Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

16 Applying Pharmacogenomics in Therapeutics
include phenotyping subgroups of PMs, intermediate metabolizers (IMs), EMs,
and UMs. 108,109 The EMs are considered to have normal enzyme activity. 113–116 The
median AUC of the morphine metabolite increases from PMs to EMs to UMs. 109 The
CYP2D6*3, *4, *5, *6, and *7 alleles have been reported to account for the majority
of decreased CYP2D6 enzyme activity. 110,112 In addition, the decreased activity of
CYP2D6 in IMs has been shown to result from CYP2D6*9 and *10 alleles. 110 Gene
duplication of CYP2D6 found in UMs is associated with higher plasma concentration
and AUCs of morphine than in EMs. 109
Clinical Relevance
The prescribing information for codeine states that the prevalence of CYP2D6 phenotype
varies widely and has been estimated at 0.5–1% in Chinese and Japanese; 0.5–1%
in Hispanics; 1–10% in whites; 3% in African Americans; and 16–28% in North
Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. 106
Studies have shown that increased pain threshold is found in EMs but not in
PMs, and that morphine in urine samples is not found in PMs. 111,117 The PMs have
impaired O-demethylation; therefore, codeine does not have analgesic effects in
PMs. 108 Even though PMs may not experience analgesic effects expected from
codeine, they can still develop side effects (e.g., sedation, headaches, dizziness,
and dry mouth), which may be related to codeine itself rather than its metabolites,
including morphine. 118 UMs of CYP2D6 experience greater analgesic effects but
have increased risks for toxicity. 109,119,120 For example, UMs have a higher incidence
of sedation compared to EMs (91% vs. 50%, p = 0.069). 109 Other potential side
effects for UMs include euphoria, dizziness, and visual disturbances 119–121 or more
severe symptoms, such as extreme sleepiness, confusion, shallow breathing, or
respiratory suppression. 106
A case report by Koren et al. in 2006 described an adverse drug event related to
codeine in a breastfeeding mother taking codeine 30 mg and paracetamol 600 mg
for postpartum episiotomy pain management. 122,123 Her codeine dosage on day 1
was 60 mg (2 tablets) every 12 hours. However, due to side effects of somnolence
and constipation, she lowered the dose by half on day 2 to 14. Unfortunately, her
13-day-old baby died from a morphine overdose with a serum concentration of
70 ng/mL (neonates breastfed by mothers receiving codeine typically have morphine
serum concentrations of 0–2.2 ng/mL). 124 The morphine concentration found
in her breast milk stored on day 10 was 87 ng/mL (normal range is 1.9–2.5 ng/mL
for doses of 60 mg every 6 hours). The mother was genotyped and determined to be
an UM of codeine (heterozygous for a CYP2D6*2A allele with CYP2D6*2×2 gene
duplication). 122 There is a correlation between increased codeine dosage and ADRs
in breastfeeding neonates. 125–127 Subsequently, the US FDA issued a warning, which
was included in codeine’s prescribing information, stating that “maternal use of
codeine can potentially lead to serious adverse reactions, including death, in nursing
infants,” and that “If a codeine-containing product is selected, the lowest dose
should be prescribed for the shortest period of time to achieve the desired clinical
effect. Mothers using codeine should be informed about when to seek immediate
medical care and how to identify the signs and symptoms of neonatal toxicity,