Up to Date State of the Art of the Use of Pharmacogenomics

REVIEW
Update on the pharmacogenomics of pain
management
This article was published in the following Dove Press journal:
Pharmacogenomics and Personalized Medicine
Alan David Kaye1
Andrew Jesse Garcia2
O Morgan Hall3
George M Jeha4
Kelsey D Cramer4
Amanda L Granier4
Anusha Kallurkar5
Elyse M Cornett5
Richard D Urman6
1
Department of Anesthesiology, LSU
Health Sciences Center, New Orleans,
LA, USA; 2
Department of
Anesthesiology, George Washington
University School of Medicine and Health
Sciences, Washington, DC, USA;
3
Department of Anesthesiology,
Louisiana State University School of
Medicine, New Orleans, LA, USA;
4
Department of Anesthesiology, LSU
Health Sciences Center New Orleans,
New Orleans, LA, USA; 5
Department of
Anesthesiology, LSU Health Shreveport,
Shreveport, LA, USA; 6
Department of
Anesthesiology, Perioperative and Pain
Medicine, Harvard Medical School,
Brigham and Women’s Hospital, Boston,
MA, USA
Abstract: Pharmacogenomics is the study of genetic variants that impact drug effects
through changes in a drug’s pharmacokinetics and pharmacodynamics. Pharmacogenomics
is being integrated into clinical pain management practice because variants in individual
genes can be predictive of how a patient may respond to a drug treatment. Pain is subjective
and is considered challenging to treat. Furthermore, pain patients do not respond to treatments in the same way, which makes it hard to issue a consistent treatment regimen for all
pain conditions. Pharmacogenomics would bring consistency to the subjective nature of pain
and could revolutionize the field of pain management by providing personalized medical care
tailored to each patient based on their gene variants. Additionally, pharmacogenomics offers
a solution to the opioid crisis by identifying potentially opioid-vulnerable patients who could
be recommended a nonopioid treatment for their pain condition. The integration of pharmacogenomics into clinical practice creates better and safer healthcare practices for patients. In
this article, we provide a comprehensive history of pharmacogenomics and pain management, and focus on up to date information on the pharmacogenomics of pain management,
describing genes involved in pain, genes that may reduce or guard against pain and discuss
specific pain management drugs and their genetic correlations.
Keywords: pharmacogenomics, pharmacogenetics, pain, anesthesiology, polymorphism,
genetics
Introduction
Pain affects approximately 100 million Americans and furthermore costs the US
approximately $600 billion per year.1 According to the International Association for
the Study of Pain, pain is defined as “an unpleasant sensory and emotional
experience that is associated with actual or potential tissue damage or described
in terms of such damage”.
2 Pain can be acute or chronic; somatic or visceral;
nociceptive, neuropathic, or inflammatory in nature. Nociceptive pain refers to the
response to noxious stimuli and continues only in the maintained presence of
noxious stimuli.3 Inflammatory pain results from injury of tissues and subsequent
activation of inflammatory markers, which sensitize nociceptive pathways resulting
in patients experiencing pain with otherwise innocuous stimuli and heightens
sensitivity of pain perception. Neuropathic pain is the maladaptive response of
the nervous system to damage.4 Lower back pain is the primary cause of disability
worldwide and has a prevalence of 9.4%, which increases with age. Approximately
20% of US adults have chronic pain and it is one of the most common reasons
adults seek medical care.5,6 Chronic pain is particularly debilitating because it
affects all aspects of life including physical, mental, social, occupational, and
Correspondence: Elyse M Cornett
Department of Anesthesiology, LSU
Health Shreveport, 1501 Kings Highway,
Shreveport, LA 71103, USA
Tel +1 248 515 9211
Email ecorne@lsuhsc.edu
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family environments.7 Additionally,psychiatric disorders
are common among patients with chronic pain and include
depression (2–83%), anxiety (1–65%) and substance use
disorders (1–25%).8
There are several options available to treat pain,
including nonpharmacologic measures, pharmacotherapy,
and surgical interventions. Opioids are commonly used to
treat pain conditions however, they have the potential to be
abused and to cause addiction. Misuse of prescription
opioids (including abuse, dependence, and overdose) is a
serious public health problem and costs approximately $78
billion per year in the US.9 The Centers for Disease
Control and Prevention (CDC) officially declared fatal
prescription drug overdose as an epidemic in 2012.10
More recently in 2017, approximately 70,237 people died
due to drug overdose (including illicit drugs and prescription drugs) of which, 25% were due to prescription
opioids. And overall from 1999–2017, 218,000 people
have died in the US from opioid overdoses. Taken
together, opioids are clearly a potential danger to certain
patients, but until recently, pain management physicians
had no way to decipher which patients could become
addicted. Pharmacogenomics can be a powerful tool to
tackle the opioid epidemic, by which physicians could
elucidate individual genetic variants in patients, and thus,
patient potential for drug abuse.
Pharmacogenomics is the study of the role of the
genome in drug response. It focuses on the genetic variants
that impact drug effects through changes in a drug’s pharmacokinetics (the study of how the organism affects the
drug, ie, absorption, distribution, metabolism, elimination)
or pharmacodynamics (the study of how a drug affects an
organism, ie, physiologic, biochemical, and molecular
effects of drugs on the body and involves receptor binding
and chemical interactions).11 In 1959, Friedrich Vogel first
created the term “pharmacogenetics”, however, the origins
of pharmacogenomics can be traced back to 510 BC.
Pythagoras observed that some individuals ingesting fava
beans experienced potentially fatal hemolytic anemia,
whereas others did not. It was later found out to be due
to an inherited deficiency of glucose-6-phosphate dehydrogenase (G6PD).12 Elliott Vesell and George Page showed
that monozygotic twins displayed significantly less variability in antipyrine pharmacokinetics.13 In the 1960s, Price
Evans et al observed a considerable variation of isoniazid
metabolism among certain individuals and believed it to be
due to genetic factors.14 Decades later, Blum et al showed
that the genetic polymorphism in isoniazid acetylation was
due to inherited variants in the gene encoding N-acetyltransferase 2 (NAT2).15 Subsequent studies showed the
pattern of inheritance for many drug effects, and in 1987
CYP2D6 (the hepatic cytochrome P450 2D6), the
first polymorphic human drug metabolizing gene to be
cloned.16 For an explanation of gene nomenclature, see
Table 1. Since then, hundreds of CYP2D6 alleles have
been identified. CYP2D6 is highly polymorphic; it
accounts only for 2–5% of the total hepatic P450 enzymes;
however, it is involved in the metabolism of 25% of all
drugs used in clinical practice.17 Several commonly used
opioids, including codeine, tramadol, hydrocodone, oxycodone are metabolized by CYP2D6. The analgesic effect
of codeine stems from its conversion to morphine; and, the
amount of morphine produced from the parent drug
codeine can be highly variable between individuals
depending on rate of metabolism of codeine, which is in
turn dependent on the CYP2D6 polymorphism of the individual. Individuals with certain gene alleles can be classified into metabolic categories: ultrarapid metabolizer
(UM) with higher than normal function of the enzyme,
extensive metabolizer (EM), intermediate metabolizer
(IM), and poor metabolizer (PM) where an individual has
little or no enzymatic action.18 These differences reinforce
the fact that individual patients vary significantly in their
response to the “universal” doses of opioids that are used
in practice where one dose of medicine can be ineffective
to one person and lethal to another.
Several candidate genes involved in the metabolism of
opioids (pharmacokinetic related candidate genes such as
CYP2D6, CYP3A4/A5, UGT2B7, ABCB1, ABCC3,
SLC22A1) and pharmacodynamic related candidate genes
such as OPRM1, COMT, KCNJ6) are under investigation
and seem promising for clinical use in the future.19
Knowledge of pharmacogenomics is slowly being integrated into mainstream clinical practice. For example,
Vanderbilt university is carrying out panel-based pharmacogenomic testing through the Vanderbilt Pharmacogenomic
Resource for Enhanced Decisions in Care and Treatment
Table 1 Gene nomenclature explanation
CYP2C19*17
CYP Superfamily
2 Family
C Subfamily
19 Gene
*17 Allelic variant
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(PREDICT) program and has enrolled more than 10,000
patients.20 StJude’s Children’s Research Hospital has developed the PG4KDS protocol which aims to use the pharmacogenetic tests in the electronic health record (EHR) to
preemptively guide prescribing.21 In 2016, ACPE
(Accreditation Council for Pharmacy Education) incorporated pharmacogenomics into pharmacy education and
pharmacogenomics is included as one of the factors that
should be emphasized in the evidence-based clinical decision-making and medication therapy management aspects
of clinical practice.22
Pharmacogenomics is rapidly evolving, and numerous
efforts are in the pipeline to apply the knowledge of
pharmacogenomics into clinical practice so as to offer
better and safer healthcare to patients. In this article, we
focus on the pharmacogenomics of pain management,
describing genes involved in pain, genes that may reduce
or guard from pain and discuss specific pain management
drugs and their genetic correlation.
Types of pain
Acute pain
Acute pain is characterized by pain that has an inciting
event, is sudden in onset, is time-limited, and has the
potential to develop into a pathological condition.23 By
providing information about the location and magnitude of
harmful stimuli, acute pain heightens vigilance and promotes appropriate responses to address the stimuli.24 In
this way, acute pain is characterized as having a useful
biological purpose. Acute pain typically lasts less than 3
months and its treatment involves interrupting painful
nociceptive signals and addressing their underlying
cause.25,26
Chronic pain
In contrast to acute pain, chronic pain is a disease state that
serves no biological purpose, lacks a recognizable endpoint, and if related to disease or injury, extends beyond
the time period expected for healing.25 Chronic pain
usually lasts longer than 3–6 months and is considered a
unique clinical entity.26 Many patients with chronic pain
additionally experience changes involving emotion, behavior, and affect.24 Chronic pain can be subdivided into
several etiologies (see Figure 1).26 Treatment of chronic
pain involves a multidisciplinary approach and the utilization of various therapeutic strategies.25
Inflammatory pain
Inflammatory pain is due to the excitability of peripheral
nociceptive fibers due to anti-inflammatory mediators such
as cytokines, chemokines, bradykinin, prostaglandins, and
proteases.27 These mediators are released by injured tissues and activated immune cells in response to harmful
stimuli and interact with one of the following categories of
receptors: G-protein coupled receptors, tyrosine kinase
receptors, and ionotropic receptors. Regardless of the
receptor utilized, the result of these receptor-ligand interactions is the lowering of action potential threshold via
depolarization and subsequent hyperexcitability of sensory
neurons.27
Both acute and chronic pain are characterized by regulation of gene expression within the sensory neuron,
which includes modification in the expression of receptors
implicated in pain sensation. Changes in receptor transcription during acute inflammation involves local changes
at the site of inflammation. In contrast, chronic inflammation prompts transcriptional changes at the level of the
dorsal root ganglion.27
Neuropathic pain
Neuropathic pain is caused by malfunction of the somatosensory nervous system and is characterized by both positive and negative symptoms such as sensations of burning
and evoked pain.28,29 Conditions associated with neuropathic pain include diabetes, HIV infection, alcohol abuse,
vitamin or mineral deficiencies, and vasculitis.29
Neuropathic pain is relatively common and occurs in
Chronic pain
Primary
chronic Cancer
Post-surgical
or posttraumatic
Headache or
orofacial Visceral Musculoskeletal
Figure 1 Types of chronic pain.
