The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the "Major Recommendations" field.
Interpretation of Genetic Test Results
The combination of alleles is used to determine a patient's diplotype. Cytochrome P450 2D6 (CYP2D6) alleles are characterized as wild-type (normal function), reduced-function, or nonfunctional based on the expected activity level of the enzyme for which they encode. Each functional group is assigned an activity value ranging from 0 to 1.0 (e.g., 0 for nonfunctional, 0.5 for reduced function, and 1.0 for fully functional). Supplementary Table S4 (see the "Availability of Companion Documents" field) describes the activity score values assigned to selected alleles. If multiple copies of the CYP2D6 gene are detected, the activity score is multiplied by the number of copies of each allele present. The total CYP2D6 activity score is the sum of the values assigned to each allele, which typically ranges from 0 to 3.0 but may exceed 3.0 in rare cases.
The CYP2D6 activity score relates to the phenotype classification system (see Table 1 below).
Table 1. Assignment of Likely Codeine Metabolism Phenotypes Based on CYP2D6 Diplotypes
||Examples of Diplotypes
|Ultrarapid metabolizer (~1–2% of patients)
||An individual carrying more than two copies of functional alleles
|Extensive metabolizer (~77–92% of patients)
||An individual carrying two alleles encoding full or reduced function or one full function allele together with either one nonfunctional or one reduced-function allele
||*1/*1, *1/*2, *2/*2, *1/*41,*1/*4,*2/*5, *10/*10
|Intermediate metabolizer (~2–11% of patients)
||An individual carrying one reduced and one nonfunctional allele
|Poor metabolizer (~5–10% of patients)
||An individual carrying no functional alleles
||*4/*4, *4/*5, *5/*5, *4/*6
a The frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See Supplementary Data in the "Availability of Companion Documents" field for estimates of phenotype frequencies among different ethnic/geographic groups.
b Note that some investigators define patients with an activity score of 0.5 and 1.0 as intermediate metabolizers and define patients with an activity score of 1.5 and 2.0 as extensive metabolizers. Classifying patients with an activity score of 1.0 as extensive metabolizers in this guideline is based on data specific for formation of morphine from codeine in these patients.
Linking Genetic Variability To Variability in Drug-Related Phenotypes
There is substantial evidence linking CYP2D6 genotype to variability in codeine efficacy and toxicity (see Supplementary Table S6 online in the "Availability of Companion Documents" field). Decreased codeine analgesia has been observed in poor metabolizers, whereas severe or life-threatening toxicity after normal doses of codeine has been documented in ultrarapid metabolizers. This body of evidence, rather than randomized clinical trials involving pharmacogenetic testing, provides the basis of the therapeutic recommendations in Table 2 below.
Table 2. Codeine Therapy Recommendations Based on CYP2D6 Phenotype
||Implications for Codeine Metabolism
||Recommendations for Codeine Therapy
||Classification of Recommendation for Codeine Therapy
||Increased formation of morphine following codeine administration, leading to higher risk of toxicity
||Avoid codeine use due to potential for toxicity. Consider alternative analgesics such as morphine or a nonopioid. Consider avoiding tramadol.a
||Normal morphine formation
||15–60 mg every 4 h as needed for pain (label recommendation)b
||Reduced morphine formation
||Begin with 15–60 mg every 4 h as needed for pain.b If no response, consider alternative analgesics such as morphine or a nonopioid. Monitor tramadol use for response.
||Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief
||Avoid codeine use due to lack of efficacy. Consider alternative analgesics such as morphine or a nonopioid. Consider avoiding tramadol.a
CYP2D6, cytochrome P450 2D6
aAlthough detailed recommendations for using CYP2D6 phenotype in tramadol therapy are beyond the scope of this guideline, there is strong evidence for decreased efficacy of tramadol in poor metabolizers and a single case report of toxicity in an ultrarapid metabolizer with renal impairment following tramadol postsurgery. Use of other analgesics in CYP2D6 poor metabolizers and ultrarapid metabolizers may therefore be preferable.
bFor pediatric patients who are extensive or intermediate metabolizers, use label recommended age- or weight-specific dosing.
CYP2D6 Genetic Test Interpretation and Suggested Clinical Action
Table 2 summarizes the therapeutic recommendations for codeine based on CYP2D6 phenotype. A standard starting dose of codeine, as recommended in the product label, is warranted in patients with an extensive metabolizer phenotype (i.e., a CYP2D6 activity score of 1.0 to 2.0). Likewise, a standard starting dose of codeine is warranted in patients with an intermediate metabolizer phenotype (i.e., a CYP2D6 activity score of 0.5); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if required. If the CYP2D6 substrate tramadol is selected as alternative therapy in intermediate metabolizers, close monitoring should be carried out because of the possibility of low response.
If clinical genotyping identifies a patient as a CYP2D6 poor metabolizer (i.e., a CYP2D6 activity score of 0), current evidence suggests that the use of codeine be avoided because of the possibility of lack of effect, and that an alternative analgesic should be used. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in poor metabolizers. There is insufficient evidence in the literature to recommend a higher dose of codeine in poor metabolizers, especially given that adverse effects do not differ between poor metabolizers and extensive metabolizers.
In a patient identified as a CYP2D6 ultrarapid metabolizer (i.e., a CYP2D6 activity score of >2.0), the choice of an alternative analgesic should be made to avoid the risk of severe toxicity associated with a "normal" dose of codeine. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in ultrarapid metabolizers.
Strength of Therapeutic Recommendations
Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.
Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.
Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.