Annotation of Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information
for codeine and CYP2D6

last updated 05/02/2017


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.


Note that the FDA released a safety announcement on 4/20/2017 stating that codeine and tramadol should not be used in children under 12 years.

This annotation is based on the CPIC® guideline for codeine and CYP2D6.

August 2015 Update on PharmGKB

  • Supplemental table S3 (Association between allelic variants and CYP2D6 enzyme activity) was updated with Supplemental table S2 from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors (2015 Supplement) PMID: 25974703. The table is an updated version including additions to functional status and additional alleles.

April 2014 Update

Advance online publication January 2014.

  • The 2014 update of CPIC guidelines regarding CYP2D6 and codeine have been published in Clinical Pharmacology and Therapeutics. Literature up to August 2013 was reviewed. The update addresses the FDA warning regarding codeine use in children following tonsillectomy with or without adenoidectomy, pediatric considerations, and additional considerations for use of alternative opioids metabolized by CYP2D6. In addition, supplemental information was updated.
  • Excerpts from the 2014 guideline update:
    • "CYP2D6 genotype is expected to be equally reliable for inferring phenotype 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."
    • "Caution should be used when prescribing codeine to a breastfeeding woman with an ultrarapid metabolizer status."
    • "In February 2013, the FDA announced its strongest and new black box warning against codeine use to manage postoperative pain in children following tonsillectomy with or without adenoidectomy. This warning was in response to further FDA review of the codeine-related deaths and serious adverse drug reactions. The FDA warning is applicable to all children undergoing tonsillectomy with or without adenoidectomy irrespective of their obstructive sleep apnea status or CYP2D6 genotype/phenotype."
  • These guidelines are applicable to:
    • pediatric patients
    • adult patients
  • Download and read:

Adapted from Tables 1 and 2 of the 2014 guideline update manuscript.

Likely phenotype.aActivity scoreGenotypesExamples of diplotypesImplications for codeine metabolismRecommendations for codeine therapy.bClassification of recommendation for codeine therapyConsiderations for alternative opioids
Ultrarapid metabolizer (~1-2% of patients)>2.0An individual carrying more than two copies of functional alleles*1/*1xN, *1/*2xNIncreased formation of morphine following codeine administration, leading to higher risk of toxicityAvoid codeine use due to potential for toxicity.StrongAlternatives 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.d,e
Extensive metabolizer (~77-92% of patients)1.0-2.0.cAn 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/*10Normal morphine formationUse label recommended age- or weight-specific dosing.Strong
Intermediate metabolizer (~2-11% of patients)0.5.cAn individual carrying one reduced and one nonfunctional allele*4/*10, *5/*41Reduced morphine formationUse label recommended age- or weight-specific dosing. If no response, consider alternative analgesics such as morphine or a non-opioid.ModerateMonitor tramadol use for response.
Poor metabolizer (~5-10% of patients)0An individual carrying no functional alleles*4/*4, *4/*5, *5/*5, *4/*6Greatly reduced morphine formation following codeine administration, leading to insufficient pain reliefAvoid codeine use due to lack of efficacy.StrongAlternatives 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.d,e

a Frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See 2014 supplement above for estimates of phenotype frequencies among different ethnic/geographic groups.

b Rating scheme is described in supplemental material - see 2014 update above.

c 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 [Article:19395173].

d 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 2014 update above).

e 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.

February 2012

Advance online publication Dec 2011.

CPIC codeine guideline

Total publications: 2

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