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25% of diabetic patients and 35% of HIV-positive
patients.28 Clinically, neuropathic pain must be differentiated from nociceptive pain because management differs
between the two.29 Current first-line medications for the
treatment of neuropathic pain include serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants,
gabapentin, and pregabalin. Second-line options include
transdermal patches of capsaicin or lidocaine. Opioids
are reserved as third-line agents.28
Cancer pain
Up to 80% of patients with invasive cancer experience
cancer pain, and the number of cancer diagnoses is estimated to reach 20 million by the year 2025.30,31
Unfortunately, up to 50% of cancer patients have inadequate pain control and 25% actually die in pain.30 As such,
cancer pain is a significant clinical problem and optimizing
its management is important. Although the exact pathophysiology is not fully understood, cancer pain is thought
of as a distinct pain entity resulting from complicated
interactions between neoplastic cells and cells of the
patient’s immune and neurological systems. Opioids are
the most effective pharmacologic agents in the treatment
of cancer pain.31
Other factors that result in
individual pain differences
Environmental factors
Environmental factors likely contribute to the multifactorial causes of individual pain symptom differences among
patients. Associations between pain severity and demographic factors such as race, ethnicity, preferred language,
sex, and age have been reported.32 An inverse relationship
between socioeconomic status and chronic widespread
pain prevalence has also been described.33 For instance,
lower levels of education were found to be significantly
and inversely related to more severe pain and functional
impairment in women with chronic pelvic pain.34
Additionally, living in less affluent areas is associated
with frequent analgesic use and increased morbidity of
chronic noninflammatory musculoskeletal pain when compared to patients living in more affluent areas.35
The relationship between stress, illness, and pain is
complex. While short-term stress has several positive
effects, such as enhanced immune system activity, chronic
stress may contribute to illness and variances in pain
perception.36 In adolescents, perceived stress may be related
to variation in pain intensity and probability of reporting
pain.37 Stress is also thought to potentiate pain in patients
with fibromyalgia.38 Along with other environmental and
psychological factors, stress has also been described as a
risk factor for the development of tension headaches.39
The interplay between pharmacologic agents may also
contribute to individual pain differences amongst patients.
The use of certain psychoactive drugs such as benzodiazepines or selective serotonin reuptake inhibitors in
patients undergoing surgery has been associated with significantly higher utilization of morphine postoperatively
when compared to patients who did not take such drugs
preoperatively.40
Biological factors
Age and gender also contribute to differences in pain management and pain perception. Age-dependent differences in distribution, metabolism, and elimination of various
medications make age a critical consideration for medication
dose requirements. For example, advanced age has been
associated with increased sensitivity to the analgesic effects
of morphine.40 Studies examining sex-related differences in
opiate utilization in the postoperative period have found that
men consume more morphine postoperatively than women.41
Psychological factors
The interaction between depression and pain symptoms is
a growing area of study, and numerous reviews have
described associations between depression and pain.33,35,42
Both the prevalence of pain in depressed cohorts and the
prevalence of depression in pain cohorts are higher than
when these two conditions are examined in isolation.43
Psychological factors such as anxiety and depression
have been described as risk factors for the development
of tension headaches.39 Additionally, it has been suggested
that psychological factors may contribute to the observation that low socioeconomic status is inversely associated
with higher levels of chronic pain. After controlling for
psychologic factors, the strength of this inverse relationship is lessened.33 Thus while it is generally accepted that
that pain symptoms and psychological factors such as
depression are common comorbidities, a thorough understanding of the interplay between the two is complicated
and not fully understood.43
Genetic factors
Individual responses to opioids have been examined using
twin studies, which estimate that 24–60% of the variances
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in cold-pressor pain and heat pain are attributable to
genetic factors.44 Epigenetic mechanisms are thought to
play a role in both the expression of pronociceptive genes
and the evolution of acute pain into chronic pain.45
Interestingly, single nucleotide polymorphisms (SNPs)
within specific genes (caspase 9, interleukin 16) increase
the rate of self-reporting of pain by patients without interfering with the progression of underlying disease
processes.45 Additionally, polymorphisms involving the
serotonin 5-HT2A receptor, serotonin transporter, and
dopamine-4 receptor are more common in patients with
fibromyalgia.45 Harnessing the genetic polymorphisms in
transporters, receptors, drug-metabolizing enzymes, and
other drug targets linked to individual differences in the
efficacy and the toxicity of drugs can revolutionize the
field of pain management.
Ethnic factors
There is considerable evidence suggesting ethnicity is also
a factor in pain differences.46
For example, African Americans report greater pain
and suffering compared to Caucasians for conditions
such as glaucoma, AIDS, migraine, jaw pain, headache,
postoperative pain, angina pectoris, joint pain, arthritis,
myofascial pain.47 Furthermore, 27% of African
Americans and 28% of Hispanics over 50 years old report
having severe pain most of the time, compared to only
17% of non-Hispanic white individuals.48 African
Americans also have lower thresholds for pain, cold,
heat, pressure, and ischemia compared to Caucasions.49
American Indians, Alaska Natives and Aboriginal people
of Canada also have a higher prevalence of pain symptoms
and painful conditions compared to the general US
population.50 Individuals from Singapore and individuals
of Malayan descent have a lower pain severity compared
to Chinese individuals, whereas Indian individuals report
greater pain severity compared to Malayan and Chinese
individuals.51 Australian women also rate menstrual pain
as more intense compared to Chinese women.52 Swedes
report more frequent pain in lower back, neck, shoulders,
hands, and elbows compared to Sami (northern
Scandinavian indigenous individuals) men and women.53
There are also intra-ethnic differences that should be
accounted for. For example, one study examining
European individuals found significant differences in the
way in which pain was expressed by individuals from
different European countries, yet there were no reported
differences in pain perception.54 This same group also
reported different emotional responses to chronic pain
and pain intensity within a group of individuals classified
as white.55 This group included Hispanic, old American
(third-generation US born non-Hispanic Caucasian), Irish,
Italian, French-Canadian and Polish heritages. The
Hispanic group reported significantly higher pain intensity
ratings, followed by Italians. Overall, there is a wide
variety of individual differences in pain, especially when
considering ethnicity. Health-care providers should take
these differences into account when treating patients for
pain.81,82,120 See Table 2.
Biological polymorphisms involved
in pain
Cytokines
Pathological pain involves the release of pro-inflammatory
cytokines from activated macrophages in response to
stress or injury. In contrast, some cytokines produced,
such as IL-10, have anti-inflammatory properties that act
in opposition to the pro-inflammatory cytokines.
IL-6 is a pro-inflammatory cytokine linked to responses
to nerve injury and has effects on regeneration and feelings
Table 2 Ethnic differences in CYP2D6 activity
CYP2D6 genetics
Type Activity Ethnic differences
Poor metabolizer None Asian: 0-1.2%, African American: 2–5%, Ethiopian/Nigerian: 1.8-8.1%, Caucasians: 3–10%, Mexican
American/Hispanic: 2.2–6.6%
Intermediate metabolizer Low Asian: 51%, Caucasian: 1-2%, Ethiopian/Nigerian: NA, Mexican American/Hispanic: NA
Extensive metabolizer Normal Most individuals fall into this category
Ultrarapid metabolizer High Asian: 0.9%, Danes and Finns: 1%, Ethiopian/Nigerian: 29-30%, Greeks: 10%, Mexican American/Hispanic:
1.7%, North Americans (white): 0.8-4.3%, Portuguese: 10%, Saudis: 20%
Notes: Data from these studies.81,82
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of neuropathic pain. A study examining IL-6 infusions
intrathecally revealed IL-6 causes increased neuronal
responses and hyperalgesia to temperature changes.56
Another study analyzing inflammatory cytokines and pain
reported that following primary total knee arthroplasty,
there is a positive correlation between serum IL-6 concentrations and the degree of pain reported postoperatively.57
Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that mediates its effects via the surface
receptors TNFR1 and TNFR2 and activation of NFkB.
TNFα promotes regulation of pathways of apoptosis,
pain, and inflammatory responses. Neurons and nociceptors contain TNFα receptors, and TNFα injections into
nerves lead to degeneration of the nerve distal to the
point of injection and hyperalgesia. Both effects are eliminated with administration of systemic TNF binding protein, which blocks the effects of TNFα.
57
IL-10 is an anti-inflammatory cytokine that dampens the
activity of the pro-inflammatory cytokines by preventing
their release from macrophages. IL-10 also diminishes the
effects of IL-6 and TNFα through receptor blockade. Some
clinical studies have found evidence suggesting that low
levels of serum IL-10 contribute to chronic pain states or
patients with chronic, diffuse inflammation.57 Another study
found that administration of IL-10 postmyocardial infarction
reduced inflammation enough within the ventricle to promote
and facilitate healing of the damaged myocardium.58
Enzymes
Catechol O-methyl transferase (COMT) is an enzyme present at nerve terminals and is responsible for the degradation
of the catecholamines dopamine, epinephrine, and norepinephrine. Different haplotypes of COMT enzyme expression
are associated with variations in pain sensitivity through
differences in pain processing. A study involving patients
with diagnoses of chronic pain conditions associated with the
Val(158)Met polymorphism with a poorly functioning
COMT enzyme, causing increased sensitivity to perioperative pain and fibromyalgia. Reduced levels of functioning
COMT enzyme was also linked to increased responsiveness
to opioids for the treatment of chronic pain.59
The enzyme GTP cyclohydrolase (GTPCH) is encoded
by the GCH1 gene and is involved in the pathway leading
to the production of tetrahydrobiopterin (BH4). The level
of BH4 is positively correlated with pain sensitivity following injury to sensory neurons. SNPs within the GCH1
gene are linked to pain sensitivity, with some variations
being protective from pain and others exacerbating it. This
concept has been primarily studied in African Americans
with sickle cell disease, with the presence of variant
rs8007267 being protective from chronic pain and variant
rs3783641 being associated with increased crisis pain.60
CYP2D6 is a well-studied cytochrome P450 enzyme
responsible for the metabolism of many opioid analgesics.
