Annotation of Dutch Pharmacogenetics Working Group (DPWG) guideline information
for codeine and CYP2D6

last updated 05/02/2017

Summary

Select alternative analgesics for patients who are CYP2D6 poor metabolizers, intermediate metabolizers, or ultrarapid metabolizers.

Annotation

Note that the FDA released a safety announcement on 4/20/2017 stating that codeine and tramadol should not be used in children under 12 years.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotypes [Article:21412232]. They recommend alternative analgesics for patients carrying the poor metabolizer (PM) alleles, intermediate metabolizer (IM) alleles or ultrarapid metabolizer (UM) allleles.

Phenotype (Genotype)Therapeutic Dose RecommendationLevel of EvidenceClinical Relevance
PM (two inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) alleles)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: no.Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.
IM (two decreased-activity (*9, *10, *17, *29, *36, *41) alleles or carrying one active (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele, or carrying one decreased-activity (*9, *10, *17, *29, *36, *41) allele and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to symptoms of insufficient pain relief. Cough: noPublished controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5; Kinetic effect (S).
UM (a gene duplication in absence of inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) or decreased-activity (*9, *10, *17, *29, *36, *41) alleles)Analgesia: select alternative drug (e.g., acetaminophen, NSAID, morphine-not tramadol or oxycodone) or be alert to ADE. Cough: be extra alert to ADEs due to increased morphine plasma concentration.Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.
  • *See Methods or [Article:18253145] for definition of "good" and "moderate" quality.
  • S: statistically significant difference.
  • Please see attached PDF for detailed information about the evaluated studies: Codeine CYP2D6

DPWG Guideline publication

Total publications: 1

Reference
1. Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee A H, Mulder H, Rongen G A P J M, van Schaik R H N, Schalekamp T, Touw D J, van der Weide J, Wilffert B, Deneer V H M, Guchelaar H-J. PubMed

Guideline History