Introduction
Tramadol (brand names ConZip, Ultram, UltramER, Odolo) is an analgesic used to treat
moderate to severe pain. It is used for a variety of pain conditions, including
post-operative pain, cancer pain, and musculoskeletal pain. Tramadol is a centrally
acting opioid analgesic with mu-opioid binding activity as well as weak inhibition
of reuptake of norepinephrine and serotonin.
The CYP2D6 enzyme converts tramadol to the active metabolite, O-desmethyltramadol
(M1), which has a significantly higher affinity for the mu-opioid receptor than
tramadol. The M1 metabolite is up to 6 times more potent than tramadol in producing
analgesia.
Individuals who have reduced CYP2D6 activity are known as “intermediate metabolizers”
and those with absent CYP2D6 activity are known as “poor metabolizers.” The standard
recommended doses of tramadol may not provide adequate pain relief in these
individuals because of reduced levels of M1. Whereas in individuals who have
increased CYP2D6 activity (“ultrarapid metabolizers”), standard doses of tramadol
may result in a higher risk of adverse events because of increased exposure to
M1.
The 2021 FDA-approved drug label warns that individuals who are ultrarapid
metabolizers (UMs) should not use tramadol because of the risk of life-threatening
respiratory depression and signs of opiate overdose (for example, extreme
sleepiness, confusion, or shallow breathing) (Table 1) (1).
The prevalence of CYP2D6 UM varies but is thought to be present in approximately
1–10% of Caucasians (European, North American), 3–4% of Blacks (African Americans),
and 1–2% of East Asians (Chinese, Japanese, Korean). The frequency of UM phenotype
has been reported to be even higher in some groups, including Ashkenazi Jews and
regional populations in the Middle East.
Furthermore, tramadol is not recommended in nursing mothers due to the potential
exposure to high levels of M1 causing life-threatening respiratory depression, if
the mother is a UM. At least one death was reported in a nursing infant who was
exposed to high levels of morphine in breast milk because the mother was an UM of
codeine, which—similar to tramadol—is activated by CYP2D6 metabolism.
Tramadol is contraindicated for all children younger than age 12 and for all
individuals under the age of 18 when being used for post-operative analgesia
following tonsillectomy or adenoidectomy, or both. The label warns that
life-threatening respiratory depression and death have occurred in children who
received tramadol, and in at least one case, the child was an UM of tramadol.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an
individual identified as a CYP2D6 UM, a different non-CYP2D6 dependent analgesic
should be used to avoid the risk of severe toxicity with standard dosing of
tramadol. The CPIC also recommends avoiding tramadol in individuals identified as
CYP2D6 poor metabolizers (PMs) due to the possibility of lack of effect (Table 2)
(2).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for
the Advancement of Pharmacy (KNMP) provides dosing recommendations for tramadol
based on CYP2D6 genotype (Table 3). The DPWG states
it is not possible to calculate a dose adjustment for tramadol, because when the
ratio of tramadol and M1 is altered, the nature and total analgesic effect of
tramadol also changes. For CYP2D6 UM, DPWG recommends selecting an alternative drug
to tramadol - but not codeine, which is also metabolized by CYP2D6. Alternative
drugs include morphine (not metabolized by CYP2D6) and oxycodone (which is
metabolized by CYP2D6 to a limited extent, but this does not result in differences
in side effects in clinical practice). For CYP2D6 poor (PM) and intermediate
metabolizers (IM), DPWG recommends increasing the dose of tramadol, and if this does
not have the desired effect, selecting an alternative drug (not codeine) (Table 3)
(3).
Table 1.
The FDA Tramadol Dosing Recommendation based on CYP2D6 Genotype (2021)
View in own window
| CYP2D6
ultrarapid metabolizers |
|---|
| All
ultrarapid metabolizer individuals | Some individuals may
be ultrarapid metabolizers because of a specific CYP2D6 genotype. These
individuals convert tramadol into its active metabolite,
O-desmethyltramadol (M1), more rapidly and completely than other people.
This rapid conversion results in higher than expected serum M1 levels.
Even at labeled dosage regimens, individuals who are ultrarapid
metabolizers may have life-threatening or fatal respiratory depression
or experience signs of overdose (such as extreme sleepiness, confusion,
or shallow breathing). Therefore, individuals who are ultrarapid
metabolizers should not use tramadol hydrochloride tablets. |
| Ultrarapid
metabolizer children | Life-threatening
respiratory depression and death have occurred in children who received
tramadol. Some of the reported cases followed tonsillectomy or
adenoidectomy, or both; in at least one case, the child had evidence of
being an ultrarapid metabolizer of tramadol due to a CYP2D6
polymorphism. Tramadol hydrochloride is contraindicated in children
younger than 12 years of age and in children younger than 18 years of
age following tonsillectomy or adenoidectomy, or both. Avoid the use of
tramadol hydrochloride tablets in adolescents 12–18 years of age who
have other risk factors that may increase their sensitivity to the
respiratory depressant effects of tramadol |
| Infants
nursing from ultrarapid metabolizer mothers | Tramadol is subject to
the same polymorphic metabolism as codeine, with ultrarapid metabolizers
of CYP2D6 substrates being potentially exposed to life-threatening
levels of the active metabolite O-desmethyltramadol (M1). At least one
death was reported in a nursing infant who was exposed to high levels of
morphine in breast milk because the mother was an ultrarapid metabolizer
of codeine. A baby nursing from an ultrarapid metabolizer mother taking
tramadol hydrochloride tablets could potentially be exposed to high
levels of M1, and experience life-threatening respiratory depression.