There are more than 80 unique alleles of CYP2D6, and
variations in expression affect drug metabolism and alter
the efficacy of these drugs, see Table 3.
61 Extensive metabolizers have two wild-type alleles, which allow regular
enzyme activity and predictable drug responses. In one
extreme are the poor metabolizers, with two nonfunctional
alleles, leading to near absent enzyme activity. Conversely,
some individuals inherit either multiple copies of the functional allele, or an overactive promoter that results in
increased gene transcription and elevated enzyme activity.
Intermediate metabolizers have an allele with reduced
functionality and impaired enzymatic activity.61 Studies
show that 7–10% of the Caucasian population may be
poor CYP2D6 metabolizers, meaning that these individuals are at risk for failure of drug therapy in prodrugs
that require activation by this enzyme, or they are at risk
for toxicity in drugs that require breakdown by this
enzyme.62 See Table 3.
Table 3 Phenotypic effects of SNPs on drug metabolism
Drug given Prodrug Active drug
Metabolizer
level
Poor Rapid Poor Rapid
Drug exposure Decreased conversion Increased conversion Decreased inactivation Increased inactivation
Drug activity Decreased efficacy Increased efficacy Increased efficacy Decreased efficacy
Adverse effects Increased if prodrug is
toxic
Increased if active compound is
toxic
Increased if drug is
toxic
Decreased if drug is
toxic
Increased if drug is toxic
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Ion channels
Transient receptor potential (TRP) channels are found
throughout peripheral afferent nerves and are responsive
to many intra- and extracellular mechanical, chemical,
osmotic, and thermal stimuli.63 TRP channels are pronociceptive, responding mostly to noxious inflammatory stimuli. Therefore polymorphisms that make TRP less
sensitive, such as Ile585Val in TRPV1, have been shown
to decrease the experience of pain in patients with knee
osteoarthritis.64 Additionally, TRP channel polymorphisms
can change the somatosensory nature of pain—different
people will have varying heat, cold, or mechanical pain
thresholds from polymorphisms in TRP channels.65
Voltage-gated potassium channels play a significant
role in nociceptive signaling and regulation of pain
pathways. KCNS1 is a genetic polymorphism in the
voltage-gated potassium channels that leaves individuals
susceptible to pain associated with HIV, back pain, and
phantom limb pain following amputation. KCNS1 is
expressed in tissues all throughout the body. The role
of this ion channel was confirmed with KCNS-knockout
mice exhibiting a predisposition to neuropathic pain and
enhanced sensitivity to mechanical pain.66
CACNG2 encodes for the protein stargazin that is
needed for trafficking and ion flow through glutamatergic
AMPA receptors in the nervous system. Polymorphisms in
CACNG2 have been linked to susceptibility to neuropathic
pain. A study investigating neuropathic pain in breast
cancer patients following mastectomy found that a specific
3 SNP haplotype of CACNG2 was linked to the tendency
to develop phantom breast pain, confirming CACNG2 as a
modifier of neuropathic pain.67
CACNA2D3 encodes the alpha-2/delta protein in voltage-gated Ca2+ channels and has been documented to
contribute to nociceptive pain response to noxious heat. In
humans, a specific SNP has been located that leads to
reduced pain sensitivity to heat and chronic back pain
postsurgically. Interestingly, when studied in mice, mutant
CACNA2D3 exhibited impaired pain and heat sensitivity,
but had intense activation of sensory brain regions including
sight, smell, and hearing, showing impaired transmission of
signals between high-order pain pathways with possible
cross-activation of other sensory pathways in the brain.68
Receptors
OPRM1 is the human mu-opioid receptor gene that is
known to play a role in the analgesic effects of opioids.
Inadequate pain management in cancer patients has been
linked to hypermethylation of OPRM1, yielding a decreased
response to the analgesic effects of opioids. Chronic or
high-dose use of opioids was correlated with this hypermethylation and downregulation of receptors, confirming a
mechanism of tolerance.69 Furthermore, the presence of a
specific A118G polymorphism in OPRM1 leads to a less
active receptor that has been linked to individuals with
reduced analgesic responses to morphine postoperatively.70
ADRA2 is an alpha-2-adrenergic G protein-coupled
receptor that plays a significant role in the regulation and
release of sympathetic nervous system neurotransmitters.
Pharmacologically, this receptor is the target of pain control therapies, such as central acting alpha-2 agonists, that
reduce the release of sympathetic neurotransmitters and
relieve symptoms of opioid withdrawal. Alpha-2 adrenergic receptors located in the spinal column dorsal horns,
when activated with an agonist, inhibit the release of
substance P and the activity of the nociceptive neurons,
leading to analgesia. This is illustrated by the clinical use
of clonidine, an alpha-2 agonist, in the treatment of
chronic pain as well as opioid withdrawal symptoms.71
Dopamine receptor D2 (DRD2) is a G-protein coupled
receptor that inhibits adenylyl cyclase. This receptor is
well-known as the site of action of many antipsychotic
drugs, but it has also been studied in migraine headaches.
A specific SNP rs1800497 was linked to increased prevalence of migraine headaches in Chinese females, leading
to the proposal of the possible use of DRD2 antagonists in
the prevention of treatment of migraine headaches.72
Transporters
DAT-1 is a transporter that regulates the reuptake of dopamine into the presynaptic neuron from the synaptic cleft.
Polymorphisms in this transporter have been linked to
individual differences in cold pain tolerance in healthy
subjects. The specific polymorphism studied was a 40
base-pair repeat in the transporter within the 3ʹ untranslated region that led to decreased transport and low activity of dopamine, suggesting that low dopaminergic activity
yields higher sensitivity to pain.73
The serotonin transporter (5HTT) is responsible for
serotonin’s reuptake from the synaptic cleft. Specific polymorphisms known as the 5-HT transporter-linked polymorphic region (5-HTTLPR) has been studied intensely
in patients with chronic pain, looking at high-, intermediate-, and low-expressing groups. A study analyzing the
variations of the triallelic 5-HTTLPR and perception of
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heat pain found that individuals with high levels of serotonin transporter expression had lower pain thresholds for
heat pain than those with intermediate levels of expression, highlighting the complex role of serotonin in pain
modulation.74
ABCB1 is an ATP-binding cassette transporter responsible for transport of various molecules across membranes,
including the blood–brain barrier, and is a member of the
multidrug resistance family of transporters. ABCB1 transports various opioid analgesics across the blood–brain
barrier, and specific polymorphisms are linked to changes
in analgesic effects of these drugs. In a study of lung
cancer patients undergoing radical operations, patients
possessing homozygous rs2032582 and rs1128503 loci
consumed significantly higher doses of sulfentanil postoperatively to achieve adequate analgesic effects, supporting that these specific SNPs cause decreased transport
activity.75 See Figure 2.
Opioid receptor polymorphisms
Variations in the mu, kappa, and delta opioid receptors
also play a significant role in the opioid response. Over
100 variants of the opioid receptor mu 1 gene (OPRM1)
have been identified. The most studied allele, 118 A>G
polymorphism (rs1799971), is prevalent in 2–48% of the
population.76 This particular mutation results in an
increased binding of beta-endorphins to the mu opioid
receptor, and is hypothesized provide higher pain relief
in homozygotes, and thus decreased daily requirements for
morphine.77,78
Polymorphisms with similar clinical relevance have
been found for the OPRK1 and OPRD1 genes as well. κopioid receptor activation is responsible for spinal
analgesia and is responsible for similar adverse effects
as the μ-receptor (respiratory depression, sedation, and
dysphoria), while the δ-opioid receptor is implicated in
dysphoria and psychomimetic effects.76 These receptors,
particularly the δ-receptor, have importance with regards
to addiction as mentioned in the buprenorphine section,
and thus serve as potential future targets of targeted
addiction therapy.79,80
Genetic polymorphisms associated
with drugs used to treat pain
Morphine
Morphine is metabolized through glucuronidation via
UGT2B7 and UGT1A1, forming the active metabolite
morphine 6-glucuronide as well as the inactive metabolite
morphine 3-glucuronide. UGT2B7 is the primary enzyme
involved in biotransformation, accounting for 60% of
Biological polymorphisms involed in pain
Enzymes
Ion channels
TRP pro-nociceptive, polymorphisms change perception
Voltage gated potassium channel KCNS1 polymorphism
with sensitivity to neuropathic/mechanical pain
modify neuropathic pain
and head sensitivity
pain
CACNG2 stargazin channel CACNG2 polymorphisms
CANA2D3 voltage gated calciuim Cchannel SNP
COMT enzyme activity linked to
responsiveness
GTP
CYP2D6
pain and opioid IL-10
IL-6
TNFa
OPRM1 Mu-opioifd
DAT-1 dopaminergic activity cold pain sensitivity
expression heat pain threshold
ABCB1 transports drugs across BBB, SNPs
5HTT
dampens proinflammatory cytokines
associated with pain
promotes inflammation and cell death
hypermethylation analgesia
agonism SNS pain response
DED2 GPCR SNP linked to increased migraines
ADRA2 a2 GPCR
Cytokines
Receptors
Transporters
cyclohydrolase level of BH4 produced correlates
with pain sensitivity
variants affect drug metabolism and efficacy
changing transpport acitvity change analgesia
Figure 2 Biological polymorphisms involved in pain.
