Pharmacogenetics of PainMaree T Smith, Centre for Integrated Preclinical Drug Development, University of

Queensland, Brisbane, Queensland, Australia

Arjun Muralidharan, Centre for Integrated Preclinical Drug Development, University of

Queensland, Brisbane, Queensland, Australia

Marked interindividual variability in pain severity ratings

and the analgesic dosing requirements of patients with

apparently similar pain states is underpinned by genetic

and environmental factors, and their interactions. Over

the past decade, rodent heritability studies, familial

aggregation and twin studies in humans have provided

insight into the genetic factors contributing to inter-

individual variability in pain sensitivity. Concurrently, a

large number of genetic association studies using the

candidate gene paradigm have investigated the impact

of single nucleotide polymorphisms in numerous genes

encoding receptors, ion channels, enzymes and trans-

porters, on pain sensitivity. Despite initial promise, most

genetic association studies have either failed to replicate

or have been only partially replicated by independent

investigators; the underlying issues are addressed herein.

Apart from deficiencies in study design and execution

and inappropriate choice of statistical methods, subtle

between-study differences in interacting environmental

factors that affect pain phenotypes (epigenetics), are a

likely explanation.

Introduction

According to the International Association for the Studyof Pain, pain is ‘an unpleasant sensory and emotionalexperience associated with actual or potential tissuedamage, or described in terms of such damage’ (http://www.iasp-pain.org). Acute pain following a surgical pro-cedure or due to traumatic injury has a protective role byproducing guarding behaviour that promotes healing andgives a survival advantage. By contrast, chronic painconditions such as fibromyalgia and many types of per-ipheral neuropathic pain are characterised by on-goingpain either in the absence of apparent injury or long afteran injury has healed. Such persistent pain states are

regarded as maladaptive and ‘disease’ entities in their ownright. See also: Pain and AnalgesiaThe considerable interindividual variability in pain

severity ratings self-reported by patients with apparentlysimilar pain states is well known to clinicians (Young et al.,2012; Vuilleumier et al., 2012) as it manifests in markedinterpatient variability in analgesic dosing regimensneeded to produce satisfactory analgesia with tolerableside-effects. Significant interindividual variability in self-reported pain severity ratings is not confined to patientswith clinical pain as this is mirrored in healthy humansubjects exposed to standardised acute noxious nociceptivestimuli in a laboratory setting. Interestingly, healthy indi-viduals who reported high pain severity scores also exhib-ited more robust nociceptive stimulus-evoked corticalactivation when assessed using functional magnetic reso-nance imaging, and vice versa (Ploner et al., 2010; Bro-dersen et al., 2012). Factors contributing to interindividualvariability in self-reported pain severity ratings include themotivational-emotional response to nociceptive stimuli, aswell as environmental and genetic factors and their inter-play (epigenetics) (Bain and Shaw, 2012; Doehring et al.,2013; Figure 1; Seo et al., 2013). Genetic factors may affectthe regulation of neurotransmitters, receptors, enzymesand ion channels in nociceptive signalling pathways as wellas those that underpin analgesic drug pharmacodynamics(Svetlik et al., 2013). Environmental factors include patientage, sex, disease comorbidities including hepatic and renalfunction, concurrent medications, as well as lifestyle vari-ables such as alcohol consumption and smoking (Smithand Muralidharan, 2010).In the following sections, research in rodents and

humans aimed at identifying genetic factors potentiallycontributing to interpatient variability in pain severityratings is reviewed.

Pain Genetics: Insights from Mice

Seminal work in the late 1990s using quantitative sensorytrait analysis in 11 different mouse strains across 12 testingmodalities demonstrated that there were pronouncedbetween-strain differences in the levels of nociception/hypersensitivity behaviours evoked by application ofstandardised acute noxious thermal, mechanical and che-mical stimuli and that these pain-related traits were

Advanced article

Article Contents

. Introduction

. Pain Genetics: Insights from Mice

. Heritability Studies in Humans

. Conclusion

Online posting date: 9th December 2013

eLS subject area: Genetics & Disease

How to cite:Smith, Maree T; and Muralidharan, Arjun (December 2013)

