Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the list below.
Important Instructions: Please use CYP2D6 Activity Score to select the appropriate row in the list below.
Ultrarapid Metabolizer (Activity Score >2.25)
Clinical Implication
- Increased CYP2D6 enzyme activity.
- Increased risk of adverse events (e.g., respiratory depression, death), even at low doses.
Therapeutic Recommendation
- Use non-opioid if possible.**
- If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**
Normal – Ultrarapid Metabolizer (Activity Score 1.5+ or 2+)*
Clinical Implication
- Normal to increased CYP2D6 enzyme activity.
- Possible increased risk of adverse events (e.g., respiratory depression, death), even at low doses.
Therapeutic Recommendation
- Use non-opioid if possible.**
- If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**
Normal Metabolizer (Activity Score 1.25-2.25)*
Clinical Implication
- Normal CYP2D6 enzyme activity.
- Normal response expected.
Therapeutic Recommendation
- Use label recommended age-specific or weight-specific dosing.
Intermediate – Ultrarapid Metabolizer (Activity Score 0.25+, 0.5+, 0.75+, or 1+)*
Clinical Implication
- Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations.
- Increased risk of adverse events (e.g., respiratory depression, death), even at low doses, normal response OR little to no pain relief expected.
Therapeutic Recommendation
- Use non-opioid if possible.**
- If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**
Intermediate Metabolizer with an enzyme Activity Score 1*
Clinical Implication
- Slightly decreased CYP2D6 enzyme activity.
- Normal response expected.
Therapeutic Recommendation
- Use label recommended age-specific or weight-specific dosing.
Intermediate Metabolizer with an enzyme Activity Score of 0.25-0.75*
Clinical Implication
- Decreased CYP2D6 enzyme activity.
- Little to no pain relief expected.
Therapeutic Recommendation
- Use non-opioid if possible.**
- If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**
Poor Metabolizer (Activity Score 0)
Clinical Implication
- No CYP2D6 enzyme activity.
- Little to no pain relief expected.
Therapeutic Recommendation
- Use non-opioid if possible.**
- If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**
Unable to Genotype or Assay Failure
- The analysis failed to yield an informative result and thus no genotype is reported.
Unknown Phenotype
- This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.
*Previously some labs have designated an Activity Score of 1 as Normal Metabolizers
**There is less evidence for this recommendation for hydrocodone
Reference
- Adapted from Crews KR et al., Clin Pharmacol Ther. 2021 Oct;110(4):888-896. PMID: 33387367.