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metabolite formation.83 While numerous studies detail the
effects of genetic polymorphisms on morphine’s biotransformation, efficacy to treatment, and potential for toxicity,
guidelines to support dose selection of morphine are lacking. Genotypes related to morphine’s ability to treat pain,
such as the GG genotype for OPRM1, may help inform
appropriate dose selection. In one study, patients with the
GG genotype often require higher daily doses of morphine
to achieve appropriate levels of analgesia, in comparison
to the wild-type A allele (225+143 mg/day vs 97+89 mg/
day in those with the A allele for OPRM1, P=0.006).84
Another study showed variability for the development of
respiratory depression in individuals with polymorphisms
for the p-glycoprotein transporter ABCB1, resulting in
extended hospital stay.85
Codeine
Codeine is a prodrug metabolized by O-demethylation to
the active analgesic morphine via the CYP2D6 pathway.
This mechanism accounts for about 10% of the overall
elimination of codeine. CYP2D6 activity can vary considerably among individuals, as there are approximately 100
different variants of the genes that have been identified to
date.76 The most clinically significant polymorphisms arise
from those harboring two loss of function variants, also
known as poor metabolizers, and those harboring at least
three normal function variants, also known as ultrarapid
metabolizers. Poor metabolizers produce low plasma concentrations of the active morphine metabolite, and thus are
less likely to achieve adequate pain control with codeine.
Ultrarapid metabolizers, however,run the risk of reaching
supratherapeutic levels of morphine. Furthermore, there is
a relationship between the metabolism of codeine and
morphine when the drugs are adiministered at the same
time. Genotypic differences in UGT2B7, which is responsible for metabolizing morphine into morphine-6-glucuronide and morphine-3-glucuronide, can impact codeine’s
therapeutic effect. In particular, the UGT2B7*2/*2 genotype, which results in a reduced function of the enzyme,
has been associated with higher toxicity. Several pharmacokinetic studies have illustrated the effects of these phenotypes on metabolite formation. In one study, a single
dose of 30 mg codeine was administered to 12 UM individuals in comparison to 11 EMs and three PMs.86
Significant differences were detected between EM and
UM groups for areas under the plasma concentration versus time curves (AUCs) for morphine with a median
(range) AUC of 11 (5–17) μg*h*L−1 in EMs and
16 (10–24) μg*h*L−1 in UMs relative to individuals with
the PM phenotype (0.5 μg*h*L−1
, P=0.02).
The codeine-CYP2D6 interaction is the only opioidgene interaction that currently has an actionable Clinical
Pharmacogenetics Implementation Consortium (CPIC)
guideline for pharmacogenetic-based recommendations,
primarily due to the severe nature the toxicities related to
rapid metabolism phenotypes in young users, such as
respiratory depression.87 On the basis of these guidelines,
it is strongly recommended that UMs and PMs should
avoid codeine due to potential for toxicity and lack of
efficacy, respectively. Recent updates by the US Food
and Drug Administration (FDA) to the label for both
codeine and tramadol also contraindicate the use of
codeine for pain or cough in patients younger than 12
years of age.88 Furthermore, the FDA warns against the
use of codeine in obese adolescents and those with
obstructive sleep apnea or severe lung disease.
Tramadol
Tramadol, like codeine, is also a prodrug bioactivated by
the CYP2D6 enzyme, through which it is metabolized to
its active metabolite O-desmethyltramadol (ODT). Similar
to codeine, tramadol’s effects are impacted by individuals
with UM and PM phenotypes. In one study, tramadol
failed to provide adequate pain relief at 48 hours following
surgery in patients with the CYP2D6 polymorphism
(P<0.001).89 In UMs, respiratory depression may occur,
and has been described in at least one case report to date.89
The same cautions were made by the FDA in response to
tramadol as were made for codeine in April 2017, namely
a contraindication for the use of tramadol in individuals
less than 18 years of age following tonsillectomy or
adenoidectomy.88 Although there is no CPIC guideline
for tramadol, its metabolism by CYP2D6 would make it
an unsuitable alternative to codeine and thus be treated in a
similar fashion to codeine with regards to cautions and
recommendations for use.
Hydrocodone
Hydrocodone, a semisynthetic opioid, follows metabolism
via CYP2D6 and CYP3A4 to form hydromorphone and
norhydrocodone respectively. These are further conjugated
by UGT enzymes into water soluble metabolites that are
excreted by the kidneys. Importantly, hydromorphone’s
affinity for the μ-opioid receptor is far higher than that of
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hydrocodone, up to 100-fold greater. Like tramadol and
codeine, variations in CYP2D6 have an impact on analgesia from hydrocodone.87 At least one study determined
that patients who underwent cesarean section delivery
and were determined to be UMs of CYP2D6 had approximately a 10-fold increase in hydromorphone plasma concentration compared to those with PM phenotype.90 Based
on this profile, hydrocodone may not be a good alternative
to codeine or tramadol based on the CPIC guidelines for
codeine. This recommendation is based mainly on hydrocodone’s role as a substrate for CYP2D6, rather than from
robust evidence. Given this status, CPIC currently recommends more research for this particular drug with respect
to the impact of genetic polymorphisms. Recent studies
have shown an opportunity to use hydrocodone pharmacogenetics to tailor responses to therapy, while at the same
time assessing conversion of hydrocodone to hydromorphone in the body.91
Oxycodone and oxymorphone
Oxycodone and oxymorphone are metabolized by CYP450
and to a lesser extent, UDP-glucuronosyltransferases
(UGT), specifically UGT2B7.92 The UGTs are a secondary
metabolizing system responsible for the formation of glucuronides. Geneticvariability in the enzyme 2B7 exisits,
however, the in vitro and in vivo functional significance of
these allele variants are not well defined.93 Like hydrocodone, oxycodone is metabolized via the specific enzymes
CYP3A4 and CYP2D6 into noroxycodone and oxymorphone, respectively. Unlike hydrocodone and tramadol,
however, the parent drug for oxycodone exhibits some
analgesic effect, and the drug also undergoes a more
complex metabolic pathway than the previous two.
CYP3A4 mediates the primary metabolic pathway,
accounting for more than 50% of the overall conversion
of oxycodone. In similar fashion to codeine and tramadol,
PMs of CYP2D6 exhibit lower conversion into its active
metabolites and thus exhibit a lower analgesic response as
well as a lower potential for adverse effects in comparison
to extensive metabolizers.94 Moreover, UMs tend to have a
much higher response and potential for side effects to
doses of oxycodone. One study of cancer patients noted
that differences in CYP3A impacted patient response to
oxycodone.95 Given the complex interplay between oxycodone metabolism and its associated pharmacogenetics,
current CPIC guidelines recommend further studies before
definitive treatment guidance can be given.87
Diamorphine
Diamorphine, more commonly known by the street name
“heroin” is metabolized into 6-monoacetylmorphine (6-
MAM) primarily via the enzymes hCE-1 and partly by
hCE-2.96 Additionally, variations in loci for the kappa and
delta opioid receptor genes OPRK1 and OPRD1 have been
connected to the potential for addiction and dependence to
diamorphine. Additional research involving these interactions could elucidate their role as targets for addiction
therapy.80
Fentanyl
Fentanyl is metabolized by the enzymes CYP3A4 and
CYP3A5. Variations in CYP enzymes have been demonstrated to impact plasma concentrations of fentanyl. In one
study of 60 adult patients with cancer receiving transdermal fentanyl, the plasma concentration of fentanyl was
shown to be twice as high in CYP3A5*3 homozygotes
compared to CYP3A5*1 carriers.97 The same study also
showed that polymorphisms in the gene ABCB1 can lead
to significant changes in fentanyl plasma concentrations,
with the ABCB1 1236TT variant being associated with a
lower need for rescue medication. To date there have been
no statistically significant findings for fentanyl-related
adverse effects, in the previous study or current body of
literature. As such, more research is needed before clinical
adoption of fentanyl pharmacogenetics would be useful.
Buprenorphine
Buprenorphine, a semisynthetic opioid, is metabolized via
CYP3A4. Used mainly for treating opioid addiction, the
drug exerts its effects at the OPRD1 receptor. Most notably, the connection between specific SNPs such as rs58111
and rs529520 have been predictive of outcomes for the use
of buprenorphine in treating opioid dependence, with the
rs58111 SNP being associated with a more favorable
response to buprenorphine.98
Nonsteroidal anti-inflammatory drugs
(NSAIDs)
Patient variability to NSAIDs is impacted by variations in
select CYP enzymes, namely CYP2C9, which metabolizes
many NSAIDs. Two allelic variants of CYP2C9,
CYP2C9*2 and CYP2C9*3, result in reduced inactivation
of NSAID substrates by 50% and 15% respectively. This
lower metabolism results in prolonged action of the drugs,
and thus higher of side effects such as GI bleed.99 A
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prospective multicenter, study identified a higher rate of
acute upper GI bleeding related to use of nonaspirin
NSAIDs in patients with the CYP2C9*3 variant when
compared to patients receiving aspirin, indicating the
potential risk associated with certain NSAIDs in patients
with the CYP2C9*3 loss-of-function allele.100
Additionally, variability of the prostaglandin-endoperoxidase synthase 1 and 2 genes (PTGS1 and PTGS2) influences response to particular NSAIDs.99 PTGS1 encodes
for COX1, and PGTS2 codes for COX2. Mutations resulting in a higher number of COX2 over COX1 were determined to respond better to selective agents such as
rofecoxib, while agents with COX1 effects such as ibuprofen showed better pain response in individuals expressing more PTGS1.
Ketamine
Ketamine metabolism occurs via N-demythylation by
CYP3A4, CYP2B6, and CYP2C, with significant analgesic
and sedative activity achieved through antagonism of the
NMDA receptor. Despite there being several cytochrome
enzymes involved in ketamine’s metabolism, strong correlates between polymorphisms and clinical importance have
yet to be identified.101
Lidocaine
Lidocaine, a local anesthetic with activity at sodium channels, is metabolized via CYP3A4, and thus is theoretically
impacted by influence of inducers and inhibitors of
CYP3A4. The most pronounced effects on variation in
clinical efficacy, however, are due to mutations in the
sodium channel gene SCN9A.
