Codeine and tramadol are pro-drugs, meaning that after being taken orally they must be metabolized in the liver to their active forms, morphine and O-desmethyltramadol, respectively. The protein in the liver responsible for this activation is the cytochrome p450 enzyme CYP2D6 (pronounced "sip two dee six").

Across populations, CYP2D6 protein alleles can have different genetic variants that impact its ability to activate codeine and tramadol. The different alleles can produce four different metabolism phenotypes: ultrarapid, normal, intermediate, and poor metabolism. The ultrarapid metabolism phenotype has been shown to be associated with a greater formation of active metabolites leading to an increased risk of developing severe toxicities with codeine and tramadol. The intermediate and poor metabolism phenotypes have been shown to be associated with inadequate formation of active metabolites for codeine and tramadol and may result in diminished analgesia. 

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a group who evaluates the evidence for the use of pharmacogenetics and then develops clinical practice guidelines.  For codeine and tramadol, extensive guideline information can be found at: https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/ a reference maintained by CPIC. 

Here are two videos that review the CPIC guideline for these drugs: 
codeine: https://www.youtube.com/watch?v=pfovk7flpoM

tramadol: https://www.youtube.com/watch?v=dVatX-mxv_8

At UCHealth the use of pharmacogenetics when prescribing codeine or tramadol will occur in patients who meet the following conditions:
1) Provided a blood or saliva sample to the CCPM biobank, consented for the return of their results, and this sample has undergone genotyping OR the patient is being seen in a clinic which is currently using pharmacogenetic testing as part of standard care (e.g., the UCHealth GI Oncology Clinic).  
2) Are prescribed codeine or tramadol.

For patients enrolled in the biobank, this process takes a minimum of 4-6 weeks but may take several years. Therefore, results will not be available at initial presentation if a patient has not previously enrolled in the biobank.

If you are a provider AND your patient is a CYP2D6 ultrarapid metabolizer, a best practice alert (BPA) will warn you if you attempt to prescribe codeine or tramadol in UCHealth's EHR. This BPA will fire in both the inpatient and ambulatory settings in the UCHealth EHR. The BPA recommends that you avoid both codeine and tramadol in these patients. 

If you are a provider AND your patient is a CYP2D6 intermediate or poor metabolizer, an inline medication warning will appear if you attempt to prescribe or refill codeine (for both intermediate and poor metabolizers) or tramadol (poor metabolizers only) in UCHealth's EHR. If the inline medication warning is visible, links to resources will be listed for your reference.  

There is patient education text available for UCHealth providers to use in discharge paperwork or the after visit summary (AVS).