Introduction
Oxycodone (brand names OxyContin, Roxicodone, Xtampza ER, and Oxaydo), is an opioid
analgesic used for moderate to severe pain caused by various conditions for which
alternative analgesic treatments are inadequate.(1) Oxycodone exerts its analgesic affects by
binding to the mu-opioid receptors (MOR) in the central and peripheral nervous
system. While it is an effective pain reliever, this agent also has a high potential
for addiction, abuse, and misuse.
Oxycodone is metabolized by members of the cytochrome P450 (CYP) enzyme superfamily.
The CYP3A4, CYP3A5, and CYP2D6 enzymes convert oxycodone to either less-active
(CYP3A4 and CYP3A5) or more-active (CYP2D6) metabolites. Most of the analgesic
effect is mediated by oxycodone itself, rather than its metabolites. Variation at
the CYP3A4 and CYP3A5
loci leading to altered enzyme activity is rare. A handful of altered-function
alleles are known, but there is no documented evidence to support altered oxycodone
response in the presence of these variant alleles. The FDA approved drug label for
oxycodone cautions that co-medication with CYP3A inhibitors or inducers may lead to
altered pharmacokinetics and analgesia, but does not discuss genotype-based
recommendations for prescribing (1).
Genetic variation at the CYP2D6 locus has conflicting
evidence regarding altered response of individuals to oxycodone therapy. Thus, the
Clinical Pharmacogenetics Implementation Consortium (CPIC) has determined that there
is insufficient evidence to recommend alterations to standard clinical use based on
CYP2D6 genotype (2). Similarly, the Dutch Pharmacogenetics Working
Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
recognizes the drug-gene interaction between CYP2D6
and oxycodone but states that the interaction does not affect analgesia achieved by
the medication (3, 4). The PharmGKB online resource
reports that drug labels in Switzerland (regulated by Swissmedic) state that CYP2D6 variation can alter oxycodone response (5, 6).
Interactions among drugs from polypharmacy may be further enhanced by genetic
variation, but there are no professional recommendations to alter prescribing based
on drug-drug-gene interactions. Regardless of genotype, oxycodone is contraindicated
in individuals with significant respiratory depression, acute or severe bronchial
asthma, known or suspect gastrointestinal obstruction, or known hypersensitivity to
the medication (1).
Drug: Oxycodone
Oxycodone is a semi-synthetic derivative of thebaine, belonging to the drug class of
opioid agonists. It is used to treat both chronic and acute pain of moderate to
severe intensity when alternative treatments are inadequate. (1) Oxycodone has a similar half-life (2–4 hours) as
morphine and approximately twice the bioavailability (7, 8). However, oxycodone is 4-fold less potent than morphine as a MOR
agonist, with similar receptor activation efficiency (9). Oxycodone is approximately twice as analgesic
as morphine, perhaps reflecting the increased bioavailability, but may be less
effective for some pain conditions, such as diabetic neuropathy (10, 11).
However, oxycodone has a high abuse potential (11, 12). It is one of the most widely abused opioid analgesics, with
increased abuse reported among all ethnic and economic groups since the 1960s (12, 13). Oxycodone is classified as a Schedule II
substance by the US Drug Enforcement Agency (DEA) due the high potential for abuse
leading to psychological or physical dependance (1, 13). The factors predisposing any individual to addiction are complex
and as such the risk of opioid addiction should be assessed on a case-by-case basis.
Clinicians are advised to ensure that the analgesic benefits outweigh the addiction,
abuse, or misuse risks for each individual. A risk evaluation and mitigation
strategy educational program may be offered as a part of continuing education for
prescribing clinicians. (1)
Clinicians should be advised that naloxone, an opioid antagonist medication is
available to counter opioid overdose and individuals taking oxycodone should be at
least aware of this medication. Current guidelines from the Substance Abuse and
mental Health Services Administration (SAMHSA) recommend naloxone prescription to
anyone on high doses of opioids or using long acting/extended release opioids.(14)
Oxycodone has multiple administration modalities, including intravenous, epidural,
rectal, or oral. Oral formulations come in the form of liquid medications or tablets
for immediate or extended release. Regardless of administration route, the
pharmacokinetics are dose dependent, and most of the oxycodone metabolism occurs in
the liver.