78 One invitro study showed
that the 395N>K mutation in this gene produces greater
resistance to lidocaine, and another showed that individuals with phenotypes associated with red hair in the
melanocortin-1 receptor gene (MCR1) had reduced efficacy to subcutaneous lidocaine.102
Remifentanil
Remifentanil is a synthetic opioid analgesic drug that is
potent and short-acting. It is used during surgery to treat
pain and as an adjunct to anaesthetics. Remifentanil is a
specific mu-type-opioid receptor agonist. There is evience
to suggest increased pain sensitivity in Met158 individuals
following treatment with remifentanil. As previsouly mentioned, the COMT gene has variations that can affect
opioid drug metabolism, specifically at the 158 codon
where either Val or Met can be present. A 2006 study
suggested that individuals with Val alleles show increased
COMT activity and have decreased prefrontal extracellular
dopamine compared to those with the Met substitution.103
Val158 alleles may also be associated with an advantage in
the processing of aversive stimuli, or pain. Individuals
who are homozygous for the Met158 allele show increased
pain sensitivity, likely through a lower-functioning
μ-opioid system response to prolonged pain.104,105 A
cohort study investigating repeated thermal-pain stimulation both before and after one single dose of opiate in
caucasions showed that individuals with the Val158 genotype did not respond to either the initial noxious stimulus
or the analgesic response to remifentanil.106 Yet, reported
pain in Met15 individuals were higher following repeated
heat stimulation and postremifentanil treatment, suggesting that the initial pain response is not mediated by COMT
and may only present after the endogenous pain response
is challenged. This reaction could be produced by an
increased susceptibility of these individuals to opioidinduced hyperalgesia.102
Escitalopram
Escitalopram is an SSRI used to treat autism spectrum
disorder, but it can also be used to treat neuropathic pain.
CYP2C19 is the enzyme responsible for metabolizing
escitalopram and individuals can carry up to 30 different
alleles. The majority of patients will carry the
CYP2C19*1, *2, or *17 alleles, where *17 allele is an
ultrarapid metabolizer. A normal functioning enzyme is
indicated by CYP2C19*1, while CYP2C19*2 and
CYP2C19*3 are the most common non-functioning
alleles.107 Ultrarapid metabolizers should be administered
an alternative drug that is not metabolized by CYP2D19.
Extensive and intermediate metabolizers should be administered medication normally. Poor metabolizers should
have a 50% reduction in the recommended starting dose
with a titration to the response dose or should be given a
drug that is not metabolized by CYP2D19.107
See Table 4 for an overview of drugs, their clinical
utility, associated polymorphisms and phenotypic effect of
the genetic variant.
Pharmacogenomics improving pain
management
Pain-associated genetic factors vary with pain classification,
but all classifications have some genetic component. The
effect of polymorphisms in the OPRM1 and COMT genes,
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Table 4 A list of drugs, their clinical utility, associated polymorphisms and phenotypic effect of the genetic variant
Drug Clinical utility Genes Phenotypic effect of the genetic variant
Codeine Management of mild- to moderately-severe pain CYP2D6 Poor metabolizers may fail to reach adequate analgesia
Ultrarapid metabolizers may reach high levels of morphine following low to
standard dosing leading to increased risk of toxic systemic concentrations of
morphine87,88,108
Loss of function mutation in UGTB7 is associated with decreased metabolism
of morphine, resulting in increased risk of toxicity86
UGTB7
Tramadol Management of pain severe enough to require an opioid analgesic and for which alternative
nonopioid treatments are inadequate
CYP2D6 Poor metabolizers fail to reach adequate analgesia87
Ultrarapid metabolizers may experience life-threatening serotonin or opioid
receptor-mediated adverse events89
Hydrocodone Management of pain severe enough to require daily around-the-clock opioid, long-term
treatment and for which alternative treatment options are inadequate
CYP2D6 CYP2D6 enzyme demethylates hydrocodone into hydromorphone, which has
stronger mu receptor binding activity. Ultrarapid metabolizers may reach
higher levels of hydromorphone from conversion of hydrocodone and thus
be at higher risk of toxicity87,90
Poor CYP2D6 metabolizers may not reach desired analgesic effect with
standard dosing
CYP3A4
Oxycodone Pain management in patients for whom alternative treatment options are ineffective, not
tolerated, or would be otherwise inadequate to provide sufficient management of pain
CYP3A4 Patients designated as PMs have been reported to need more oxycodone to
achieve adequate analgesia
Complex phenotypic effects impacted by parent drug’s inherent analgesic
effect94,95
Weak evidence suggests a higher risk of side effects such as respiratory
depression, tiredness, or nausea
CYP2D6
Morphine Management of pain severe enough for which alternative treatments are inadequate that
require an opioid analgesic
ABCB1 Associations between ABCB1 polymorphisms and prolonged recovery
room stays and postoperative morphine requirement83,85
GG genotype for OPRM1 associated with increased requirement for postoperative opioids85
OPRM1
Diamorphine Not recommended clinical utility to date hCE-1
hCE-2
Variation in OPRK1 and OPRD1 may be connected to potential for
addiction80,96
OPRK1
OPRD1
Fentanyl Surgery: adjunct to general or regional anesthesia; preoperative medication; analgesic
during anesthesia and in the immediate postoperative period
Transdermal device: acute postoperative pain
Transdermal patch: management of pain in opioid-tolerant patients
Transmucosal: management of breakthrough cancer pain in opioid-tolerant patients
OPRM1 Variations in median effective dose required to exhibit analgesia among
polymorphisms such as ABCB197 ABCB1
(Continued)
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which transcribe opioid receptor mu 1 and catechol-Omethyltransferase respectively, are relatively well categorized in their effect on acute postoperative, cancer-related,
and chronic pain.109,110 When patients are homozygous for
the common amino acid substitution val158met, they
require a dose of morphine that is significantly higher than
homozygous met/met patients.109 Similarly, cancer patients
with a 118GG polymorphism in the OPRM1 gene need a
higher morphine dose than patients with 118AA (1,2,3).
Other genes, such as CREB1, GIRK2, and CACNA1E,
have similar consequences on the pain relieving effects of
opioids.111
Improving pain management necessitates expanding
upon the clinical features analyzed when making treatment
decisions.111 Pharmacogenomics can provide valuable
information to guide drug choice and dosing for more
effective, safer treatments.111,112 CYP2D6 tests—including
full sequence analysis and targeted variant analyses utilizing
PCR—are available to determine a patient’s metabolizer
level of codeine.18,111 DNA is gathered via a buccal swab
which prevents unnecessary burden on the patient while
providing the clinician with a powerful tool to improve
the patient’s treatment112 Instead of analyzing a specific
gene in relation to one treatment as in the case of codeine
and CYP2D6, creating a pain-related gene panel would
allow more informed and effective initial treatment by the
clinician.112 Panels already exist in this regard for laboratory experimentation, however, they are not FDA approved,
nor are they ready to be implemented in the clinic.113
Interpretation of pain is an incredibly complex pathophysiological process, which can only be partially explained by
genetics, but studying and understanding variability in
adverse effects and treatment effectiveness based on pharmacogenetics can benefit patient outcomes.111
An recent breakthrough study suggests a direct benefit
of personalized patient medical care. Smith et al investigated CYP2D6-guided opioid therapy as a possible way to
improve patient pain control. They found that, in fact,
CYP2D6 does improve pain control in CYP2D6 intermediate and poor metabolizers. Patients experiencing chronic
pain from seven different clinics were enrolled in the
study. The patients were randomly assigned to either a
CYP2D6-guided care group or a usual care group.
Future directions
There are several major challenges for the future of pharmacogenomics in pain management. Primarily, the cost
associated with implementing a pharmacogenomics
Table 4 (Continued).
Drug Clinical utility Genes Phenotypic effect of the genetic variant
Buprenorphine Use for moderate to severe pain
Opioid dependence
CYP3A4 OPRD1 SNPs such as rs58111 and rs529520 may help predict outcomes of
buprenorphine use in treating opioid dependence98 OPRD1
NSAIDS Pain for which an opioid analgesic is not required CYP2C9 Two variants of CYP2C9, CYP2C9*2 and CYP2C9*3, result in decreased
inactivation of NSAID, increasing risk for side effects such as GI bleed100
Mutations resulting in varying concentrations of PTGS1/2 associated with
variable response based on selectivity of NSAID for COX1 or COX2100
PTGS1,
PTGS2
Ketamine Induction and maintenance of general anesthesia and procedural sedation/analgesia CYP2B6,
CYP3A4,
CYP2C
Decreased enzyme binding and reduced drug clearance in polymorphisms
have been noted, but clinical significance has yet to be identified.101
Lidocaine Local and regional anesthesia by infiltration, nerve block, epidural, or spinal techniques SCN9A
MCR1
Reduced efficacy in polymorphisms102
Abbreviations: PM, poor metabolizer; NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase.
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program is high and this can be a deterrent to health-care
institutions. To address this, identifying patients who,
based on the pharmacogenetics, may not respond to drug
treatments, have a high risk of adverse events, or a high
risk of drug abuse and addiction, could improve costs
associated with chronic pain management and patient
outcomes.113 By developing predictive formulas for
patient outcomes, physicians could utilize patient characteristics (height, weight, age, etc), genotypes from pharmacogenetic testing, and drug pharmacokinetics/
pharmacodynamics along with additional predictive markers to better treat patients, see Figure 3. Yoshida et al
used this approach to develop a predictive formula for
postoperative fentanyl dose requirement using patients’
SNP profile for several genes involved in pain relieving
effects of opioids.111 The precision of the developed formula proved to be low, but promising nonetheless.111
Further study and identification of SNPs related to analgesics dosing, effectiveness, metabolism, and adverse effects
will allow for new variables to be included in similar
formulas to expand their predictive power.101
Furthermore, Next-Generation Sequencing (NGS),
Illumina, Inc., San Diego, CA, USA is the new standard for
sequencing technologies and is vital to understanding pharmacogenetics. The costs associated with NextGen
Sequencing are decreasing, which will improve the affordability of genetic testing to the individual patient.114 Testing
time is another major challenge associated with pharmacogenomics in pain management and cutting down on this
testing time is crucial to the widespread acceptance of this
system.101 Patients in severe pain cannot afford to wait for
results to return before receiving treatment, therefore, protocols should be in place to immediately help the patient while
waiting for test results before a transition to the best longterm treatment option. Another challenge mentioned earlier,
suggests that further research is needed to understand the
pharmacogenetics behind both pain perception and pain
management, especially to move beyond studying dosing
and toxicity to investigate the efficacy of employing one
pain relief medication versus another in an individual
patient.101,114 For example, studies exploring ethnicitybased genetic polymorphisms associated with metabolizer
type have a variety of categorized results, even in recent
studies. Table 5 outlines several studies ranging from 2002–
2018 which have overlapping polymorphisms associated
with each category of metabolizer. More research is needed
to make the results of these studies more consistent with one
another. If these major challenges are addressed there is an
increased likelihood that pharmacogenomics in the field of
pain management will have a more widespread acceptance.