For this reason, breastfeeding is not recommended during treatment with
tramadol hydrochloride tablets. |
Table 2.
The CPIC Tramadol Therapy Recommendations Based on CYP2D6 Phenotype (2021)
View in own window
| Phenotypea | Activity
scoreb | Implications | Genotype | Examples
of diplotypesb | Recommendations for tramadol therapyd |
|---|
| Ultrarapid
metabolizer | > 2.25 | Increased formation of
O-desmethyltramadol (active metabolite) leading to higher risk of
toxicity | More than 2 copies of
normal-function alleles |
*1/*1xNc
*1/*2xN
| Avoid tramadol use
because of potential for toxicity. If opioid use is warranted, consider
a non-codeine opioid. |
| Normal
metabolizer | 1.25–2.25* | Expected
O-desmethyltramadol (active metabolite) formation | 2 normal-function
alleles, or one normal-function allele and one decreased-function
allele, or combinations of duplicated alleles that result in an activity
score of 1.25–2.25 |
*1/*10
*1/*41
*1/*9
*10/*41x3
*1/*1
*1/*2
*2x2/*10
| Use tramadol
label-recommended age- or weight-specific dosing. |
| Intermediate metabolizer | 0.25–1* | Reduced O-
desmethyltramadol (active metabolite) formation. | One decreased-function
allele and one no-function allele, or 2 decreased-function alleles |
*4/*10
*4/*41
*10/*10
*10/*41
*41/*41
*1/*5
| Use tramadol
label-recommended age or weight-specific dosing. If no response and
opioid use is warranted, consider a non-codeine opioid |
| Poor
metabolizer | 0 | Greatly reduced
O-desmethyltramadol (active metabolite) formation leading to diminished
analgesia. | 2 no-function
alleles |
*3/*4
*4/*4
*5/*5
*5/*6
| Avoid tramadol use
because of possibility of diminished analgesia. If opioid use is
warranted, consider a non-codeine option. |
| Indeterminant metabolizer | n/a | n/a | An individual having
one or 2 uncertain-function alleles |
*1/*22
*1/*25
*22/*25
| No recommendation |
-
a
See the CYP2D6 Frequency Table for
race-specific allele and phenotype frequencies from PharmGKB and CPIC.
-
b
Assignment of allele function and allele activity values including citations
for allele function can be found at
PharmGKB (CYP2D6 Allele
Definition Table and CYP2D6 Allele
Functionality Table) and CPIC.
For a complete list of CYP2D6 diplotypes and
resulting phenotypes, see the CYP2D6 Genotype
to Phenotype Table at PharmGKB and CPIC.
-
C
Where xN represents the number of CYP2D6 gene
copies. For individuals with CYP2D6
duplications or multiplications, see supplemental data in (2) for additional
information on how to translate diplotypes into phenotypes.
-
d
The strength of therapeutic recommendations is “moderate” for intermediate
metabolizers, and “strong” for all other metabolizers.
Table is adapted from (2).
Table 3.
The DPWG Recommendations for Tramadol Dosing based on CYP2D6 Phenotype (2017)
View in own window
| CYP2D6
phenotype | Dosing
recommendations |
|---|
Poor
metabolizer
(gene dose 0, absent enzyme activity) | It is not possible to
provide a recommendation for dose adjustment, because the total
analgesic effect changes when the ratio between the mother compound and
the active metabolite changes. - 1.
be alert to a reduced
effectiveness - 2.
in
the case of inadequate effectiveness: - 3.
if
no alternative is selected: advise the individual to report
inadequate analgesia
|
Intermediate
metabolizer
(gene dose 0.5-1, decreased enzyme activity) |
Ultrarapid
metabolizer
(gene dose ≥ 3)
(enhanced enzyme
activity) | As the total analgesic
effect changes when the ratio between the mother compound and the active
metabolite changes, the effect of a dose reduction cannot be predicted
with certainty. - 1.
select an
alternative* - 2.
if an
alternative is not possible: use 40% of the standard
dose advise the individual
to report side effects (such as drowsiness,
confusion, constipation, nausea and vomiting,
respiratory depression or urine
retention).
|
- *
Do not select codeine, as this is also metabolized by CYP2D6. Morphine is not
metabolized by CYP2D6. Oxycodone is metabolized by CYP2D6 to a limited
extent, but this does not result in differences in analgesia and side
effects in clinical practice.
This table is adapted from (3).
