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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines: Codeine Therapy for Cytochrome P450 2D6 Genotype

The Drug: Codeine

Codeine is an opioid analgesic that is usually administered to relieve mild to moderate levels of pain. Upon ingestion, codeine is converted to morphine as the latter has a 200 fold higher affinity for the receptors. Almost 80% of codeine is converted to inactive metabolites. Only 5-10% of codeine is O-Demethylated to morphine and this is done by the enzyme Cytochrome P450 2D6 (CYP2D6). Morphine then gets converted to other metabolites including morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-glucuronide is the active form in humans that has analgesic activity.

The Gene: CYP2D6

The Cytochrome P450 (CYPs) enzymes metabolize thousands of different chemicals including drugs and products of several metabolic pathways, especially in the liver. Cytochrome P450 2D6 (CYP2D6) have been seen to play a role in the metabolism of Codeine to morphine through the process of O-Demethylation. It also similarly acts on other opioids tramadol, hydrocodone, and oxycodone to convert them to O-desmethyltramadol, hydromorphone, and oxymorphone, respectively.

Genetic Variants

CYP2D6 is highly polymorphic. There are over 100 defined CYP2D6 alleles, but many of them have not been evaluated in clinical trials. Activity scores ranging from 0-3 are assigned to individuals based on their genotype- this further helps categorize them into different phenotypes.

The alleles found can be categorized into

  • Wild type alleles show normal enzymatic function
  • Reduced function alleles like *10 or *41
  • Nonfunctional alleles like * 4 or *5

Drug-Gene Relationship

The CYP2D6 genotype is used to determine the efficacy and toxicity of codeine to a great extent. Table 1 shows the phenotypic classification based on the genotype and the how this in turn affects the conversion of codeine to morphine.




Activity Score

CYP2D6 Genotype

Effect on Codeine Metabolism

Ultrarapid metabolizer ~1-2% of patients >2.0 > 2 functional alleles Increased metabolism of codeine to morphine
Extensive metabolizer ~77-92% of patients 1.0-2.0
  • 2 full function alleles
  • 2 reduced function alleles
  • 1 full function and one reduced function allele
  • 1 full function and one nonfunctional allele
Normal metabolism of codeine to morphine
Intermediate metabolizer ~2-11% of patients 0.5 1 reduced function and 1 nonfunctional allele Reduced metabolism of codeine to morphine
Poor metabolizer ~5-10% of patients 0 2 nonfunctional alleles Greatly reduced metabolism of codeine to morphine


Table 1. Effect of Genotype on Codeine Metabolism

On codeine administration to ultrarapid metabolizers at normal doses, we can observe extremely high toxicity levels which can prove to be life-threatening.

Poor metabolizers can however, display decreased analgesic effects with the same doses of codeine.

Therapeutic Recommendations

Table 2 shows codeine therapy recommendations based on CYP2D6 phenotype

Individuals who are extensive or intermediate metabolizers can generally be administered a label-recommended age-specific or weight-specific dosing.

In case of ultrarapid metabolizers, normal dosing can be seen to cause toxicity.

In poor metabolizers, normal dosing is not seen to have the desired analgesic effect.

Those who are ultrarapid or poor metabolizers should be administered non-opioids or opioids that are not metabolized by the enzyme CYP2D6 such as morphine, oxymorphone, buprenorphine, fentanyl, methadone and hydromorphons.



Effect on Codeine Metabolism

Therapy recommendations

Recommendation Type

Alternate therapy considerations

Ultrarapid metabolizer High

Potential toxicity

Avoid codeine use Strong
  • Morphine and nonopiod analgesics are recommended as they are not affected by the CYP2D6 phenotype.
  • Tramadol, hydrocodone and oxycodone are not recommended as they are affected by the CYP2D6
Extensive metabolizer Normal label-recommended age – or weight-specific dosing Strong N/A
Intermediate metabolizer Reduced label-recommended age – or weight-specific dosing

If no response is observed, consider alternative analgesics

Moderate Moderate tramadol use
Poor metabolizer Greatly reduced

No efficacy

Avoid codeine Strong
  • Morphine and nonopiod analgesics are recommended as they are not affected by the CYP2D6 phenotype.
  • Tramadol, hydrocodone and oxycodone are not recommended as they are affected by the CYP2D6


Table 2. Codeine therapy recommendations based on CYP2D6 phenotype


There is a chance that carriers of rare variants may be assigned a wild-type genotype (CYP2D6*1). In case this allele turns out to be a loss-of-function variant, the patient experiences inadequate pain response to codeine.

Hence it is important to stress that the genotyping results be considered a one of multiple pieces of information that guides clinicians in therapeutic decision making.



Xcode is a pioneer in personal genomics, focussed on enabling personalized preventive healthcare. We are dedicated to empowering physicians, wellness professionals and customers with the most validated, accurate and actionable genomic information to positively impact and improve their client’s health and quality of life.

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