Discussion
The opioids codeine, hydrocodone, tramadol, and oxycodone are
metabolized by the CYP2D6 enzyme to active metabolites that are
primarily responsible for their analgesic effects (morphine,
hydromorphone, O-desmethyltramadol and oxymorphone, respectively).
Consequently, CYP2D6 IMs have reduced enzyme activity that alters the
CYP2D6-mediated activation of these opioids, thereby reducing analgesic
effects and increasing risk of side effects.4,5 Figure
1 illustrates how the Medication Risk Mitigation Matrix™ allows users to
view simultaneous multi-drug interactions, drug-gene interactions, and
PGx results, when present. From this illustration, it can been seen that
this patient was taking duloxetine and metoprolol which are known
substrates with higher affinity than oxycodone for CYP2D6. Hence, when
these drugs are taken concomitantly with oxycodone, competitive
inhibition of CYP2D6 enzyme could occur.8 Under these
conditions, phenoconversion is observed (a disconnect between the
genotype-predicted phenotype and likely phenotype observed clinically),
and the patient’s CYP2D6 enzyme behaved like that of a poor metabolizer
(PM), which further reduced the activation of oxycodone into
oxymorphone.
Several studies have demonstrated that single nucleotide polymorphisms,
or genetic variations, in the CYP2D6 gene can significantly
affect the efficacy and safety of opioids.4,5 There
are numerous variant alleles, or different forms, of the CYP2D6gene that an individual can possess that will result in decreased or
increased enzyme function and, consequently, reduced or enhanced
capacity to convert the aforementioned opioids to their active
metabolites.
Studies have shown that individuals carrying copies of the CYP2D6loss-of-function alleles, otherwise known as CYP2D6 PMs, exhibit lower
concentrations of opioid active metabolites than normal metabolizers
(NMs), resulting in reduced analgesia and poor pain
control.4,5 Another study in the post-surgical setting
found that compared with CYP2D6 ultra-rapid metabolizers (UMs;
individuals carrying multiple copies of the functional alleles), CYP2D6
PMs required a 33% higher dose of tramadol in the recovery
room.6 In an experimental study among a small group of
healthy volunteers, researchers demonstrated a 1.5 to six-fold increase
of analgesic effect in CYP2D6 UMs when compared to NMs; when NMs were
compared to PMs, the PMs experienced a two to 20-fold reduction of
analgesic effects.4
Yet another study showed that CYP2D6 UMs, had higher hospitalization
rates than CYP2D6 NMs.7 Due to increased rates of
overdoses and fatalities among infants of breastfeeding mothers who were
CYP2D6 UMs and prescribed codeine and among children who were CYP2D6 UMs
receiving codeine, this opioid now carries a Black Box Warning in its
prescribing information.9
The Clinical Pharmacogenetics Implementation Consortium (CPIC) is an
international organization facilitating the use of PGx for patient care.
CPIC developed evidence-based guidelines for using PGx information to
guide codeine and alternative opioid therapy. 3 These
recommendations are summarized in Table 1 at the end of this article.
For CYP2D6 IMs or PMs, CPIC recommends choosing an alternative opioid
that is not metabolized by CYP2D6, such as hydromorphone or morphine.
The rationale is that the use of codeine, and other opioids such as
hydrocodone, tramadol, and oxycodone in patients with CYP2D6 IM or PM
status is associated with a high risk of reduced efficacy and poor pain
control.
This case highlights the value of utilizing PGx information to enhance
clinical decision-making and potentially improve therapeutic outcomes in
patients with CNCP whose pain cannot be controlled with non-opioid
therapy require opioid therapy.