Drug: Tramadol
Tramadol is a synthetic opioid used to treat moderate to severe pain. Tramadol is
used for both acute and chronic pain, and is commonly prescribed for post-operative
pain, pain caused by cancer, and musculoskeletal pain. In the USA, tramadol is
classified as a Schedule IV controlled substance (1, 4). Drugs and other substances that are considered controlled substances
under the Controlled Substances Act (CSA) are divided into 5 schedules based on
whether they have an accepted medical indication and the potential for abuse or
addiction. Schedule II drugs have a high potential for abuse that may lead to severe
psychological or physical dependence, and schedule III have a lower potential for
abuse. Schedule IV drugs have even further reduced potential for abuse relative to
schedule III. (5)
Tramadol is structurally similar to codeine and morphine. Opioid prescriptions are
common in the USA. One study estimated that between 2011 and 2012, nearly 7% of the
adult population had taken an opioid in the 30 days before participation in the
study (6). Opioid prescribing
rates peaked in the USA in 2012, with over 255 million prescriptions annually and a
prescribing rate of 81.3 prescriptions per 100 persons. Prescribing rates have
consistently declined and in 2018, 51.4 prescriptions were written per 100 persons.
(7)
As an opioid, tramadol is relatively weak. However, it is thought to have a unique
mechanism of action involving different targets. Tramadol is administered as a
racemic mixture of 2 enantiomers, (+) tramadol and (-) tramadol, which inhibit pain
transmission at the spinal cord by inhibiting serotonin reuptake (+ tramadol) and
noradrenaline reuptake (- tramadol). (2)
Both tramadol and its major active metabolite, M1, bind to the mu-opioid receptor.
However, M1 has a significantly higher affinity (approximately 200 times greater)
for the opioid receptor than tramadol and is thus more potent at providing
analgesia. However, tramadol and its metabolites are proposed to exert their
antinociceptive effect via a multimodal mechanism that includes serotonin and
norepinephrine reuptake inhibition, as well as binding to the mu-opioid receptor.
(8, 9, 10, 11, 12, 13)
Tramadol requires bioactivation in the liver to be converted to M1 and exert its full
analgesic effect. This process is primarily mediated by the CYP2D6 enzyme, and the
level of activity of the CYP2D6 enzyme influences the plasma concentration of M1.
Other CYP enzymes (CYP2B6 and CYP3A4) catalyze the production of N-desmethyl
tramadol (M2), an inactive metabolite (14). Other enzymes are involved in further metabolism, pharmacokinetics
and pharmacodynamics of tramadol, but the clinical relevance of variants in those
genes has yet to be determined (15).
Adverse effects of tramadol therapy include dizziness, nausea, constipation, and
headache. Owing to its effects on serotonin and norepinephrine reuptake, additional
risks of tramadol therapy include the risk of seizures, suicidal tendencies, and
serotonin syndrome. Seizure risk is especially notable in individuals who are
already taking antidepressants or other drugs that decrease the seizure threshold.
There is also an increased risk of suicide, therefore tramadol should not be
prescribed for individuals who are suicidal or prone to addictions—the use of
non-narcotic analgesics should be considered instead (1). Serotonin syndrome is a potentially
life-threatening syndrome that may occur with the use of tramadol, especially if
other serotonergic medications such as antidepressants (selective serotonin reuptake
inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic
antidepressants) or other drugs that impair the metabolism of tramadol are used
concurrently (for example, CYP2D6 and CYP3A4 inhibitors such as amiodarone,
quinidine, erythromycin, or ritonavir). Symptoms of serotonin syndrome can variably
include changes in mental status (for example, agitation, hallucinations, coma),
autonomic instability (for example, tachycardia, labile blood pressure,
hyperthermia), neuromuscular aberrations (such as hyperreflexia, incoordination) and
gastrointestinal symptoms (for example, nausea, vomiting, diarrhea) (1, 16).
Because tramadol has mu-opioid agonist activity, there is a risk of abuse and
addiction, even under appropriate medical use. Therefore, as for all individuals
treated with opioids, there should be careful monitoring of individuals taking
tramadol. The longer an individual is on continuous tramadol therapy, the greater
the risk of tolerance (the need to increase the dose of drug to maintain a defined
level of analgesia in the absence of disease progression). Physical dependence upon
tramadol is manifested by withdrawal symptoms after the use of tramadol is stopped
abruptly. Symptoms include restlessness, rhinorrhea, lacrimation, and chills (1, 12). Concomitant medication with benzodiazepines or
other CNS depressants is also discouraged due to the heightened risk of profound
sedation, respiratory depression, coma, and death. Consider naloxone or
nalmefene—opioid antagonists—prescription for emergency treatment of opioid overdose
causing respiratory depression, but be aware that naloxone administration may
increase the risk of seizure (1).
The drug label warns that women of reproductive age should be informed that tramadol
can cause fetal harm, and women should inform their healthcare provider if they
suspect or know they are pregnant. The prolonged use of tramadol during pregnancy
can result in neonatal opioid withdrawal syndrome, which may be life threatening if
not recognized and treated. The signs are diverse, and include feeding difficulties,
breathing problems, and seizures. Additionally, chronic use of opioids can reduce
fertility in both females and males of reproductive potential; these effects may or
may not be reversible (1).