Pharmacogenetics of Pain. In: eLS. John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0025152

eLS & 2013, John Wiley & Sons, Ltd. www.els.net 1

heritable (Mogil et al., 1999). These findings were extendedby subsequent research using rodent models of inflamma-tory and neuropathic pain to show that genetic factorscontributed significantly to measures of pain sensitivity aswell as pain relief produced by opioid and nonopioidanalgesics (Mogil, 2012). Although there are limitations inthe use of mouse pain models in hereditary studiesincluding the divergence in mechanisms for alternativegene splicing events between mice and humans (Ermakovaet al., 2006), mice are nevertheless the preferred species dueto their short generation time and the relative ease forconstructing transgenic and knockout mice (Lacroix-Fralish and Mogil, 2009).Amajor assumption underpinning heritability studies in

mice using quantitative trait loci mapping to identify spe-cific genes underlying complex traits, such as pain sensi-tivity, is that the respective contributions of genetic andenvironmental factors to phenotypic variability can bedissociated. However, inadvertent contravention of thisassumption may occur due to subtle environmental chan-ges including cage density, housing, humidity, testingprocedures, season and time of day; the net result is sig-nificant changes in the behavioural pain phenotypeobserved (Lacroix-Fralish and Mogil, 2009). This is illu-strated by the fact that despite use of highly standardised

behavioural testing protocols for concurrent nociceptivetesting of several mouse strains by three different researchlaboratories, gene� environment interactions wereimportant sources of variability in the data generated(Crabbe et al., 1999). The impact of gene� environmentinteractions on pain-related traits has been affirmed bymultiple independent investigators (Lacroix-Fralish andMogil, 2009). Sex differences in pain and analgesia are alsowell-documented; see review by Mogil and Bailey (2010).See also: Quantitative Trait Loci (QTL) Mapping

Heritability Studies in Humans

Since completion of the human genome and InternationalHapMap projects, numerous candidate pain genes andsingle nucleotide polymorphisms (SNPs) that potentiallyaffect pain sensitivity have been identified. To date, 390candidate pain genes are proposed to contribute to heri-table differences in pain sensitivity. This information isavailable in a publicly accessible database (http://www.jbldesign.com/jmogil/PainGenedb_content_Wide.html; accessed 3 July 2013). See also: HapMap Project;Human Genome Diversity Project (HGDP)

Sensory afferentnerve terminal DRG

Spinal cord

Nociceptive signalling

Beneficialor

adverseeffects

SNPs in genes encoding

Modulation of pain phenotypes

(a) Receptors(e.g. MOP-R, MC1R and 5HTR)

(c) Enzymes (Neurotransmitter levels)(e.g. COMT, MAO and GCH-1)

(d) Transporters(e.g. NET and SERT)

(b) Ion channels(e.g. Na+ and K+)

Spin

otha

lam

ictr

act

Environmental factors

Des

cend

ing

inhi

bito

rypa

thw

ay

Figure 1 Schematic diagram illustrating the considerable interindividual variability in pain sensitivity ratings is underpinned by genetic and environmental

factors, as well as their interactions. Adapted with permission from Muralidharan and Smith (2013). & Springer.

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Pharmacogenetics of Pain

Human twin studies

Classical twin studies have proven invaluable in improvingour understanding of phenotypic variability due to geneticand environmental factors. Unlike familial aggregationstudies, twin studies allow the heritability of a trait to beestimated. However, a significant limitation is that they donot provide insight into the genes involved. The proportionof trait variance explained by inherited genetic factors in anumber of painful conditions including back pain, spinalpain, sciatica, musculoskeletal pain and irritable bowelsyndrome have been assessed using the twin studyapproach; see reviewbyNielsen et al. (2012).See also: TwinStudiesApart from clinical pain, the heritability of pain

responses by healthy human subjects to experimentallyapplied noxious stimuli in a laboratory setting has beeninvestigated in several twin studies. Exposure of 98 pairs ofhealthyCaucasian female twins (51monozygotic (MZ)and47 dizygotic (DZ)) to a variety of experimental noxiousthermal and chemical pain stimuli, showed that geneticfactors could explain 22–55% of the interindividualvariability inpain responses (Norbury et al., 2007). In otherwork in 53 identical MZ, 39 DZ twins and 4 single twins,there was 26% and 60% variance in heat pain and cold-pressor pain responses, respectively (Nielsen et al., 2008).However, only 7% of the variance in cold-pressor and 3%of the variance in heat pain were explainable by geneticfactors (Nielsen et al., 2008).More recently, genetic factorswere found to account for 49% of the interindividualvariance of twins in cold-pressor pain tolerance (Angstet al., 2012b). In the same study, 12–60% of the inter-individual variability in analgesia produced by the strongopioid analgesic, alfentanil, for relief of cold-pressor painand heat pain, were explainable by genetic factors (Angstet al., 2012b). Significant heritability (30–59%) of alfen-tanil-induced opioid-related adverse effects was alsoobserved (Angst et al., 2012a).