Oxycodone is metabolized by members of the CYP enzyme superfamily, with a small
amount of oxycodone being excreted without undergoing metabolic processing. Most of
the hepatic oxycodone metabolism (roughly 45–50% of the total dose) is performed by
the CYP3A enzymes (CYP3A4 and CYP3A5) to form noroxycodone, a largely inactive
metabolite. (11, 12, 15) Approximately 10–19% of an oxycodone dose is
also metabolized by the CYP2D6 enzyme to form a potent opioid oxymorphone. Oxycodone
and its metabolites can be further reduced or can undergo glucuronidation by
UDP-glucuronosyltransferase (UGT) enzymes. (11)
Inhibition of the CYP2D6 enzyme by concomitant medications (such as paroxetine)
reduces oxycodone analgesia (16)
due to reduced oxymorphone formation. Similarly, CYP3A inhibition results in
increased oxycodone and oxymorphone exposure and analgesia (17); (16). Where CYP3A4 or CYP3A5 inhibition or induction is a concern due to
multiple co-medications, oxymorphone can be substituted.
Many opioids undergo CYP2D6 metabolism to varying degrees. Oxycodone is an active
analgesic with minimal metabolism by CYP2D6, whereas codeine and tramadol are
pro-drugs that require activation by CYP2D6 and thus are more directly affected by
CYP2D6 enzyme activity. (18, 19) Another opioid, hydrocodone, is also metabolized by CYP2D6 into an
active analgesic—hydromorphone—but like oxycodone, the parent and metabolite
compounds can both provide analgesic effect, though with differing potency (2, 20, 21, 22).
Oxycodone and oxymorphone both activate MOR in the central nervous system and in
peripheral tissues. At pharmacologically relevant concentrations oxycodone and
oxymorphone act selectively through MOR, with oxymorphone being 8-fold more potent
as a MOR activator than oxycodone. Unlike oxycodone, oxymorphone has also been shown
to bind to delta and kappa opioid receptors, but the demonstrated affinities greatly
exceed therapeutic plasma concentrations. Following oxycodone administration,
oxymorphone has been reported to only account for a small portion of total opioid
exposure, while the parent, oxycodone, accounts for roughly 90% of the total
analgesic effect (23).
Conversely, some experts have concluded that the small amount of oxymorphone
produced following oxycodone administration may account for most of the analgesic
effect (15). The relative role
of the parent and oxymorphone metabolite may depend on the route of drug
administration with more oxymorphone being produced following oral dosing than seen
with parenteral dosing (8). In
addition, oxymorphone is a higher potency MOR agonist and exhibits a longer
half-life than oxycodone—it is the predominate MOR activator 6 hours after oxycodone
dosing. Given the conflicting views regarding the contribution of oxymorphone to
analgesia following oxycodone administration, the role of CYP2D6 activity in an
individual’s response to oxycodone is also debated and is discussed further below.
In contrast, the CYP3A metabolite noroxycodone, exhibits a 3-fold lower reduced
binding affinity than the parent and appears to be an antagonist/very weak partial
agonist. (11)
Clearance of oxycodone, either unmodified or following its metabolism by cytochrome
P450 enzymes and UGT enzymes, is partially dependent upon renal function, hepatic
metabolism, and seems to vary with age and gender. The plasma half-life for
oxycodone is 3–5 hours in healthy adults(12), it decreases by 25% in geriatric individuals
(24). Plasma protein binding
of oxycodone is approximately 45% and so unlikely to be a significant variable
affecting free oxycodone exposure in the elderly (25). Repetitive bolus simulations suggest that
geriatric individuals have a 20% higher exposure and thus some increased risk of
adverse effects from oxycodone at standard dosage (1). In neonates the clearance rate increases from
birth to 6 months (11) .