Breastfeeding is not recommended during tramadol treatment (1, 17).
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.
The CYP2D6 enzyme is responsible for the metabolism of many commonly prescribed
drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers
(18).
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 normal,
decreased, or absent enzyme function (Table 4). (19)
The combination of CYP2D6 alleles that a person has
is used to determine their diplotype (for example, CYP2D6
*4/*4). Based on function, each allele can be assigned an activity
score from 0 to 1, which in turn is often 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 defined by the
sum of the 2 activity scores, which is usually in the range of 0 to 3.0: (20)
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 4.
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 (20).
The CYP2D6*1 allele is the wild-type allele when no
variants are detected and is associated with normal enzyme activity and the
“normal metabolizer” 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) (21, 22, 23, 24) or an enzyme with decreased activity (for
example, *10, *17,
and *41) (25, 26, 27) (see
Table
4). 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.
(28)
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.
Allele Frequencies Vary between Populations
Among Asians and in individuals of Asian descent, only approximately 50% of
CYPD6 alleles are of normal function, and the
frequency of CYP2D6 duplications is as high as
45%, although this may have been overestimated by not accounting for tandem
hybrid alleles (for example, *36+*10). (29) Other studies on a USA
population suggested less than 50% of alleles detected within Asian-descent
individuals are normal-function alleles in a single copy, with 30% of alleles
arising from structural variants (duplications or deletions). (30) Common no-function variants
are CYP2D6*36 and CYP2D6*4. (30)
Both these alleles contain the variant “c.100C>T”, which if present alone,
results in CYP2D6*10 (see Nomenclature table). (28, 29, 31, 32) The
CYP2D6*36 allele is the result of a gene
conversion event with the pseudogene CYP2D7 (33). This no-function allele is
most commonly found in individuals of Asian ancestry (30).
Among Africans and African Americans, only approximately 50% of CYP2D6 alleles are normal function. (21, 27, 28, 34) African
Americans also have been found to have a higher frequency of no-function
structural variants or decreased-function single-copy variant alleles versus
Caucasian or Hispanic Americans. (30)
Middle-Eastern countries show a great diversity in phenotypic and allelic
distribution for CYP2D6 (35), though on average, these individuals show
a lower frequency of PM phenotypes (0.91%) and higher ultrarapid phenotypes
(11.2%) than other ethnicities (Note: Oceania and Middle-Eastern ethnicities are
combined in this study). (36)
Among European countries, there is diversity of allelic distribution. Gene
duplications were more common in the south-eastern countries (Greece, Turkey:
6%) and less common in northern countries (Sweden and Denmark, <1%).
Meanwhile, CYP2D6*4 and CYP2D6*5 alleles were more common in the north and less common in
the south. (37) Worldwide
CYP2D6 genotype and phenotype frequencies have
been catalogued and recently published (36).
CYP2D6 Phenotype
CYP2D6 Phenotype Frequencies Vary between
Populations
Normal metabolizers: Between 43–67% of individuals have 2 normal-function alleles
(*1 or *2), or
one normal-function allele and one decreased-function allele, resulting in a
“normal metabolizer” phenotype based on the CPIC/PharmGKB activity scores (38). These individuals are most
likely to have a phenotypically normal response to tramadol. However, there is a
large amount of variability in tramadol response within individuals genotyped as
normal metabolizers (NMs), and the causes of this variation, among individuals
with the same diplotype, are unknown. (39)
Intermediate metabolizers: Between 10–44% of individuals are IMs—they have either
2 decreased-function alleles or one normal- or decreased-function and one
no-function allele. (36,
38) These individuals may
not respond as well to tramadol because the metabolism of tramadol to M1 is
reduced. A study of a diverse USA urban population of children found that
roughly 8% of subjects were IMs, though this may be higher due to the broader
range for IM activity scores. (40) Within the USA, it has been observed that individuals of African
or Asian descent were most likely to be classified as IMs (20–28% of population
by ethnicity). (30)
Similarly, PharmGKB reports that the highest frequency of IM activity scores are
found in Sub-Saharan-African and East-Asian populations (38).
Poor metabolizers: Between 0.4–6.5% of individuals are PMs—they have 2
no-function alleles. (38,
41) In these individuals,
tramadol will provide little or no pain relief. Poor metabolizers are more
commonly found in European Caucasians and their descendants. The no-function
CYP2D6*4 and *5
alleles largely account for the PM phenotype in these populations (23, 26, 42). It should be noted that the frequency of PMs can be much lower
in certain populations including East Asian, Oceania and Middle-Eastern (36). Studies of USA
multi-ethnic populations have estimated the prevalence of PMs to be between
1.5–5.7% (30, 40).
Ultrarapid metabolizers: Individuals who are UMs have an enzyme activity score
greater than 2.25, often due to an increased copy number of the CYP2D6 gene. The UM phenotype has been estimated to be
present in 1–2% of individuals, but the prevalence varies widely in different
populations. It is estimated to be present in up to 28% of North Africans,
Ethiopians, and Arabs; up to 10% in Caucasians; 3% in African Americans, and up
to 1% in Hispanics, Chinese, and Japanese (41, 43). PharmGKB reports that the Oceanian population has the highest
prevalence of UM phenotype (38). Ultrarapid metabolizers made up 9% of subjects in an urban
multi-ethnic population with a large portion of Hispanic/Latino subjects (40). A larger study of USA
individuals predicted an UM phenotype in only 2.2% of individuals, regardless of
ethnicity (30).