Collectively, the aforementioned data from twin studiesshow that extrapolationof findings fromonepainmodalityto another is unwise.

Genetic association studies in humans

Despite great advances in our understanding of the neu-robiology of chronic pain, translation of this wealth of newknowledge from laboratory bench to patient bed-side,remains to be achieved. Hence, the pharmacologicalarmamentarium available for prescribing by cliniciansfor the alleviation of clinical pain remains similar to thatwhich was available two decades ago (Muralidharan andSmith, 2011). Additionally, as already noted, pain is asubjective experience with wide interindividual variabilityin pain severity ratings and analgesic dosing requirements(Muralidharan and Smith, 2011).The contribution of genetic variability to the large

interindividual differences in pain severity ratings bypatients with apparently similar pain states, their analgesic

dosing requirements and adverse event profiles, have beeninvestigated in a large number of genetic association stu-dies. Using this approach, it was anticipated that key SNPsin candidate pain genes encoding receptors, enzymes and/or ion channels would have a large impact on levels of painreported and that this information could then be used todevelop point-of-care diagnostics to assist clinicians toindividually tailor analgesic drug therapy. However, thereality is that genetic association study outcomes havegenerally failed to replicate or have been only partiallyreplicated by independent investigators (Table 1; Kim et al.,2009). Hence, development of point-of-care devices forpatient genotyping to enable individual tailoring ofanalgesic drug therapy is unlikely in the near-term (Sad-hasivam and Chidambaran, 2012). See also: Genetic Var-iation: Polymorphisms and Mutations; Single NucleotidePolymorphism (SNP)In the following sections, recent research on genetic

factors potentially contributing to interindividual varia-bility in pain sensitivity is discussed.

Genetic determinants: G protein coupled receptors(GPCRs) and pain sensitivity

m-Opioid receptor (OPRM1)

The human m-opioid receptor (MOP-R) is amember of thesuperfamily of seven-transmembrane spanning GPCRs.The MOP-R gene, OPRM1 (chromosome 6q24–q25)spans over 200 kb with at least 9 exons and 19 differentsplice variants under the control of multiple promoters.See also: Opiates and OpioidsAlthough multiple functional OPRM1 polymorphisms

have been identified, genetic association studies havefocused primarily on the influence of the A118G SNP(Asp40Asn) located in exon 1 of the OPRM1 gene.Although there are reports of positive correlations betweenthe A118G SNP in OPRM1 and pain sensitivity, opioiddosing and/or opioid-induced side-effects (Hajj et al.,2013), these have generally failed to replicate (Table 1; seereviews byMura et al., 2013; Hajj et al., 2013; SadhasivamandChidambaran, 2012). Hence, the conclusion of ameta-analysis was that the relevance of the OPRM1 A118Ggenetic variant is questionable due to inconsistency in itsassociation with various pain-related phenotypes (Walterand Lotsch, 2009).Although the IVS1-C2994T and IVS2+G31A SNPs in

the OPRM1 gene were reportedly correlated significantlywith pain sensitivity and pressure pain thresholds, respec-tively (Shabalina et al., 2009), independent investigatorsfound no significant association between these SNPs andany pain-related traits in patients with chronic widespreadpain or fibromyalgia (Finan et al., 2010; Holliday et al.,2009).In more recent work undertaken in two independent

patient cohorts, a relationship between chronic opioidexposure and increased deoxyribonucleic acid (DNA)methylation was observed, suggesting that epigenetic

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Pharmacogenetics of Pain

Table 1 The outcomes of genetic association studies for single nucleotide polymorphisms (SNPs) in genes implicated in the modulation of pain are often conflicting

Gene Gene product Genotype Study populationa Study outcomes References

OPRM1 m-opioid receptor OPRM1 118A4G EXP 2� Significant associations

1. This SNP was associated with higher thermal

pain thresholds in men, lower thermal pain

thresholds in women and higher mechanical pain

thresholds in both men and women

2. Individuals carrying the OPRM1 118GG

genotype required 2–4-fold higher alfentanil

plasma concentrations to achieve analgesia and

10–12-fold higher alfentanil concentrations to

evoke respiratory depression, when compared

with individuals not carrying this genotype

Fillingim et al. (2005),

Oertel et al. (2006)

CLIN No significant association between this SNP and

opioid dose for relief of acute postoperative pain.

