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Christina Aquilante, Pharm.D., FCCP
Learning Objectives
CODEINE
• Provide examples of CYP2D6 genotype(s) that would result in CYP2D6 UM, NM, IM, and
PM phenotypes
• Describe the relationship between CYP2D6 phenotype and codeine PK
• Describe the relationship between CYP2D6 phenotype and tramadol, hydrocodone, and
oxycodone PK
• Given a patient’s CYP2D6 genotype, provide the predicted CYP2D6 phenotype and
describe the impact on metabolism of codeine or tramadol
• Given different patient scenarios and CYP2D6 genotype/phenotype results, provide
recommendations for the use of codeine based on CPIC guidelines
• List opioid analgesics that are not metabolized by CYP2D6
• Discuss the FDA recommendations regarding codeine use in children undergoing
tonsillectomy and/or adenoidectomy
• Describe how codeine use in a mother who is a CYP2D6 UM may impact her breastfed
infant
• Describe the recommendations for codeine use in nursing mothers who are known to be
CYP2D6 UMs
Codeine
https://www.pharmgkb.org/guideline/PA166104996
Genetically‐Mediated CYP2D6 Phenotypes
• A patient is receiving a CYP2D6 substrate (e.g., codeine) and is prescribed a
concomitant CYP2D6 inhibitor (e.g., paroxetine). How does addition of the
CYP2D6 inhibitor alter the genetically‐determined CYP2D6 phenotype?
• Classify the CYP2D6 inhibitor as strong, moderate, or weak
– http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm
• Strong CYP2D6 inhibitor = multiply CYP2D6 activity score by “0”
• Moderate or weak CYP2D6 inhibitor = multiply CYP2D6 activity score by “0.5”
• Reference (tamoxifen):
– Borges et al. J Clin Pharmacol. 2010 Apr; 50(4):450‐8
CYP2D6 Phenotype and Codeine PK
• CYP2D6 PMs slowly metabolize codeine to morphine
– Decreased morphine plasma concentrations and decreased analgesic effects
following codeine administration
• CYP2D6 UMs rapidly metabolize codeine to morphine
– Increased morphine plasma concentrations, exaggerated therapeutic efficacy,
and an increased risk of adverse effects following codeine administration
Example: Impact of CYP2D6 Phenotype on
Codeine Metabolism
Pain, 1998;76:27‐33
• Summary: Following administration of a 170 mg oral dose of codeine,
CYP2D6 PMs had ~95% lower morphine AUC and Cmax than CYP2D6 NMs
Example: Impact of CYP2D6 Phenotype on
Codeine Metabolism
Pharmacogenomics J, 2007;7:257‐265
• Summary: Following a 30 mg oral dose of codeine, CYP2D6 UMs had 45%
higher morphine AUC and 24% higher morphine Cmax than CYP2D6 NMs
Other Opioids: Tramadol
• Tramadol is metabolized (in part) by CYP2D6 to O‐desmethyltramadol (ODMT)
• ODMT has 200‐fold greater affinity for the μ‐opioid receptor
• CYP2D6 PMs have lower ODMT plasma concentrations and decreased
analgesic response to tramadol compared with CYP2D6 NMs
• CYP2D6 UMs have higher ODMT plasma concentrations and increased
analgesic response and adverse effects from tramadol compared with CYP2D6
NMs
Other Opioids: Hydrocodone
• Hydrocodone is metabolized by CYP2D6 to hydromorphone
• Hydromorphone has 10‐ to 33‐fold greater affinity for the μ‐opioid
receptor than the parent drug
• CYP2D6 PMs have lower peak hydromorphone concentrations after
hydrocodone administration than CYP2D6 NMs
– No information on the PK of hydrocodone in CYP2D6 UM
• Insufficient evidence exist to conclude whether CYP2D6 phenotype
alters analgesic efficacy or the risk of toxicity following hydrocodone
administration
Other Opioids: Oxycodone
• Oxycodone (11%) is metabolized by CYP2D6 to oxymorphone (minor
metabolite)
• Oxymorphone has 40‐fold greater affinity for the μ‐opioid receptor
than the parent drug
• CYP2D6 PMs have lower peak oxymorphone concentrations after
oxycodone administration than CYP2D6 NMs
• Conflicting data exist regarding the impact of CYP2D6 phenotype on
analgesic efficacy and the risk of toxicity following oxycodone
administration
• Differences in the associations of CYP2D6 phenotype with codeine
versus hydrocodone or oxycodone may be due to differences in the
relative contribution of the parent drug and circulating metabolites
to analgesic response
CPIC Guidelines: Codeine
https://www.pharmgkb.org/guideline/PA166104996
Pragmatic Clinical Trial
• Non‐randomized, prospective, pragmatic trial to compare CYP2D6‐
guided versus usual management of chronic pain over 3 months
• Greater improvement in pain control among IM/PMs (prescribed
codeine or tramadol at baseline) in the CYP2D6‐guided group vs
usual care
Genet Med. 2019; PMID: 30670877
Codeine use in Children
• DW is a 5 year old boy status post tonsillectomy and
adenoidectomy (T and/or A). Is codeine an appropriate analgesic
for this patient?
• Codeine is contraindicated as postoperative pain management in
children who have undergone T and/or A (FDA boxed warning)
– Life‐threatening adverse events and death have occurred in children who
received codeine after T and/or A for obstructive sleep apnea syndrome.
Some of these children had evidence of being CYP2D6 UMs.
– Boxed warning is applicable to all children undergoing T and/or A,
irrespective of obstructive sleep apnea status or CYP2D6
genotype/phenotype
– In general, codeine is not recommended in children less than 2 years of age
Codeine Use in Mothers who are
Breastfeeding
• Case report: 13‐day‐old breastfed infant died from a morphine
overdose. The mother was taking codeine for episiotomy pain.
– Lab tests showed high levels of morphine in the baby’s blood, and genetic
testing showed that the baby’s mother was a CYP2D6 UM
• Infants of nursing mothers taking codeine may have increased risk of
morphine overdose if their mothers are CYP2D6 UMs
– Do not use codeine in a nursing mother who is known to be a CYP2D6 UM
– If the mother’s CYP2D6 status is not known, use codeine with caution