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-medication, can lead to a phenomenon called
phenoconversion whereby an individual with one metabolizer genotype can have
enzymatic activity of a different metabolizer group (higher or lower, depending
on the medications). Enzymatic activity of CYP2D6 can be inhibited or reduced by
medications including duloxetine, paroxetine, fluoxetine, bupropion, amiodarone
(note: this is a weak inhibitor), and quinidine (43, 44, 45, 46). This can result in NMs or
IMs responding to medications as if they were PMs. Thus, co-medication with
multiple CYP2D6 substrates may result in reduced metabolism of these drugs. In
the case of tramadol, this may present as reduced analgesic effect. In contrast,
discontinuing a co-medication can increase the rate of CYP2D6 metabolism to the
genotype predicted activity level.
Other Genes of Note
OPRM1
The mu-opioid receptor is encoded by the OPRM1
gene. The mu-opioid receptor 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 (47, 48). 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).
COMT
Catechol-o-methyltransferase (COMT) is an enzyme 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 (49). The
variant rs4680 (p.Val158Met) in COMT has been
suggested to result in decreased levels of methylation activity (2, 49). 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).
CYP2B6 and CYP3A4/5
Other cytochrome P450 enzymes are involved in the metabolism of tramadol. The
formation of the inactive metabolite M2 is mediated by CYP3A4 and CYP2B6.
Variants leading to reduced function of these enzymes may lead to increased
levels of tramadol, though there are no specific prescribing recommendations
based on the presence of these alleles. (11, 50)
Linking Gene Variation with Treatment Response
It has been established that genetic variation in the CYP2D6 gene can be responsible for the variability in CYP2D6 enzyme
expression, and consequently, for variability in an individual’s analgesic response
to tramadol. Individuals with normal levels of CYP2D6 activity (“CYP2D6 normal
metabolizers”) are mostly likely to benefit from tramadol therapy (51).
The standard recommended doses of tramadol may lead to severe adverse effects in
individuals who have increased CYP2D6 activity. In these individuals, tramadol is
converted to M1 more rapidly and completely, leading to higher than expected levels
of M1 and a higher risk of adverse events. In contrast, individuals who have absent
CYP2D6 enzyme activity may have little analgesic effect from standard doses of
tramadol and may request a stronger opioid. This is not drug seeking; this is an
inability to benefit from tramadol therapy because of an inability to produce
adequate levels of M1.
Therefore, clinicians should consider CYP2D6 testing in individuals who either have a
minimal response to standard doses of tramadol (possible CYP2D6 PMs), or who have
unexpected adverse effects (possible CYP2D6 UMs) (48, 52, 53). Several
studies have investigated the feasibility and impact of pharmacogenetic testing for
CYP2D6 variation and have concluded that—in
multiple care settings—this is both feasible and has the potential to improve pain
management while decreasing adverse reactions (45, 54, 55, 56).
Tramadol should not be used in individuals with increased CYP2D6 activity. Even at
labeled dosage regimens, individuals (especially children) may have life-threatening
or fatal respiratory depression, or experience the signs of opiate overdose, such as
extreme sleepiness, confusion, and shallow breathing.
There have been several cases of respiratory depression and death of children who
have received tramadol. A case report describes a child with the CYP2D6 ultrarapid genotype, who had severe respiratory
depression after taking tramadol for pain relief following a tonsillectomy, a day
case procedure (57, 58, 59).
Because of the risks of respiratory depression, tramadol is contraindicated for all
children younger than age 12 years of age and is contraindicated in children of any
age undergoing tonsillectomy or adenoidectomy, or both. Tramadol should also be
avoided in children who are obese, have obstructive sleep apnea, have severe lung
disease, or any other risk factors that may increase their sensitivity to the
respiratory depressant effects of tramadol. This warning is similar to the drug
label warning for codeine - a
structurally similar opioid that is also bioactivated by CYP2D6.
For CYP2D6 intermediate and PMs, an increased dose of tramadol may be required.
Alternatively, a different analgesic (a non-CYP2D6-dependent opioid or a non opioid)
may be more appropriate. However, codeine as well as hydrocodone are not suitable
alternatives to tramadol because they are also metabolized by CYP2D6. Oxycodone is
to a lesser degree metabolized by CYP2D6 (it is primarily metabolized by CYP3A4),
but neither the CPIC nor the DPWG find sufficient evidence to support a CYP2D6 genotype correlation with altered analgesia or side
effects, thus oxycodone can be considered as an alternate opioid. Opioids that are
not primarily metabolized by CYP2D6 include morphine, oxymorphone, buprenorphine,
fentanyl, methadone, and hydromorphone. (6, 12, 48, 60, 61, 62, 63, 64, 65, 66, 67, 68)
The enzymatic activity of CYP2D6 can also be affected by co-medications. The
FDA-approved drug label does not specifically recommend adjusting dosage, but
encourages close monitoring of individuals taking CYP2D6 inhibitors. (1) One recent study reported a
higher incidence of breakthrough pain requiring additional medication in the
hospital setting for tramadol individuals also taking fluoxetine and bupropion
(69).
