Annotation of DPWG Guideline for codeine and CYP2D6

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Summary

The Pharmacogenetics Working Group Guideline for codeine includes individual recommendations for cough or pain for CYP2D6 poor, intermediate, and ultrarapid metabolizer. In addition, for ultrarapid metabolizer, higher or lower doses and additional risk factors are taken into consideration.

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Important information about alleles in DPWG guidelines.

Annotation

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.

Read more about how PharmGKB curates DPWG guidelines using extra information provided by DPWG to enable the interactive genotype tool above.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2D6 and opioids (codeine, tramadol and oxycodone). European journal of human genetics (2021)

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the November 2018 update including more details and scoring the clinical implementation [Article:34267337]

November 2018 update

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotype. The guideline includes individual recommendations for cough or pain for CYP2D6 poor, intermediate, and ultrarapid metabolizer. In addition, for ultrarapid metabolizer the recommendations consider higher or lower doses and additional risk factors.

Wording in table taken from the Dutch guidelines November 2018 update

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
CYP2D6 UM	codeine	The genetic variation increases the conversion of codeine to morphine. This can result in an increase in side effects. Death has occurred in children who received analgesic doses. One adult with reduced kidney function and co-medication with two CYP3A4 inhibitors became comatose after use of codeine for a cough.	DOSES HIGHER THAN 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND/OR ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function: Codeine is contra-indicated. if possible, select an alternative - For PAIN: do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in side effects in patients. - For COUGH: noscapine is not metabolised by CYP2D6. DOSES LOWER THAN OR EQUAL TO 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older AND NO ADDITIONAL RISK FACTORS, such as co-medication with CYP3A4 inhibitors and/or reduced kidney function: No action required.
CYP2D6 IM	codeine	The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia.	For COUGH: 1. No action required. For PAIN: It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype. 1. Be alert to a reduced effectiveness. 2. In the case of inadequate effectiveness: 1. Try a dose increase., 2. If this does not work: choose an alternative. Do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients. 3. If no alternative is selected: advise the patient to report inadequate analgesia.
CYP2D6 PM	codeine	The genetic variation reduces the conversion of codeine to morphine. This can result in reduced analgesia.	For COUGH: 1. No action required. For PAIN: It is not possible to offer adequately substantiated advice for dose adjustment based on the limited available literature for this phenotype. 1. Choose an alternative. Do not select tramadol, as this is also metabolised by CYP2D6. Morphine is not metabolised by CYP2D6. Oxycodone is metabolised by CYP2D6 to a limited extent, but this does not result in differences in analgesia in patients. 2. If an alternative is not an option: advise the patient to report inadequate analgesia.

Read for more information about this recommendation, Read about gene information from DPWG

Preemptive genotyping

Excerpts from the DPWG risk analysis document for codeine and CYP2D6:

The Dutch Pharmacogenetics Working Group considers genotyping before starting codeine in doses higher than 20 mg every 6 hours for adults and 10 mg every 6 hours for children aged 12 years or older, and in patients with additional risk factors, such as co-medication with CYP3A4 inhibitors and/or impaired renal function, to be beneficial for drug safety. It is advised to genotype these patients before (or directly after) drug therapy has been initiated to guide drug and dose selection.

2011 Guideline

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotypes [Article:21412232]. They recommend alternative analgesics for patients carrying the poor metabolizer (PM) alleles, intermediate metabolizer (IM) alleles or ultrarapid metabolizer (UM) allleles.

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Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
PM (two inactive (3-8, 11-16, 19-21, 38, 40, *42) alleles)	Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no.	Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x10⁹/l; leucopenia > 3.0x10⁹/l; thrombocytopenia > 75x10⁹/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (9, 10, 17, 29, 36, 41) alleles or carrying one active (1, 2, 33, 35) and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele, or carrying one decreased-activity (9, 10, 17, 29, 36, 41) allele and one inactive (3-8, 11-16, 19-21, 38, 40, 42) allele)	Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no	Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S).
UM (a gene duplication in absence of inactive (3-8, 11-16, 19-21, 38, 40, 42) or decreased-activity (9, 10, 17, 29, 36, *41) alleles)	Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to ADE. Cough: be extra alert to ADEs due to increased morphine plasma concentration.	Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.

*See Methods or [Article:18253145] for definition of "good" and "moderate" quality.
S: statistically significant difference.
Please see attached PDF for detailed information about the evaluated studies: Codeine CYP2D6

PharmGKB ID

PA166104970