Conclusion
A universal approach to health care, especially related to
pain management, is no longer an option. Since all patients
Pharmacokinetics/
pharmacodynamics
Patient
characteristics:
-height, weight, age,
sex, race
Drug receptor SNPs
Drug metabolizing
enzyme SNPs
SNPs related to pain
perception
Genetic
predisposition to
abuse and addiction
Response to prior
drugs
Predictive
formula for
improved
outcome
Figure 3 Predictive factors for personalized medicine.
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Table 5 Evidence for correlations between ethnicity or gene polymorphisms based on metabolizer status
Poor metabolizer/none Intermediate metabolizer/low Extensvine
metabolizer/
normal
Ultrarapid metabolizer/high
Bijl et al, 2007115 *3, *4, *5, *6 *10, *41 *1, *2 “Ultrarapid metabolizers” (UMs) have >2 functional copies of the
CYP2D6 gene and exhibit extremely high enzyme activity. Many genotyping assays determine the duplication of any CYP2D6 gene, including nonfunctional genes, leading to false positive UM assignment. In this
way, genotyping will only detect 10–30% of CYP2D6 UMs.
Bernard et al, 2005116 *3, *4 *9, *10, *17, *41 n/a n/a
Zhou 2009117 *3, *4, *5, *6, *7, *8, *11, *12, *13,
*14, *15, *16, *18, *19, *20, *21,
*38, *40, *42, *44, *56 and *62
*10, *17, *36 and *41 *2 n/a
Dean 2012118 *4/*4, *4/*5, *5/*5, *4/*6 *4/*10, *5/*41 *1/*1, *1/*2, *2/
*2, *1/*41, *1/
*4, *2/*5, *1/
*10
*1/*1xN
*1/*2xN
Gaedigk et al, 2017119 *3, *4, *4xN,*5, *6, *7, *8, *11, *12,
*36, *40, *42, *56
*9, *10, *17, *29, *41, *44, *49 *2, *35, *43,
*45
*1xN, *2xN
Del Tredici et al, 2018120 *3, *3xN, *4, *4xN, *4N, *5, *6,
*6xN, *36, and *36xN
*9, *9xN, *10, *10xN, *17, *17xN, *29,
*29xN, *36-*10, *36-*10xN, *36xN-
*10, *36xN-*10xN, *41, and *41xN
*1, *1xN, *2,
*2xN, *2A,
*2AxN, *35, and
*35xN
n/a
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have different responses to medications and pharmacogenomics now allows us to explain these differences in
response, it is clear that individualized medicine tailored
to each individual patient is the future of patient care. This
should, however, be viewed with promise, as individualized
patient-specific care can save money, improve patient
experiences and improve patient outcomes. Monitoring the
DNA polymorphisms in each patient can allow health-care
providers to predict how a patient will respond to a drug
and could potentially save a patient’s life. This is of particular importance when considering the relationship between
pain management and drug addiction. There are established
genetic polymorphisms in individuals who abuse drugs, yet
a clinician currently assesses the potential for abuse by
interacting with the patient and reports from those close to
the patient, thereby missing potentially crucial genetic predispositions to abuse.113 Therefore, a health-care provider
could prevent the possibility of a patient to abuse a drug
based on their polymorphisms and suggest an alternate
treatment regimen. By applying the knowledge of pharmacogenomics into clinical practice health-care providers can
offer safer comprehensive health care to patients.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Institute of Medicine (US) Committee on Advancing Pain Research,
Care and E. Relieving pain in America: a blueprint for transforming
prevention, care, education, and research – PubMed – NCBI. Natl Acad
Collect Rep Funded Natl Inst Heal. 2011. doi:10.7205/MILMED-D16-00012
2. IASP Group. Pain terms: a list with definitions and notes on usage.
Recommended by the IASP subcommitee on taxonomy. Pain. 1979.
doi:10.1016/0304-3959(79)90175-1
3. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive
response of the nervous system to damage. Annu Rev Neurosci.
2009. doi:10.1146/annurev.neuro.051508.135531
4. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms,
mechanisms, and management. Lancet. 1999. doi:10.1016/S0140-
6736(99)01307-0
5. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and
high-impact chronic pain among adults — United States, 2016.
MMWR Morb Mortal Wkly Rep. 2018. doi:10.15585/mmwr.
mm6736a2
6. Schappert SM, Burt CW. Ambulatory care visits to physician offices,
hospital outpatient departments, and emergency departments: United
States, 2001–02. Vital Health Stat. 2006;13. Available from: http://
europepmc.org/abstract/MED/16471269.
7. Dueñas M, Ojeda B, Salazar A, Mico JA, Failde I. A review of chronic
pain impact on patients, their social environment and the health care
system. J Pain Res. 2016. doi:10.2147/JPR.S105892
8. Hooten WM. Chronic pain and mental health disorders: shared neural
mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016.
doi:10.1016/j.mayocp.2016.04.029
9. Florence CS, Zhou C, Luo F, Xu L. The economic burden of
prescription opioid overdose, abuse, and dependence in the
United States, 2013. Med Care. 2016. doi:10.1097/
MLR.0000000000000625
10. Paulozzi L, Baldwin G, Franklin G, et al. CDC grand rounds:
prescription drug overdoses – a U.S. Epidemic. Morb Mortal
Wkly Rep. Vol 61. 2012;[pii].
11. Vogel F. Moderne Probleme der Humangenetik. Ergeb Inn Med
Kinderheilkd. 1959. doi:10.1007/978-3-642-94744-5_2
12. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature.
2015;526(7573):343–350. doi:10.1038/nature15817
13. Vesell ES, Page JG. Genetic control of drug levels in man: antipyrine. Science (80-). 1968. doi:10.1126/science.161.3836.72
14. Price Evans DA, Manley KA, McKusick VA. Genetic control of
isoniazid metabolism in man. Br Med J. 1960. doi:10.1136/
bmj.2.5197.485
15. Blum M, Demierre A, Grant DM, Heim M, Meyer UA. Molecular
mechanism of slow acetylation of drugs and carcinogens in
humans. Proc Natl Acad Sci. 1991. doi:10.1073/pnas.88.12.5237
16. Gonzalez FJ, Skodat RC, Kimura S, et al. Characterization of the
common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988. doi:10.1038/331442a0
17. Ingelman-Sundberg M, Evans WE. Unravelling the functional
genomics of the human CYP2D6 gene locus. Pharmacogenetics.
2001. doi:10.1097/00008571-200110000-00002
18. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome
P450 2D6 genotype and codeine therapy: 2014 update. Clin
Pharmacol Ther. 2014;95(4):376–382. doi:10.1038/clpt.2013.254
19. Matic M, De Wildt SN, Tibboel D, Van Schaik RHN. Analgesia and
opioids: a pharmacogenetics shortlist for implementation in clinical
practice. Clin Chem. 2017. doi:10.1373/clinchem.2016.264986
20. Van Driest SL, Shi Y, Bowton E, et al. Clinically actionable
genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clin Pharmacol Ther. 2014. doi:10.1038/
clpt.2013.229
21. Hoffman JM, Haidar CE, Wilkinson MR, et al. PG4KDS: A model
for the clinical implementation of pre-emptive pharmacogenetics.
Am J Med Genet Part C Semin Med Genet. 2014. doi:10.1002/
ajmg.c.31391
22. Weitzel KW, Aquilante CL, Johnson S, Kisor DF, Empey PE.
Educational strategies to enable expansion of pharmacogenomicsbased care. Am J Heal Pharm. 2016. doi:10.2146/ajhp160104
23. Tighe P, Buckenmaier CC, Boezaart AP, et al. Acute pain medicine
in the United States: a status report. Pain Med (United States).
2015;16(9):1806–1826. doi:10.1111/pme.12760
24. Bonica JJ. Neurophysiologic and pathologic aspects of acute and
chronic pain. Arch Surg. 1977;112(6):750–761. doi:10.1001/
archsurg.1977.01370060082014
25. Grichnik KP, Ferrante FM. The difference between acute and
chronic pain. Mt Sinai J Med. (58):217–220. 1991.
26. Treede R-D, Rief W, Barke A, et al. A classification of chronic pain for
ICD-11. Pain. 2015;156(6):1. doi:10.1097/j.pain.0000000000000160
27. Linley JE, Rose K, Ooi L, Gamper N. Understanding inflammatory
pain: ion channels contributing to acute and chronic nociception.
Pflugers Arch Eur J Physiol. 2010;459(5):657–669. doi:10.1007/
s00424-010-0784-6
28. Murnion BP. Neuropathic pain: current definition and review of
drug treatment. Aust Prescr. 2018;41(3):60–63. doi:10.18773/
austprescr.2018.022
29. Gierthmühlen J, Baron R. Neuropathic pain. Semin Neurol.
2016;36(5):462–468. doi:10.1055/s-0036-1584950
30. Nersesyan H, Slavin KV. Current aproach to cancer pain management: availability and implications of different treatment options.
Ther Clin Risk Manag. 2007;3(3):381–400. doi:10.1073/
pnas.0705759104
Kaye et al Dovepress
submit your manuscript | www.dovepress.com
DovePress
140 Pharmacogenomics and Personalized Medicine 2019:12
Pharmacogenomics and Personalized Medicine downloaded from https://www.dovepress.com/ by 141.50.8.169 on 21-Aug-2021
For personal use only.