The CYP2D6 Gene Interactions with Medications Used
for Additional Indications
The CYP family of enzymes is involved in metabolism of many substances and CYP2D6
especially has been implicated in altered pharmacologic responses for many
compounds. The drugs can be categorized into many different classes:
Antipsychotics—for example, aripiprazole, risperidone, thioridazine and—to a
lesser extent—clozapine is metabolized by CYP2D6. According to the FDA,
aripiprazole dosage should be reduced for PMs and thioridazine is
contraindicated for individuals who are known to have reduced CYP2D6
activity due to increased risk of potentially fatal side effects. Ultrarapid
metabolizers may have a decreased plasma concentration of risperidone.
Tricyclic antidepressants—for example, amitriptyline, and imipramine may
require dosage adjustments, potentially guided by therapeutic drug
monitoring, to achieve the desired therapeutic range in UMs or PMs.
Ultimately, tricyclic antidepressants may be ineffective in CYP2D6 UMs
Serotonin and norepinephrine reuptake inhibitors—for example atomoxetine and
venlafaxine may have reduced efficacy in UMs at standard doses while PMs are
at risk of elevated plasma concentrations for both medications. The DPWG
advises against use of venlafaxine in CYP2D6 PMs and IMs.
Cardiovascular dysfunction—for example, carvedilol, metoprolol, and
propafenone are all metabolized by CYP2D6 and PMs will have higher plasma
concentrations of these medications compared with NMs resulting in
potentially undesired side effects or (in the case of metoprolol) extensive
slowing of the heart rate.
Anti-cancer medications—for example, tamoxifen is activated by CYP2D6 and IMs
or PMs may have reduced benefit from tamoxifen therapy.
Various therapies for genetic disorders—for example eliglustat used in the
treatment of Gaucher disease, and deutetrabenazine used in the treatment of
Huntington disease—have reduced dose recommendations for CYP2D6 PMs. The
CYP2D6 UMs may not achieve adequate concentrations of eliglustat and
therefore CYP2D6 genotyping is required before initiation of eliglustat
therapy.
It is important to note that CYP2D6 is the most common
biomarker in drug responses for FDA drug labels, the list provided here is by no
means exhaustive. Additional information on gene-drug interactions for CYP2D6 are available from PharmGKB, CPIC and the FDA (search for “CYP2D6”).
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, the copies of the allele 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, but the report
does not specify the number of duplications nor the allele that has been
duplicated.
Genetic tests for tramadol
response and the CYP2D6 gene can be found on the
NIH Genetic Testing Registry. The available CYP2D6 tests include targeted
single-gene tests as well as multi-gene panels or genome-wide sequencing tests. In
addition, variant CYP2D6 alleles to be included in
clinical genotyping assays have been recommended by the Association for Molecular
Pathology (70).
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.
Variants in other genes, such as COMT, ABCB1, UGT2B7 and OPRM1, may also influence an individual’s response to
tramadol. However, evidence is lacking on whether genetic testing for these variants
will aid optimum dosing. (71,
72, 73, 74)
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):
Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for
Life-threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who
received tramadol. Tramadol and codeine are subject to variability in metabolism
based upon CYP2D6 genotype (described below), which can lead to increased
exposure to an active metabolite. Based upon post-marketing reports with
tramadol or with codeine, children younger than 12 years of age may be more
susceptible to the respiratory depressant effects of tramadol. Furthermore,
children with obstructive sleep apnea who are treated with opioids for
post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to
their respiratory depressant effect. Because of the risk of life-threatening
respiratory depression and death:
Tramadol hydrochloride extended-release tablets are contraindicated for
all children younger than 12 years of age.
Tramadol hydrochloride extended-release tablets are contraindicated for
post-operative management in pediatric patients younger than 18 years of
age following tonsillectomy and/or adenoidectomy.
Avoid the use of tramadol hydrochloride extended-release tablets in
adolescents 12 to 18 years of age who have other risk factors that may
increase their sensitivity to the respiratory depressant effects of
tramadol unless the benefits outweigh the risks. Risk factors include
conditions associated with hypoventilation, such as postoperative
status, obstructive sleep apnea, obesity, severe pulmonary disease,
neuromuscular disease, and concomitant use of other medications that
cause respiratory depression.
As with adults, when prescribing opioids for adolescents, healthcare
providers should choose the lowest effective dose for the shortest
period of time and inform patients and caregivers about these risks and
the signs of opioid overdose.