Oxycodone use can cause life-threatening or fatal respiratory depression. Risk of
this adverse reaction is greatest at initiation of therapy, following a dose
increase, or due to initiation or cessation of co-medications that alter CYP2D6 or
CYP3A enzyme activities. Accidental ingestion by children can result in respiratory
depression and death following a single dose of oxycodone. Respiratory depression
risk is also elevated for individuals who are elderly, cachectic or debilitated due
to altered pharmacokinetics and drug clearance (1).
Medications that inhibit CYP3A or CYP2D6 enzyme activities will result in an
increased exposure to oxycodone. Notably, CYP3A4 inhibitors such as macrolide
antibiotics, azole-antifungals and protease inhibitors may prolong opioid adverse
reactions. Furthermore, discontinuing a CYP3A inducer—rifampin, carbamazepine, or
phenytoin—can also increase oxycodone exposure. The FDA approved drug label
specifically notes the importance of CYP3A4- associated drug interactions in the
black box warning on the drug label (1).
The FDA recommends monitoring for serotonin syndrome symptoms if concomitant use is
warranted with oxycodone and selective serotonin reuptake inhibitors (SSRIs),
serotonin and norepinephrine reuptake inhibitors (SNRIs), or other drugs that affect
the serotonin neurotransmitter system (1, 26). Furthermore,
the FDA approved label says to discontinue oxycodone if serotonin syndrome is
suspected and advises against the use of oxycodone with monoamine oxidase inhibitors
(MAOIs) or for 14 days following the completion of MAOI therapy (1).
The use of oxycodone during pregnancy can result in opioid withdrawal symptoms in the
neonate, which can be life threatening. There are insufficient data to determine if
oxycodone use during pregnancy leads to increased rates of birth defects or
miscarriages. However, animal studies suggest that the neonate may experience
adverse neurobehavioral effects following in utero exposure. Additionally, data
suggests that oxycodone crosses the placenta and maternal plasma levels correlate
with neonate exposure (1, 11). Chronic opioid use may cause
reduced fertility in both males and females that is potentially irreversible (1).
Opioids are present in breastmilk, though one study estimated that an exclusively
breast-fed infant would receive, at most, 8% of the maternal weight-adjusted dose
(1, 26). However, infants are particularly sensitive
to opioids and are at a significant risk for respiratory depression. As such, other
analgesics are preferred over oxycodone in breastfeeding mothers (26).
Gene: CYP2D6
The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that
form the major system for metabolizing lipids, hormones, toxins, and drugs in the
liver. The CYP450 genes are very polymorphic and can
result in decreased, absent, or increased enzyme activity. CYP2D6 is responsible for
the metabolism of many commonly prescribed drugs, including antidepressants,
antipsychotics, analgesics, and beta-blockers (27).
The CYP2D6 Alleles
The CYP2D6 gene is highly polymorphic, as over 100
star (*) alleles have been described and cataloged at the Pharmacogene Variation
(PharmVar) Consortium, and each allele is associated with either increased,
normal, decreased, or absent enzyme function (). (28)
The combination of CYP2D6 alleles that a person has
is used to determine their diplotype (for example, CYP2D6
*4/*4). Based on their impact on enzyme function, each allele can
be assigned an activity score from 0 to 1, which in turn is then used to assign
a phenotype (for example, CYP2D6 PM). However, the activity score system is not
standardized across all clinical laboratories or CYP2D6 genotyping platforms. The CPIC revised their activity
scoring guidelines in October 2019 to promote harmonization. The CYP2D6
phenotype is predicted from the diplotype activity score defined by the sum of
the allele score values, which usually ranges from 0 to 3.0: (29)
An ultrarapid metabolizer (UM) has an activity score greater than
2.25
A normal metabolizer phenotype (NM) has an activity score of
1.25–2.25
An intermediate metabolizer (IM) has an activity score of
>0–<1.25
A poor metabolizer (PM) has an activity score of 0
Table 1.