Powered by TCPDF (www.tcpdf.org)
31. Berg D, Gerlach H. Recent advances in understanding and managing sepsis. F1000Research. 2018;7:1570. doi:10.12688/
f1000research.15758.1
32. Nahin RL. Estimates of pain prevalence and severity in adults:
United States, 2012. J Pain. 2015;16(8):769–780. doi:10.1016/j.
jpain.2015.05.002
33. Davies KA, Silman AJ, Macfarlane GJ, et al. The association
between neighbourhood socio-economic status and the onset of
chronic widespread pain: results from the EPIFUND study. Eur J
Pain. 2009;13(6):635–640. doi:10.1016/j.ejpain.2008.07.003
34. Roth RS, Punch MR, Bachman JE. Educational achievement and
pain disability among women with chronic pelvic pain. J
Psychosom Res. 2001;51(4):563–569. doi:10.1016/S0022-3999
(01)00242-2
35. Brekke M, Hjortdahl P, Kvien TK. Severity of musculoskeletal
pain: relations to socioeconomic inequality. Soc Sci Med. 2002;54
(2):221–228. doi:10.1016/S0277-9536(01)00018-1
36. Wu MT, Pan HB, Lai PH, Chang JM, Tsai SH, Wu CW. CT of
gastritis cystica polyposa. Abdom Imaging. 1994;19(1):8–10.
doi:10.1007/BF02165852
37. Østerås B, Sigmundsson H, Haga M. Perceived stress and musculoskeletal pain are prevalent and significantly associated in adolescents: an epidemiological cross-sectional study chronic disease
epidemiology. BMC Public Health. 2015;15(1):1–10. doi:10.1186/
s12889-015-2414-x
38. Fischer S, Doerr JM, Strahler J, Mewes R, Thieme K, Nater
UM. Stress exacerbates pain in the everyday lives of women
with fibromyalgia syndrome-The role of cortisol and alpha-amylase. Psychoneuroendocrinology. 2016;63:68–77. doi:10.1016/j.
psyneuen.2015.09.018
39. Song TJ, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Anxiety
and depression in tension-type headache: a population-based study.
PLoS One. 2016;11(10):1–12. doi:10.1371/journal.pone.0165316
40. Coulbault L, Beaussier M, Verstuyft C, et al. Environmental and
genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther. 2006;79(4):316–324.
doi:10.1016/j.clpt.2006.01.007
41. Periasamy S, Poovathai R, Pondiyadanar S. Influences of gender on
postoperative morphine consumption. J Clin Diagnostic Res.
2014;8(12):GC04–GC07. doi:10.7860/JCDR/2014/10770.5319
42. Elsbernd A. Zum Verh??ltnis von pflegerischem Wissen, pflegerischer Handlungsfreiheit und den Grenzen des Gehorsams der
individuellen Pflegeperson. Pflege. 1994;7(2):105–116.
doi:10.1002/npr2.12003
43. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain
comorbidity. Arch Intern Med. 2003;163(20):2433. doi:10.1001/
archinte.163.20.2433
44. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N,
Harris JR. Individual differences in pain sensitivity: genetic and
environmental contributions. Pain. 2008;136(1–2):21–29.
doi:10.1016/j.pain.2007.06.008
45. James S. Human pain and genetics: some basics. Br J Pain. 2013;7
(4):171–178. doi:10.1177/2049463713506408
46. Campbell CM, Edwards RR. Ethnic differences in pain and pain
management. Pain Manag. 2012;2(3):219–230. doi:10.2217/
pmt.12.7
47. Green CR, Anderson KO, Baker TA, et al. The unequal burden of
pain: confronting racial and ethnic disparities in pain. Pain Med.
2003;4(3):277–294. Available from: http://www.ncbi.nlm.nih.gov/
pubmed/12974827. Accessed May 1, 2019. doi:10.1046/j.1526-
4637.2003.03034.x
48. Reyes-Gibby CC, Aday LA, Todd KH, Cleeland CS, Anderson
KO. Pain in aging community-dwelling adults in the United
States: non-Hispanic whites, non-Hispanic blacks, and Hispanics.
J Pain. 2007;8(1):75–84. doi:10.1016/j.jpain.2006.06.002
49. Mossey JM. Defining racial and ethnic disparities in pain management. Clin Orthop Relat Res. 2011;469(7):1859–1870.
doi:10.1007/s11999-011-1770-9
50. Jimenez N, Garroutte E, Kundu A, Morales L, Buchwald D. A
review of the experience, epidemiology, and management of pain
among American Indian, Alaska Native, and Aboriginal Canadian
peoples. J Pain. 2011;12(5):511–522. doi:10.1016/j.jpain.2010.
12.002
51. Chan A, Malhotra C, Do YK, Malhotra R, Østbye T. Self reported
pain severity among multiethnic older Singaporeans: does adjusting
for reporting heterogeneity matter? Eur J Pain. 2011;15(10):1094–
1099. doi:10.1016/j.ejpain.2011.05.006
52. Zhu X, Wong F, Bensoussan A, Lo SK, Zhou C, Yu J. Are there
any cross-ethnic differences in menstrual profiles? A pilot comparative study on Australian and Chinese women with primary
dysmenorrhea. J Obstet Gynaecol Res. 2010;36(5):1093–1101.
doi:10.1111/j.1447-0756.2010.01250.x
53. Sjölander P. What is known about the health and living conditions
of the indigenous people of northern Scandinavia, the Sami? Glob
Health Action. 2011;4(1):8457. doi:10.3402/gha.v4i0.8457
54. Shakur H, Roberts I, Fawole B, et al. Effect of early tranexamic acid
administration on mortality, hysterectomy, and other morbidities in
women with post-partum haemorrhage (WOMAN): an international,
randomised, double-blind, placebo-controlled trial. Lancet. 2017;389
(10084):2105–2116. doi:10.1016/S0140-6736(17)30638-4
55. Bates MS, Rankin-Hill L. Control, culture and chronic pain. Soc
Sci Med. 1994;39(5):629–645. Accessed May 1, 2019. doi:10.1016/
0277-9536(94)90020-5.
56. Zhang J-M, An J. Cytokines, inflammation, and pain. Int
Anesthesiol Clin. 2007. doi:10.1097/AIA.0b013e318034194e
57. Si HB, Yang TM, Zeng Y, et al. Correlations between inflammatory
cytokines, muscle damage markers and acute postoperative pain
following primary total knee arthroplasty. BMC Musculoskelet
Disord. 2017. doi:10.1186/s12891-017-1597-y
58. Jung M, Ma Y, Iyer RP, et al. IL-10 improves cardiac remodeling
after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017.
doi:10.1007/s00395-017-0622-5
59. Tammimäki A, Männistö PT. Catechol-O-methyltransferase gene
polymorphism and chronic human pain: a systematic review and
meta-analysis. Pharmacogenet Genomics. 2012. doi:10.1097/
FPC.0b013e3283560c46
60. Sadhu N, Jhun EH, Yao Y, et al. Genetic variants of GCH1
associate with chronic and acute crisis pain in African Americans
with sickle cell disease. Exp Hematol. 2018. doi:10.1016/j.
exphem.2018.07.004
61. Muneer S. Utilizing pharmacogenomics when selecting personalized medicine for patients with chronic pain. American Health and
Drug Benefits. Faculty Perspectives in Chronic Pain. 2016.
62. Světlík S, Hronová K, Bakhouche H, Matoušková O, Slanař O.
Pharmacogenetics of chronic pain and its treatment. Mediators
Inflamm. 2013. doi:10.1155/2013/864319
63. Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to
pain relief. Curr Mol Pharmacol. 2008;1(3):255–269.
64. Valdes AM, De WG, Doherty SA, et al. The Ile585Val TRPV1
variant is involved in risk of painful knee osteoarthritis. Ann Rheum
Dis. 2011;70(9):1556–1561. doi:10.1136/ARD.2010.148122
65. Binder A, May D, Baron R, et al. Transient receptor potential
channel polymorphisms are associated with the somatosensory
function in neuropathic pain patients. Gaetano C, ed. PLoS One.
2011;6(3):e17387. doi:10.1371/journal.pone.0017387
66. Tsantoulas C, Denk F, Signore M, Nassar MA, Futai K, McMahon
SB. Mice lacking Kcns1 in peripheral neurons show increased
basal and neuropathic pain sensitivity. Pain. 2018. doi:10.1097/j.
pain.0000000000001255
Dovepress Kaye et al
Pharmacogenomics and Personalized Medicine 2019:12 submit your manuscript | www.dovepress.com
DovePress
141
Pharmacogenomics and Personalized Medicine downloaded from https://www.dovepress.com/ by 141.50.8.169 on 21-Aug-2021
For personal use only.
Powered by TCPDF (www.tcpdf.org)
67. Nissenbaum J. From mouse to humans: discovery of the CACNG2
pain susceptibility gene. Clin Genet. 2012. doi:10.1111/j.1399-
0004.2012.01924.x
68. Neely GG, Hess A, Costigan M, et al. A genome-wide Drosophila
screen for heat nociception identifies α2δ3 as an evolutionarily
conserved pain gene. Cell. 2010. doi:10.1016/j.cell.2010.09.047
69. Viet CT, Dang D, Aouizerat BE, et al. OPRM1 methylation contributes to opioid tolerance in cancer patients. J Pain. 2017.
doi:10.1016/j.jpain.2017.04.001
70. Mahmoud S, Thorsell A, Sommer WH, et al. Pharmacological
consequence of the A118G μ opioid receptor polymorphism on
morphine-and fentanyl-mediated modulation of Ca2+ channels in
humanized mouse sensory neurons. Anesthesiology. 2011.
doi:10.1097/ALN.0b013e318231fc11
71. Giovannitti JA, Thoms SM, Crawford JJ. Alpha-2 Adrenergic
Receptor Agonists: a Review of Current Clinical Applications.
Anesth Prog. 2015. doi:10.2344/0003-3006-62.1.31
72. Deng Y, Huang J, Zhang H, Zhu X, Gong Q. Association of expression
of DRD2 rs1800497 polymorphism with migraine risk in Han Chinese
individuals. J Pain Res. 2018. doi:10.2147/JPR.S151350
73. Treister R, Pud D, Ebstein RP, et al. Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain
response in healthy humans. Pain. 2009. doi:10.1016/j.
pain.2009.09.001
74. Hooten WM, Hartman WR, Black JL, Laures HJ, Walker DL.
Associations between serotonin transporter gene polymorphisms
and heat pain perception in adults with chronic pain. BMC Med
Genet. 2013. doi:10.1186/1471-2350-14-78
75. Zhao Z, Lv B, Zhao XZ, Zhang Y. Effects of OPRM1 and ABCB1
gene polymorphisms on the analgesic effect and dose of sufentanil
after thoracoscopic-assisted radical resection of lung cancer. Biosci
Rep. 2019;39(1). doi:10.1042/BSR20181211
76. Owusu Obeng A, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management.
Pharmacotherapy. 2017;37(9):1105–1121. doi:10.1002/phar.1986
77. Nielsen LM, Olesen AE, Branford R, Christrup LL, Sato H,
Drewes AM. Association between human pain-related genotypes
and variability in opioid analgesia: an updated review. Pain Pract.
