Drug interactions, pharmacogenetics influence codeine, morphine levels
Ben Kong, PharmD
In an analysis of codeine-related deaths, drug interactions and genetic polymorphisms were significantly associated with changes in post-mortem morphine-to-codeine ratios. Specifically, genetic variability in ABCB1, but not CYP2D6, was associated with significant differences in post-mortem codeine and morphine concentrations.
Opioid-related death is often associated with opioid use in combination with sedatives, hypnotics, and other central nervous system depressants. Codeine is a weak opioid that is converted into the more potent morphine via CYP2D6 activation. Population variations in CYP2D6 expression exist. Ultra-rapid CYP2D6 metabolizers produce more morphine and are at increased risk for severe side effects with codeine use; poor CYP2D6 metabolizers are at risk for lower analgesia with codeine use. However, many factors besides genotype contribute to codeine’s effects; additional data are needed to clarify clinical effects of variant CYP2D6 genotypes.
Lam et al. reviewed codeine-related deaths occurring in Ontario, Canada between 2006 and 2008. Out of a total of 1,359 deaths due to opioids, 68 cases (36 accidental and 32 suicides) met inclusion criteria. Cases were excluded in the following: use of heroin, use or suspected use of morphine, indication of codeine misuse, undetermined cause of death, femoral blood codeine/morphine below detectable level, or insufficient quantity of blood for genotype analysis. Genetic analysis was conducted for CYP2D6 (SNaPshot™; Applied Biosystems, Foster City, CA; activity score assignments based on Gaedigk et al) and other enzymes involve in codeine and/or morphine metabolism (ABCB1, UGT2B7, OPRM1, and COMT [analysis information provided]). Investigators also collected data on other factors that may influence opioid toxicity, including illicit drug use, strong or weak CYP2D6 inhibitor medication use, and CNS depressant use.
Deaths related to suicides were associated with a higher median codeine concentration than accidental deaths (455 ng/ml vs. 315 ng/ml; P = 0.038). Overall genetic variability in activity of CYP2D6, UGTB7, COMT, or OPRMI enzymes was not significantly associated with changes in the morphine-to-codeine ratio. However, the morphine-to-codeine ratio was lower when a CYP2D6 inhibitor was also detected as compared to no CYP2D6 inhibitor use (P = 0.05). As compared with patients taking no CYP2D6 inhibitor, the morphine-to-codeine ratio was also significantly lower with increasing concomitant CYP2D6 inhibitor potency and in CYP2D6 poor metabolizers (P = 0.0011). Presence of the ABCB1 1236 variant was associated with lower morphine-to-codeine ratios (P = 0.004).
This study is one of the first to associate drug interactions and genetic information with codeine and morphine levels in codeine-related deaths. Notably, the body of literature supporting clinically significant effects of genetic variability with codeine administration is much stronger for CYP2D6 than with ABCB1, despite study findings. Investigators pointed out factors that may have influenced these findings, including effects of concomitant CYP2D6 inhibitor medications; possible CYP2D6 enzyme saturation in overdoses associated with suicide deaths; and potential post-mortem changes in codeine and morphine concentrations.
Investigators hypothesized that the observed effects with ABCB1 variability could be due to its association with p-glycoprotein functioning; this enzyme has been shown to be a determinant of intracellular morphine concentrations in the brain. Evidence supporting effects of genetic variability in CYP2D6, ABCB1, and other enzymes and dosing guidelines for CYP2D6-codeine can be found at www.pharmgkb.org.
Limitations of the current study included a single post-mortem codeine and/or morphine concentration, unknown medication history prior to mortality, unknown ethnicity information, and variable circumstances leading to differences in the death investigation.
Lam J et al. Codeine-related deaths: The role of pharmacogenetics and drug interactions. Forensic Sci Int. 2014;239:50-6.