Activity Status of Selected CYP2D6
Alleles
View in own window
| Allele type | CYP2D6 alleles | Activity score |
|---|
| Normal function |
*1, *2, *27, *33
| 1 |
| Decreased function |
*17, *41, *49
| 0.5 |
| Strongly decreased function |
*10
| 0.25 |
| No
function |
*3, *4, *5, *6, *36
| 0 |
For a comprehensive list of CYP2D6
alleles, please See PharmVar. Activity scores from (29).
The CYP2D6*1 allele is the wild-type allele when no
variants are detected and is associated with normal enzyme activity and the NM
phenotype. The CYP2D6*2, *27, and *33 alleles are also
considered to have near-normal activity.
Other CYP2D6 alleles include variants that produce
a non-functioning enzyme (for example, *3, *4, *5, and *6) (30, 31, 32, 33) or an enzyme with decreased activity (for
example, *10, *17,
and *41) (34, 35, 36) (see ). There are
large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5, *6, and *41 being more common in individuals with European
ancestry, *17 more common in Africans, and *10 more common in Asians. (37)
Larger structural variants at the CYP2D6 locus have
also been described, including gene duplications, deletions, tandem alleles, and
gene conversions. As one might expect, deletions result in a no-function allele
(for example, the *5 allele is a deletion).
Duplications have been reported for alleles with normal function and decreased
function, as well. In the case of allele duplications, the activity scores for
the full complement of CYP2D6 alleles are summed
to determine the predicted metabolizer phenotype. Additional details on
structural variants are available from PharmVar (38).
The frequency of the CYP2D6 star alleles with
altered function varies across global populations, resulting in different
frequencies of the resulting metabolizer phenotype(s). Given CYP2D6’s role in
metabolism of many drugs, the literature on allele and phenotype frequency is
expansive. Most populations have a high frequency for normal-function star
alleles and thus a high proportion of the population are NMs. However,
reduced-function alleles like CYP2D6*10 are highly
prevalent in east and southeast Asian populations, leading to a higher
proportion of IM phenotype individuals in this ancestral group. Many nations in
sub-Saharan Africa have higher frequencies of decreased-function alleles like
CYP2D6*17 and *29, which can correlate with lower metabolizer scores in these
individuals. More details regarding published allele and phenotype frequencies
are available in the CYP2D6
supplemental chapter.
Pharmacologic Conversion of CYP2D6 Phenotype
Factors other than genotype can affect CYP2D6 enzyme activity and thus the
metabolizer phenotype of any individual. Administration of multiple drugs,
sometimes called polypharmacy or co-medications, can lead to a phenomenon called
phenoconversion whereby an individual with one metabolizer genotype can have the
enzymatic activity of a different metabolizer group (higher or lower, depending
on the medications). The enzymatic activity of CYP2D6 can be inhibited or
reduced by medications including duloxetine, paroxetine, fluoxetine, bupropion,
and quinidine (21, 39, 40, 41). This can result in NMs or IMs responding
to medications as if they were PMs. Thus, co-medication with multiple CYP2D6
strong or moderate inhibitors may result in reduced metabolism of drug
substrates. In contrast, discontinuing a co-medication can increase the rate of
CYP2D6 metabolism.
Other Genes of Note
The CYP3A4 and CYP3A5 Genes
Other cytochrome P450 enzymes are involved in the metabolism of oxycodone. The
CYP3A enzymes, encoded by CYP3A4 and CYP3A5, perform most of the oxycodone metabolism.
Similar to CYP26, the CYP3A enzymes are also susceptible to phenoconversion due
to medications that inhibit or activate these enzymes, as described above.