Nursing Mothers
Tramadol is subject to the same polymorphic metabolism as codeine, with
ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to
life-threatening levels of the active metabolite O-desmethyltramadol (M1). At
least one death was reported in a nursing infant who was exposed to high levels
of morphine in breast milk because the mother was an ultra-rapid metabolizer of
codeine. A baby nursing from an ultra-rapid metabolizer mother taking tramadol
hydrochloride [extended-release] tablets could potentially be exposed to high
levels of M1, and experience life-threatening respiratory depression. For this
reason, breastfeeding is not recommended during treatment with tramadol
hydrochloride extended-release tablets.
CYP2D6 Genetic Variability: Ultra-rapid
metabolizer
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as
*1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and
has been estimated at 1 to 10% for Whites (European, North American), 3 to 4%
for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese,
Korean), and may be greater than 10% in certain racial/ethnic groups (i.e.,
Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These
individuals convert tramadol into its active metabolite, O-desmethyltramadol
(M1), more rapidly and completely than other people. This rapid conversion
results in higher than expected serum M1 levels. Even at labeled dosage
regimens, individuals who are ultra-rapid metabolizers may have life-threatening
or fatal respiratory depression or experience signs of overdose (such as extreme
sleepiness, confusion, or shallow breathing). Therefore, individuals who are
ultra-rapid metabolizers should not use tramadol hydrochloride tablets.
[…]
Drug Interactions
Inhibitors of CYP2D6:
Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP2D6
inhibitors may result in an increase in the plasma concentration of tramadol and
a decrease in the plasma concentration of M1, particularly when an inhibitor is
added after a stable dose of tramadol hydrochloride tablets is achieved. Since
M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in
decreased therapeutic effects, and may result in signs and symptoms of opioid
withdrawal in patients who had developed physical dependence to tramadol.
Increased tramadol exposure can result in increased or prolonged therapeutic
effects and increased risk for serious adverse events including seizures and
serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the
inhibitor decline, the tramadol plasma concentration will decrease and the M1
plasma concentration will increase. This could increase or prolong therapeutic
effects but also increase adverse reactions related to opioid toxicity, such as
potentially fatal respiratory depression.
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow
patients closely for adverse reactions including opioid withdrawal, seizures and
serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering
tramadol hydrochloride tablets dosage until stable drug effects are achieved.
Follow patients closely for adverse events including respiratory depression and
sedation.
Examples: Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4:
Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4
inhibitors can increase the plasma concentration of tramadol and may result in a
greater amount of metabolism via CYP2D6 and greater levels of M1. Follow
patients closely for increased risk of serious adverse events including seizures
and serotonin syndrome, and adverse reactions related to opioid toxicity
including potentially fatal respiratory depression, particularly when an
inhibitor is added after a stable dose of tramadol hydrochloride tablets is
achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor
decline, the tramadol plasma concentration will decrease, resulting in decreased
opioid efficacy or a withdrawal syndrome in patients who had developed physical
dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of
tramadol hydrochloride tablets until stable drug effects are achieved. Follow
patients closely for seizures and serotonin syndrome, and signs of respiratory
depression and sedation at frequent intervals. If a CYP3A4 inhibitor is
discontinued, consider increasing the tramadol hydrochloride tablets dosage
until stable drug effects are achieved and follow patients for signs and
symptoms of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents
(e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers:
Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4
inducers can decrease the plasma concentration of tramadol, resulting in
decreased efficacy or onset of a withdrawal syndrome in patients who have
developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as
the effects of the inducer decline, the tramadol plasma concentration will
increase, which could increase or prolong both the therapeutic effects and
adverse reactions, and may cause seizures, serotonin syndrome, and/or
potentially fatal respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the tramadol
hydrochloride tablets dosage until stable drug effects are achieved. Follow
patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued,
consider tramadol hydrochloride tablets dosage reduction and monitor for
seizures and serotonin syndrome, and signs of sedation and respiratory
depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a
significantly reduced analgesic effect of tramadol. Because carbamazepine
increases tramadol metabolism and because of the seizure risk associated with
tramadol, concomitant administration of tramadol hydrochloride tablets and
carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin
[….]
Special populations: Poor/Extensive Metabolizers, CYP2D6
The formation of the active metabolite of tramadol, M1, is mediated by CYP2D6, a
polymorphic enzyme. Approximately 7% of the population has reduced activity of
the CYP2D6 isoenzyme of cytochrome P450 metabolizing enzyme system. These
individuals are “poor metabolizers” of debrisoquine, dextromethorphan and
tricyclic antidepressants, among other drugs. Based on a population PK analysis
of Phase 1 studies with IR tablets in healthy subjects, concentrations of
tramadol were approximately 20% higher in “poor metabolizers” versus “extensive
metabolizers,” while M1 concentrations were 40% lower.
Please review the complete therapeutic recommendations that are located
here: (1).
