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CPIC® Guideline for Opioids and CYP2D6, OPRM1, and COMT

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy (December 2020)

Tables and figure provided in the main manuscript of the guideline:

Table 1. Assignment of predicted CYP2D6 phenotypes based on diplotypes
Table 2. Codeine therapy recommendations based on CYP2D6 phenotype
Table 3. Tramadol therapy recommendations based on CYP2D6 phenotype
Table 4. Hydrocodone therapy recommendations based on CYP2D6 phenotype

Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy (December 2020)

Tables and figures included in the supplementa or referenced in the guideline:

Supplemental Table S1. Evidence linking CYP2D6 phenotype or genotype with opioid metabolism or response
Supplemental Table S2. Evidence linking OPRM1 genotype with 0pioid response
Supplemental Table S3. Evidence linking COMT genotype with opioid response
Supplemental Table S4. Evidence linking COMT and OPRM1 genotype with opioid response
Supplemental Table S5. Oxycodone therapy recommendations based on CYP2D6 phenotype
Supplemental Table S6. Methadone therapy recommendations based on CYP2D6 phenotype
Supplemental Table S7. Morphine therapy recommendations based on OPRM1 genotype
Supplemental Table S8. Fentanyl therapy recommendations based on OPRM1 genotype
Supplemental Table S9. Other Opioids (alfentanil, buprenorphine, codeine, hydrocodone, hydromorphone, levomethadone, methadone, naltrexone, oxycodone, remifentanil, sufentanil, and tramadol) therapy recommendations based on OPRM1 genotype
Supplemental Table S10. Opioid therapy recommendations based on COMT genotype
Figure S1. Codeine metabolism
Figure S2. Tramadol metabolism
Figure S3. Hydrocodone metabolism
Figure S4. Oxycodone metabolism
CYP2D6 allele definition table
CYP2D6 allele functionality table
CYP2D6 frequency table
CYP2D6 diplotype-phenotype table

Gene Resource Mapping

CYP2D6 gene resource mappings

Drug Resource Mapping

Codeine

Tramadol

Hydrocodone

Clinical Decision Support:b

Codeine pre- and post-test alerts and flow chart

Tramadol pre- and post-test alerts and flow chart

Hydrocodone pre- and post-test alerts and flow chart

aSome of the tables included in the guideline may have been updated on-line, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.

bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.

Original publication (February 2012):

April 2014 Update:

April 2017: On April 20, the FDA updated a drug safety advisory for codeine and tramadol (full report here):

  • The FDA has issued its strongest warning, called a Contraindication, to the drug labels of codeine and tramadol alerting that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 years.
  • A new Contraindication to the tramadol label warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.
  • A new Warning to the drug labels of codeine and tramadol to recommend against their use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems.
  • A strengthened Warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants. These can include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.

October 2019: CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus among a panel of international CYP2D6 experts for a uniform system for translating CYP2D6 genotype to phenotype (more information). Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

As a result, the following changes have been made in the CYP2D6 allele functionality table and CYP2D6 diplotype-phenotype table:

  • Diplotypes giving rise to activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer assignments.
    • Impact on the recommendations in this guideline: Because the recommendations in this guideline do not differ between a CYP2D6 normal and intermediate metabolizer, the current published recommendations for normal and intermediate metabolizers will remain unchanged.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower value of 0.25 for *10). Prior to the consensus projects, the combination of a duplicated normal function allele with a *10 allele resulted in an activity score of 2.5 which translates to an ultrarapid metabolizer. The lower value of 0.25 for CYP2D6*10 results in an activity score of 2.25 for these allele combinations, which based on the new consensus project, now translates to a normal metabolizer. See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: The authors of this guideline are currently reviewing evidence for the affected activity score (AS of 2.25) and will update this webpage and relevant tables accordingly.

This guideline has been endorsed by the American Society of Health-System Pharmacists (ASHP).