(1)
Variation at the CYP3A4 locus is relatively
uncommon and CPIC has not assigned a functional status to most variants (28). Although around 40
variant CYP3A4 alleles have been reported, most
have not been shown to alter CYP3A4 activity (42, 43). To date, only 3 loss-of-function CYP3A4 alleles have been identified (CYP3A4*6, CYP3A4*20 and CYP3A4*26) () (44, 45).
The CYP3A4*22 allele has decreased function and
explains 12% of the variation in CYP3A4 activity (46). This variant is present in 3.2–10.6% of
the Dutch population and 5.2–8.3% of the population in America (47). The Allele Frequency
Aggregator project reports this reduced-function allele to be present in
approximately 5% of the global population, with the lowest prevalence in Asian
and African populations (48). The 1000 Genomes Project phase 3 data release estimates global
prevalence to be slightly lower (~1%); a minor allele frequency of 5% is
reported for the European average (49).
The CYP3A4*20 allele has a premature stop codon
that results in a loss-of-function of CYP3A4. It
appears to be the most common CYP3A4-defective
allele but is still relatively rare, with approximately 0.2% of European
Americans and 0.05% African Americans who are heterozygous. However, in Spain,
the CYP3A4*20 allele is present in 1.2% of the
population, and up to 3.8% in specific Spanish regions (44).
Table 2.
Activity Status of Selected CYP3A4
Alleles
View in own window
| Allele type# | CYP3A4 alleles |
|---|
| Normal function |
*1
|
| Decreased function |
*22
|
| No
function | *6, *20,
*26 |
For a comprehensive list of CYP3A4
alleles, please see PharmVar.
#As of the date of
publication, there is no “CPIC Clinical Function” assessment
provided for the CYP3A4 alleles within
PharmVar. The activity status provided here is based on the
literature and historic assessment. In the event of a discrepancy
between the functional classifications provided herein and
PharmVar’s data, the authors defer to PharmVar and CPIC.
The CYP3A5 locus has less than 10 known genetic
variants. The CYP3A5*3, CYP3A5*6, and CYP3A5*7 alleles are
important no-function alleles and the *1 allele is
the normal-function allele () (28). The combination of
alleles present predicts either normal (homozygous *1), intermediate (at least one copy of *1 or compound heterozygous for no-function alleles), or PM
phenotypes (homozygous for a single no-function allele) (50, 51). The PM phenotypes have been seen more
commonly in individuals identified as “White” than African American or Black
(52, 53). The CYP3A5*3 allele has been observed at a high frequency in Egyptian
and Italian populations (54,
55).
Table 3.
Activity Status of Selected CYP3A5
Alleles
View in own window
| Allele type | CYP3A5 alleles |
|---|
| Normal function |
*1
|
| No
function | *3, *6,
*7 |
For a comprehensive list of CYP3A5
alleles, please see PharmVar.
The OPRM1 Gene
The MOR is encoded by the OPRM1 gene. The MOR is a
G-coupled protein receptor and is a key signal transducer for the desired
analgesic effect of opioids such as tramadol and codeine. There are more than
200 known variant alleles of OPRM1, and some
variants have been suggested to have a role in opioid response or predisposition
to opioid use disorders (56,
57). However, CPIC’s
expert review found inconsistent evidence linking any of these alleles to
post-operative dose requirements for some opioids and the effect on morphine
dose adjustment was deemed not to be clinically actionable (2).
The COMT Gene
The catechol-o-methyltransferase (COMT) enzyme is involved in the methylation and
degradation of adrenaline, noradrenaline, and dopamine. This enzyme regulates
the concentration of catecholamines and thus is a key regulator of the pain
perception pathways (58).
The variant rs4680 (p.Val158Met) in COMT has been
suggested to result in decreased levels of methylation activity (2, 58). However, CPIC’s review found variable
evidence associating this variant with analgesia response or opioid dose
requirements and thus makes no recommendations based on COMT genotype (2).
