Table 2.

The CPIC Tramadol Therapy Recommendations Based on CYP2D6 Phenotype (2021)

PhenotypeaActivity scorebImplicationsGenotypeExamples of diplotypesbRecommendations for tramadol therapyd
Ultrarapid metabolizer> 2.25Increased formation of O-desmethyltramadol (active metabolite) leading to higher risk of toxicityMore than 2 copies of normal-function alleles *1/*1xNc
*1/*2xN 		Avoid tramadol use because of potential for toxicity. If opioid use is warranted, consider a non-codeine opioid.
Normal metabolizer1.25–2.25*Expected O-desmethyltramadol (active metabolite) formation2 normal-function alleles, or one normal-function allele and one decreased-function allele, or combinations of duplicated alleles that result in an activity score of 1.25–2.25 *1/*10
*1/*41
*1/*9
*10/*41x3
*1/*1
*1/*2
*2x2/*10 		Use tramadol label-recommended age- or weight-specific dosing.
Intermediate metabolizer0.25–1*Reduced O- desmethyltramadol (active metabolite) formation.One decreased-function allele and one no-function allele, or 2 decreased-function alleles *4/*10
*4/*41
*10/*10
*10/*41
*41/*41
*1/*5 		Use tramadol label-recommended age or weight-specific dosing. If no response and opioid use is warranted, consider a non-codeine opioid
Poor metabolizer0Greatly reduced O-desmethyltramadol (active metabolite) formation leading to diminished analgesia.2 no-function alleles *3/*4
*4/*4
*5/*5
*5/*6 		Avoid tramadol use because of possibility of diminished analgesia. If opioid use is warranted, consider a non-codeine option.
Indeterminant metabolizern/an/aAn individual having one or 2 uncertain-function alleles *1/*22
*1/*25
*22/*25 		No recommendation
a

See the CYP2D6 Frequency Table for race-specific allele and phenotype frequencies from PharmGKB and CPIC.

b

Assignment of allele function and allele activity values including citations for allele function can be found at PharmGKB (CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table) and CPIC.

For a complete list of CYP2D6 diplotypes and resulting phenotypes, see the CYP2D6 Genotype to Phenotype Table at PharmGKB and CPIC.

C

Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data in (2) for additional information on how to translate diplotypes into phenotypes.

d

The strength of therapeutic recommendations is “moderate” for intermediate metabolizers, and “strong” for all other metabolizers.

Table is adapted from (2).

From: Tramadol Therapy and CYP2D6 Genotype

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