2020 Statement from the Clinical Pharmacogenetics Implementation Consortium
(CPIC)
For CYP2D6 normal metabolizers (i.e. CYP2D6 activity score 1.25 to 2.25), a label
recommended age- or weight-specific starting dose of codeine or tramadol, as
recommended in the product label, is warranted. A label recommended starting
dosing is also recommended for intermediate metabolizers (i.e. activity score of
0.25 to 1); these patients should be monitored closely for less than optimal
response and should be offered an alternative analgesic if warranted. For CYP2D6
poor metabolizers (i.e. activity score of 0), current evidence supports the
avoidance of codeine and tramadol and the use of an alternative analgesics due
to the likelihood of suboptimal or lack of effect. There is insufficient
evidence in the literature to recommend a higher dose of codeine or tramadol in
poor metabolizers, especially considering the evidence that some adverse events
do not differ between poor and normal metabolizers (19). For CYP2D6 ultrarapid metabolizers
(namely, activity score of >2.25), codeine or tramadol should not be used, in
order to avoid the risk of severe toxicity with label-recommended dosing.
Non-opioid analgesics and if needed, other opioids that are not affected by
CYP2D6 phenotype, are potential alternatives for use in CYP2D6 poor and
ultrarapid metabolizers based on the type, severity and chronicity of the pain
being treated.
Please review the complete therapeutic recommendations that are located
here: (2, 39).
2017 Summary of recommendations from the Pharmacogenetics Working Group of
the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
Ultra-rapid metabolizer (gene dose ≥ 3) (enhanced CYP2D6 enzyme activity)
The genetic variation increases the conversion of tramadol to a metabolite with a
stronger opioid effect. This can result in an increase in potentially
life-threatening side effects.
Recommendation:
As the total analgesic effect changes when
the ratio between the mother compound and the active metabolite changes, the
effect of a dose reduction cannot be predicted with certainty.
- 1.
select an alternative
Do not choose codeine, as it is contra-indicated for CYP2D6 UM.
Morphine
is not metabolized by CYP2D6.
Oxycodone is metabolized by CYP2D6 to a
limited extent, but this does not result in differences in side effects in
patients.
2. if an alternative is not possible:
use 40% of the standard dose
advise the patient to report side effects (such as drowsiness, confusion,
constipation, nausea and vomiting, respiratory depression or urine
retention).
Intermediate metabolizer (gene dose 0.5-1) (decreased CYP2D6 enzyme activity)
The genetic variation reduces the conversion of tramadol to a metabolite with a
higher activity. This can result in reduced analgesia.
Recommendation:
It is not possible to provide a
recommendation for dose adjustment, because the total analgesic effect changes
when the ratio between the mother compound and the active metabolite
changes.
- 1.
be alert to a reduced effectiveness
- 2.
in the case of inadequate effectiveness:
Do not select codeine, as this is also metabolized by CYP2D6.
Morphine is not metabolized by CYP2D6.
Oxycodone is metabolized by
CYP2D6 to a limited extent, but this does not result in differences in analgesia
in patients.
3. if no alternative is selected: advise the patient to report inadequate
analgesia
Poor metabolizer (gene dose 0) (absent CYP2D6 enzyme activity)
The genetic variation reduces the conversion of tramadol to a metabolite with a
higher activity. This can result in reduced analgesia.
Recommendation:
It is not possible to provide a
recommendation for dose adjustment, because the total analgesic effect changes
when the ratio between the mother compound and the active metabolite
changes.
- 1.
be alert to a reduced effectiveness
- 2.
in the case of inadequate effectiveness:
try a dose increase.
if this does not work: choose an alternative
Do not
select codeine, as this is also metabolized by
CYP2D6.
Morphine is not metabolized by
CYP2D6.
Oxycodone is metabolized by CYP2D6 to a limited
extent, but this does not result in differences in analgesia in
patients.
- 3.
if no alternative is selected: advise the patient to report inadequate
analgesia
Please review the complete therapeutic recommendations that are located
here: (3).
Nomenclature
Nomenclature of Selected CYP2D6 Alleles
View in own window
-
[1]
In the literature, 1023C>T is also referred to as 1111C>T
-
[2]
In the literature, 2851C>T is also referred to as 2938C>T
-
[3]
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.
Pharmacogenetic Allele Nomenclature: International Workgroup
Recommendations for Test Result Reporting (75).
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.
Acknowledgments
The authors would like to thank Marga Nijenhuis, PhD, Royal Dutch Pharmacists
Association (KNMP), The Hague, The Netherlands; Siegfried O.F. Schmidt, MD, PhD,
FAAFP, Professor, Department of Community Health and Family Medicine, College of
Medicine, Faculty, Pain Research and Intervention Center of Excellence, Director,
Chronic Pain Management Program at Main, UF Health Family Medicine, Gainesville, FL,
USA; and Francisco Abad-Santos MD, PhD, Clinical Pharmacology Department, Hospital
Universitario de la Princesa, Universidad Autonoma de Madrid, Madrid, Spain for
reviewing this summary.
First edition (2015)
The author would like to thank Professor Stefan Grond, Chief Physician of the Clinic
for Anesthesiology and Operative Intensive Care Medicine at Klinikum Lippe, Detmold,
Germany; and Alan D. Kaye, Professor and Chairman of the Department of
Anesthesiology at Louisiana State University Health Sciences Center, New Orleans,
LA, USA and Editor-in-Chief, Pain Physician Journal,
for reviewing this summary.
Version History
To view an earlier version of this summary from 10 September 2015, please click
here.
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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.
2.