Linking Gene Variation with Treatment Response
Altered CYP2D6 enzyme activity has been associated with altered levels and ratios of
oxycodone, noroxycodone, and oxymorphone levels in the blood; lower CYP2D6 activity
correlated with a decrease in this ratio in plasma and urine (11, 59, 60, 61, 62). However, there are conflicting reports
regarding the associated impact on analgesia or adverse outcomes.
Several studies report improved analgesia, or higher rates of adverse reactions, or
both in individuals with higher levels of CYP2D6 activity. One study in 33 healthy
volunteers reported a modest but significant decrease in analgesic effect of
oxycodone in CYP2D6 PM genotyped individuals in 3 out of 5 tests. Genotyping in this
study was limited to analysis of variants for CYP2D6*3, *4,
*6 and *9 with no detection of
duplication nor deletion; individuals were classified as CYP2D6 PMs if they had 2
no-function alleles based on this limited genotyping. (63) A small study of 10 healthy volunteers
reported a correlation between CYP2D6 activity and oxycodone analgesia, with CYP2D6
UM participants also reporting an increased incidence of negative side effects and
more intense adverse reactions to oxycodone compared with other metabolizer
phenotypes. This group also found inhibition of CYP2D6 by co-medication with
quinidine reduced the peak analgesic effect along with the oxymorphone exposure.
This study genotyped CYP2D6 variation by microarray
and thus reported testing for a total of 32 alleles, including the CYP2D6*5 deletion and duplication of a subset of alleles
(64, 65). A study of 121 post-operative individuals
found a direct correlation between CYP2D6 predicted enzyme activity and
oxymorphone/oxycodone ratio as well as higher oxycodone consumption in CYP2D6 PMs
for 48 hours post-operative self-controlled analgesia, though the pain scores were
similar across metabolizer groups. This study interrogated 8 defined CYP2D6 alleles, including the *5 deletion and gene
duplication (66). Similarly,
Deodhar and colleagues support the phenotypic assessment of CYP2D6 activity when
oxycodone is prescribed for pain management, which could include pharmacogenomics
testing to enable identification of CYP2D6 PMs or evaluation of polypharmacy leading
to phenoconversion or both. (15)
Another recent review suggests that within European populations, individuals who are
CYP2D6 UMs have an increased risk of adverse events and additionally noted the
potential impact of phenoconversion due to CYP2D6 inhibitors, which may reduce
analgesic effect (67).
In contrast, multiple studies suggest the differences in oxymorphone/oxycodone ratios
due to CYP2D6 activity do not impact pain management or other symptoms. A larger
study of 270 individuals who had recently undergone surgical procedures were
genotyped for CYP2D6 and intravenous oxycodone use for 24 hours post-surgery was
monitored. This study found no significant differences in the frequency of oxycodone
non-responders between CYP2D6 PM and other metabolizer phenotypes, nor differences
in average oxycodone consumption between the groups, indicating that CYP2D6
metabolism did not affect oxycodone analgesia even though oxymorphone/oxycodone
ratios were lower in the CYP2D6 PMs group. It should be noted that genotyping in
this study was limited to detection of the *3, *4, *6
and *9 alleles, *5 was
specifically excluded in the analysis and the *1
allele was assigned in the absence of any detected variants (68). A similar study in 450 individuals who were
being treated for cancer pain observed changes in oxymorphone/oxycodone ratios but
no difference in pain intensity, nausea, tiredness nor cognitive function, however
the scope of CYP2D6 genotyping in this study was limited and the *2 duplication, *3, *4, *5, *6,
*7 and *8 alleles were the only alleles
specifically examined (59).
Because of the conflicting and limited evidence for either CYP2D6 metabolizer
phenotypes, COMT function, or OPRM1 function being involved with altered oxycodone
response, both CPIC and DPWG have no recommendations regarding dosing or selection
when oxycodone is considered (2,
3).
As reported by PharmGKB, the Swiss drug labels for oxycodone state that CYP2D6 polymorphism can alter the efficacy of the
medication or lead to undesired effects; “slow” metabolizers (PMs) may experience
weaker analgesia and “ultra-fast” metabolizers (UMs) may have higher analgesia and
increased risk of adverse effects (69).