2015;15(6):580–594. doi:10.1111/papr.12232
78. Cohen M, Sadhasivam S, Vinks AA. Pharmacogenetics in perioperative
medicine. Curr Opin Anaesthesiol. 2012;25(4):419–427. doi:10.1097/
ACO.0b013e3283556129
79. Crist RC, Ambrose-Lanci LM, Vaswani M, et al. Case-control association analysis of polymorphisms in the δ-opioid receptor, OPRD1, with
cocaine and opioid addicted populations. Drug Alcohol Depend.
2013;127(1–3):122–128. doi:10.1016/j.drugalcdep.2012.06.023
80. Butelman ER, Yuferov V, Kreek MJ. κ-opioid receptor/dynorphin
system: genetic and pharmacotherapeutic implications for addiction. Trends Neurosci. 2012;35(10):587–596. doi:10.1016/j.
tins.2012.05.005
81. Horn JR, Hansten PD. Get to know an enzyme: CYP2D6. Pharm Times.
Available from: https://www.pharmacytimes.com/publications/issue/
2008/2008-07/2008-07-8624. Published 2008. Accessed April 24,
2019.
82. Ting S, Schug S. The pharmacogenomics of pain management:
prospects for personalized medicine. J Pain Res. 2016;9:49–56.
83. Holthe M, Klepstad P, Zahlsen K, et al. Morphine glucuronide-tomorphine plasma ratios are unaffected by the UGT2B7 H268Y and
UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol. 2002;58(5):353–356.
doi:10.1007/s00228-002-0490-1
84. Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A>G polymorphism in the human u-opioid receptor gene may increase morphine
requirements in patients with pain caused by malignant disease.
Acta Anaesthesiol Scand. 2004;48(10):1232–1239. doi:10.1111/
j.1399-6576.2004.00517.x
85. Sadhasivam S, Chidambaran V, Zhang X, et al. Opioid-induced
respiratory depression: ABCB1 transporter pharmacogenetics.
Pharmacogenomics J. 2015;15(2):119–126. doi:10.1038/
tpj.2014.56
86. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of
codeine and its metabolite morphine in ultra-rapid metabolizers due
to CYP2D6 duplication. Pharmacogenomics J. 2007;7:257–265.
doi:10.1038/sj.tpj.6500406
87. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical
Pharmacogenetics Implementation Consortium Guidelines for
Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014
Update. Clin. Pharmacol. Ther. 2014;95(4):376–382.
88. US Food and Drug Administration. FDA Drug Safety
Communication: FDA Requires Labeling Changes for
Prescription Opioid Cough and Cold Medicines to Limit Their
Use to Adults 18 Years and Older. Available from: https://www.
fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-commu
nication-fda-requires-labeling-changes-prescription-opioid-coughand-cold. Accessed May 30, 2019.
89. Stamer UM, Stüber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6
gene duplication. Anesth Analg. 2008;107(3):926–929.
doi:10.1213/ane.0b013e31817b796e
90. Stauble ME, Moore AW, Langman LJ, et al. Hydrocodone in
postoperative personalized pain management: pro-drug or drug?
Clin Chim Acta. 2014;429:26–29. doi:10.1016/j.cca.2013.
11.015
91. Linares OA, Fudin J, Daly AL, Boston RC. Individualized hydrocodone therapy based on phenotype,pharmacogenetics, and pharmacokinetic dosing. Clin J Pain. 2015;31(12):1026–1035.
doi:10.1097/AJP.0000000000000214
92. Romand S, Spaggiari D, Marsousi N, et al. Characterization of
oxycodone in vitro metabolism by human cytochromes P450 and
UDP-glucuronosyltransferases. J Pharm Biomed Anal.
2017;144:129–137. doi:10.1016/j.jpba.2016.09.024
93. Holmquist GL. Opioid metabolism and effects of cytochrome
P450. Pain Med. 2009;10(suppl1):S20–S29. doi:10.1111/j.1526-
4637.2009.00596.x
94. Zwisler ST, Enggaard TP, Mikkelsen S, Brosen K, Sindrup SH.
Impact of the CYP2D6 genotype on post-operative intravenous
oxycodone analgesia. Acta Anaesthesiol Scand. 2010;54(2):232–
240. doi:10.1111/j.1399-6576.2009.02104.x
95. Naito T, Takashina Y, Yamamoto K, et al. CYP3A5*3 affects
plasma disposition of noroxycodone and dose escalation in cancer
patients receiving oxycodone. J Clin Pharmacol. 2011;51
(11):1529–1538. doi:10.1177/0091270010388033
96. Bencharit S, Morton CL, Xue Y, Potter PM, Redinbo MR.
Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat Struct Biol. 2003;10
(5):349–356. doi:10.1038/nsb919
97. Takashina Y, Naito T, Mino Y, Yagi T, Ohnishi K, Kawakami J.
Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl
pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Drug Metab
Pharmacokinet. 2012;27(4):414–421.
98. Clarke T-K, Crist RC, Ang A, et al. Genetic variation in OPRD1
and the response to treatment for opioid dependence with buprenorphine in European-American females. Pharmacogenomics J.
2014;14(3):303–308. doi:10.1038/tpj.2013.30
99. Kapur BM, Lala PK, Shaw JLV. Pharmacogenetics of chronic pain
management. Clin Biochem. 2014;47(13–14):1169–1187.
doi:10.1016/j.clinbiochem.2014.05.065
100. Carbonell N, Verstuyft C, Massard J, et al. CYP2C9*3 loss-offunction allele is associated with acute upper gastrointestinal bleeding related to the use of NSAIDs other than aspirin. Clin
Pharmacol Ther. 2010;87(6):693–698. doi:10.1038/clpt.2010.33
Kaye et al Dovepress
submit your manuscript | www.dovepress.com
DovePress
142 Pharmacogenomics and Personalized Medicine 2019:12
Pharmacogenomics and Personalized Medicine downloaded from https://www.dovepress.com/ by 141.50.8.169 on 21-Aug-2021
For personal use only.
Powered by TCPDF (www.tcpdf.org)
101. Saba R, Kaye AD, Urman RD. Pharmacogenomics in pain management. Anesthesiol Clin. 2017;35(2):295–304. doi:10.1016/j.
anclin.2017.01.015
102. Liem EB, Teresa VJ, Tsueda K, Sessler DI. Increased sensitivity to
thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology. 2005;102(3):509–514.
103. Stein DJ, Newman TK, Savitz J, Ramesar R. Warriors versus
worriers: the role of COMT gene variants. CNS Spectr. 2006;11
(10):745–748. Accessed May 4, 2019. doi:10.1017/
S1092852900014863.
104. Diatchenko L, Nackley AG, Slade GD, et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking
stimuli. Pain. 2006;125(3):216–224. doi:10.1016/j.pain.2006.05.024
105. Vuilleumier PH, Stamer UM, Landau R. Pharmacogenomic considerations in opioid analgesia. Pharmgenomics Pers Med.
2012;5:73–87. doi:10.2147/PGPM.S23422
106. Jensen KB, Lonsdorf TB, Schalling M, Kosek E, Ingvar M. Increased
sensitivity to thermal pain following a single opiate dose is influenced by
the COMT val158met Polymorphism. Toland AE, ed. PLoS One.
2009;4(6):e6016. doi:10.1371/journal.pone.0006016
107. Hicks J, Bishop J, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19
genotypes and dosing of selective serotonin reuptake inhibitors. Clin
Pharmacol Ther. 2015;98(2):127–134. doi:10.1002/cpt.147
108. Obeng AO, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management. Pharmacotherapy.
2017;37(9):1105–1121. doi:10.1002/phar.1986
109. Reyes-Gibby CC, Shete S, Rakvåg T, et al. Exploring joint effects
of genes and the clinical efficacy of morphine for cancer pain:
OPRM1 and COMT gene. Pain. 2007;130(1–2):25–30.
doi:10.1016/j.pain.2006.10.023
110. James S. Human pain and genetics: some basics. Br J Pain. 2013;7
(4):171–178. doi:10.1177/2049463713506408
111. Yoshida K, Nishizawa D, Ide S, Ichinohe T, Fukuda K, Ikeda K.
A pharmacogenetics approach to pain management.
Neuropsychopharmacol Rep. 2018;38(1):2–8. doi:10.1002/npr2.12003
112. Purchase A, Marschler M, Webster L. Pharmacogenomics in pain
management personalized pain therapy. doi:10.1016/j.cll.2016.05.007.
Available from: https://prahs.com/resources/whitepapers/
Pharmacogenomics-in-Pain-Management.pdf
113. Belfer I. Personalized Pain Medicine: Pharmacogenetic Testing for
Pain and Opioid Addiction PA I N M E D I C I N E N E W S • SEP
TEMBER2015. Available from: https://www.painmedicine
news.com/Review-Articles/Article/09-15/Personalized-PainMedicine-Pharmacogenetic-Testing-for-Pain-and-OpioidAddiction/33480/ses=ogst?%20target=
114. Ko T-M, Wong C-S, Wu J-Y, Chen Y-T. Pharmacogenomics for
personalized pain medicine. Acta Anaesthesiol Taiwanica. 2016;54
(1):24–30. doi:10.1016/J.AAT.2016.02.001
115. Bijl MJ, Visser LE, Hofman A, et al. Influence of the CYP2D6*4
polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol. 2008;65(4):558–564. doi:10.1111/
j.1365-2125.2007.03052.x
116. Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic
differences in genetic polymorphisms of CYP2D6 in the U.S.
population: clinical implications. Oncologist. 2006;11(2):126–135.
doi:10.1634/theoncologist.11-2-126
117. Zhou S-F, Liu J-P, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev.
2009;41(2):89–295. doi:10.1080/03602530902843483
118. Dean L. Codeine Therapy and CYP2D6 Genotype. Bethesda (MD):
National Center for Biotechnology Information (US); 2012.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/28520350.
Accessed April 30, 2019.
119. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS.
Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69–76. doi:10.1038/gim.2016.80
120. Del Tredici AL, Malhotra A, Dedek M, et al. Frequency of
CYP2D6 alleles including structural variants in the United States.
Front Pharmacol. 2018;9:305. doi:10.3389/fphar.2018.00305
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