatives because their metabolism is affected by CYP2D6 activity.1,2
Extensive metabolizer (~77-92% of patients) 1.0-2.0** 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 Normal morphine formation Use label recommended age- or weight-specific dosing. Strong
Intermediate metabolizer (~2-11% of patients) 0.5** An individual carrying one reduced and one nonfunctional allele *4/*10, *5/*41 Reduced morphine formation Use label recommended age- or weight-specific dosing. If no response, consider alternative analgesics such as morphine or a non-opioid. Moderate Monitor tramadol use for response.
Poor metabolizer (~5-10% of patients) 0 An individual carrying no functional alleles *4/*4, *4/*5, *5/*5, *4/*6 Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief Avoid codeine use due to lack of efficacy. Strong Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics. Tramadol, and to a lesser extent hydrocodone and oxycodone, are not good alternatives because their metabolism is affected by CYP2D6 activity; these agents should be avoided.1,2

*Frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See Supplementary Data for estimates of phenotype frequencies among different ethnic/geographic groups.

**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.

1 There is substantial 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 post-surgery. Use of other analgesics in CYP2D6 poor and ultrarapid metabolizers may therefore be preferable (see updated guideline).
2 Some other opioid analgesics are metabolized by CYP2D6, such as hydrocodone and oxycodone. To avoid treatment complications, opioids that are not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone and hydromorphone, along with non-opioid analgesics, may be considered as alternatives for use in CYP2D6 poor and ultrarapid metabolizers.

Publications

Total publications: 2

Reference
1. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for cytochrome P450 2D6 (CYP2D6) genotype and codeine therapy: 2014 Update. Clinical pharmacology and therapeutics. 2014. Crews Kristine R, Gaedigk Andrea, Dunnenberger Henry M, Leeder J Steve, Klein Teri E, Caudle Kelly E, Haidar Cyrine E, Shen Danny D, Callaghan John T, Sadhasivam Senthilkumar, Prows Cynthia A, Kharasch Evan D, Skaar Todd C. PubMed
2. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype. Clinical pharmacology and therapeutics. 2011. Crews K R, Gaedigk A, Dunnenberger H M, Klein T E, Shen D D, Callaghan J T, Kharasch E D, Skaar T C. PubMed

Guideline History