A large study of urine drug test samples found an association between another member
of the CYP450 family: CYP2C19. The CYP2C19 UMs had a higher oxymorphone/oxycodone
ratio than PMs, like CYP2D6, suggesting that CYP2C19 may play a minor role in
oxycodone metabolism. However, these observations warrant further research to
determine if CYP2C19 genetic variations are associated with oxycodone response
(60).
Genetic variation in the CYP3A4 locus is exceedingly
rare and has not been associated with altered oxycodone analgesia. However, many
reports have stated that induction of CYP3A4 and CYP3A5 by co-medications such as
rifampin and carbamazepine are associated with decreased analgesia, though at least
one report found no effect by co-medication (11, 70).
Drug-drug interactions have been reported to influence treatment responses, most
likely due to enzyme inhibition or induction. Adverse reactions were more common in
elderly individuals taking oxycodone concomitantly with CYP2D6 or CYP3A4 inhibitor
medications (71). Rifampin has
been reported to reduce analgesia from multiple opioid medications, including
oxycodone, though the data is limited (72).
Genetic Testing
Genetic testing is available for many (~30) of the variant CYP2D6 alleles. Usually, an individual’s result is reported as a
diplotype, which includes one maternal and one paternal allele, for example, CYP2D6 *1/*2. When individuals have more than 2 copies of
the CYP2D6 allele, the copies are denoted by an “xN”,
for example, CYP2D6*1/*2x2. Some laboratories also use
the notation of DUP to indicate an increase in copy number. Depending on the testing
methodology and platform used, a laboratory may or may not be able to specify the
number of duplicated CYP2D6 alleles nor the allele that has been duplicated.
Studies in oncology and cardiovascular surgical intervention have estimated that
25–56% of these populations may be prescribed oxycodone or other opioids to manage
pain during their treatment; multiple authors recommend pharmacogenomic testing in
these individuals to optimize management of pain or other symptoms (20, 73, 74).
Genetic tests for oxycodone
response, the CYP2D6 gene, the CYP3A4 gene, and the CYP3A5 gene can be found on the
NIH Genetic Testing Registry (GTR). The available tests include targeted single-gene
tests as well as multi-gene panels or genome-wide sequencing tests.
The test results may include an interpretation of the individual’s predicted
metabolizer phenotype, which can be confirmed by checking the diplotype and
calculating the CYP2D6 activity score, as described in the “CYP2D6 Alleles” section above. Variant CYP2D6 alleles to be included in clinical genotyping assays have been
recommended by the Association for Molecular Pathology (75).
Variants in other genes, such as COMT and OPRM1, may also influence an individual’s response to
oxycodone, though there are no established guidelines for dose alterations or drug
selection based on genetic variation at any of the loci described in this
summary.
Therapeutic Recommendations based on Genotype
This section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor
other parts of this review contain the complete recommendations from the
sources.
2021 Statement from the US Food and Drug Administration (FDA):
Cytochrome P450 3A4 Interaction [drug-drug interactions]
The concomitant use of oxycodone hydrochloride tablets with all cytochrome P450
3A4 inhibitors may result in an increase in oxycodone plasma concentrations,
which could increase or prolong adverse reactions and may cause potentially
fatal respiratory depression. In addition, discontinuation of a concomitantly
used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma
concentration. Monitor patients receiving oxycodone hydrochloride tablets and
any CYP3A4 inhibitor or inducer.
[…]
Drug interactions: Inhibitors of CYP3A4 and CYP2D6, Clinical Impact
[drug-drug interactions]
The concomitant use of oxycodone hydrochloride and CYP3A4 inhibitors can increase
the plasma concentration of oxycodone, resulting in increased or prolonged
opioid effects. These effects could be more pronounced with concomitant use of
oxycodone hydrochloride and CYP2D6 and CYP3A4 inhibitors, particularly when an
inhibitor is added after a stable dose of oxycodone hydrochloride is achieved…
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the
oxycodone plasma concentration will decrease, resulting in decreased opioid
efficacy or a withdrawal syndrome in patients who had developed physical
dependence to oxycodone.
[…]
Drug Interactions: CYP3A Inducers, Clinical Impact [drug-drug
interactions]
The concomitant use of oxycodone hydrochloride and CYP3A4 inducers can decrease
the plasma concentration of oxycodone, resulting in decreased efficacy or onset
of a withdrawal syndrome in patients who have developed physical dependence to
oxycodone. After stopping a CYP3A4 inducer, as the effects of the inducer
decline, the oxycodone plasma concentration will increase, which could increase
or prolong both the therapeutic effects and adverse reactions, and may cause
serious respiratory depression.
[…]
Pharmacokinetics: Metabolism
A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass
metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the
O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is
catalyzed by CYP2D6.
Please review the complete therapeutic recommendations that are located
here: (1).
2021 Statement from the Clinical Pharmacogenetics Implementation Consortium
(CPIC)
There is insufficient evidence and confidence to provide a recommendation to
guide clinical practice at this time for oxycodone or methadone based on CYP2D6 genotype or COMT
genotype or OPRM1 genotype (Tables S5 and S6, no
recommendation, CPIC level C).
Please review the complete therapeutic recommendations that are located
here: (2).
2018 Summary of recommendations from the Dutch Pharmacogenetics Working Group
(DPWG) of the Royal Dutch Association for the Advancement of Pharmacy
(KNMP)
CYP2D6 IM: oxycodone[e]
[and] CYP2D6 PM: oxycodone[e]
NO action is required for this gene-drug interaction.
The reduced conversion of oxycodone to the more active metabolite oxymorphone
does not result in reduced analgesia for patients.
CYP2D6 UM: oxycodone[e]
NO action is required for this gene-drug interaction.
The increased conversion of oxycodone to the more active metabolite oxymorphone
does not result in an increase in side effects in patients.
Please review the complete therapeutic recommendations that are located
here: (3, 4)
Nomenclature for Selected Alleles
Nomenclature of Selected CYP2D6 Alleles
View in own window
-
[1]
CYP2D6*36 is a gene conversion with CYP2D7; variants provided here are from the
Pharmacogene Variation Consortium.
Alleles described in this table are selected based on discussion in the
text above. This is not intended to be an exhaustive description of
known alleles.
Nomenclature of Selected CYP3A4 Alleles
View in own window
CYP3A4*1.001 is the wild-type allele and is
determined to be present with no variants are detected.
Nomenclature of Selected CYP3A5 Alleles
View in own window
CYP3A5*1 is the wild-type allele and is
determined to be present with no variants are detected.
Pharmacogenetic Allele Nomenclature: International Workgroup
Recommendations for Test Result Reporting (76).
Guidelines for the description and nomenclature of gene variations are
available from the Human Genome Variation Society (HGVS).
Nomenclature for Cytochrome P450 enzymes is available from the
Pharmacogene Variation (PharmVar)
Consortium; the authors defer to that authority with regards to any
discrepancies in allele definitions.
Acknowledgments
The author would like to thank Natalie Reizine, MD, Assistant Professor of Medicine,
University of Illinois Cancer Center, Chicago, IL, USA; Aidan Hampson, PhD, National
Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA; and Houda
Hachad, PharmD., M. Res, Vice President of Clinical Operations, AccessDx, Seattle,
WA, USA for reviewing this summary.
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-
1
The FDA labels specific drug formulations. We have
substituted the generic names for any drug labels in this excerpt. The FDA
may not have labeled all formulations containing the generic drug. Certain
terms, genes and genetic variants may be corrected in accordance to
nomenclature standards, where necessary. We have given the full name of
abbreviations, shown in square brackets, where necessary.
1.