Major allele (A118) in patients with chronic painwas

associated with higher opioid dosages

Janicki et al. (2006)

Individuals sharing at least one G allele and those

homozygous for the A/A allele were poor and good

morphine responders respectively. The A118G

polymorphism appeared to significantly affect

morphine responsiveness

Campa et al. (2008)

4� Significant associations with apparently similar

findings showing that individuals homozygous for

G118 required higher morphine doses compared

with those who were homozygous for A118 or

heterozygotes

Reyes-Gibby et al. (2007),

Chou et al. (2006a, b), Sia

et al. (2008)

IVS2+G31A EXP Significant association between the IVS2+31G4A

SNP and pressure pain threshold in healthy adult

female subjects

Huang et al. (2008)

IVS1-C2994T EXP Significant association between IVS1-C2994T and

pain sensitivity in healthy male and female subjects

Shabalina et al. (2009)

CLIN 2� No significant association in patients with

chronic widespread pain or fibromyalgia with

respect to pain sensitivity

Holliday et al. (2009),

Finan et al. (2010)

MC1R Melanocortin-1

receptor

MC1R (R151C,

R160W and

D294H) (red hair

phenotype)

EXP Significant associations with apparently

contradictory findings

1. Nonfunctional MC1R associated with decreased

electrical pain sensitivity and increased m-opioidanalgesia

Mogil et al. (2003, 2005),

Liem et al. (2005)

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2. MC1R genotype significantly associated with

higher levels of pentazocine analgesia in women

but not men

3. MCR1 genotype more sensitive to thermal pain

and resistant to the analgesic effects of lignocaine

SCN9A Nav1.7 sodium

channel

rs6746030 EXP Significant association between SCN9A

polymorphism and experimental pain measures

evoked by C-fibre activation

Reimann et al. (2010)

CLIN Significant association between SCN9A

polymorphism and pain perception in patients with

five different chronic pain conditions

Reimann et al. (2010)

Significant association between SCN9A

polymorphism and pain perception in patients with

multiple regional pain, but not osteoarthritic pain

Valdes et al. (2011)

KCNS1 Kv9.1 potassium

channel

rs734784 EXP Significant association between rs734784 and

aggregate pain score calculated over 16 pain

modalities

Costigan et al. (2010)

CLIN Significant association between KCNS1

polymorphism and pain intensity observed in

cohorts of various clinical pain conditions

Costigan et al. (2010)

5HT1B and

5HT1F

Serotonin receptor

5HT1B

T-261G, A-161T

and G861C

CLIN No association between SNPs in genes encoding the

serotonin receptor and response to triptans

Mehrotra et al. (2007),

Asuni et al. (2007), Velati

et al. (2008)

Serotonin receptor

5HT1F

SNPs in 5HT1F No association between SNPs in genes encoding the

serotonin receptor and response to triptans

Vandenbrink et al. (1998)

SLC6A4 Serotonin

transporter

5HTTLPR

polymorphisms

CLIN No association between 5HTTLPR polymorphism

and migraine. A meta-analysis of 10 studies

concluded no significant association between

migraine and 5-HTTLPR polymorphism in

Europeans and Asians

Schurks et al. (2010a)

STin2 of SCL6A4 Meta-analysis of 5 studies suggested a protective

effect of the 10/12 and 10/10 genotypes cf. the 12/12

genotype formigraine in people of European descent

Schurks et al. (2010b)

Significant association between the STin2

polymorphism and migraine with aura in a

paediatric population

Szilagyi et al. (2006)

GCH1 Guanosine

triphosphate

cyclohydrolase 1

GCH1 SNPs and

haplotypes

EXP Decreased GCH1 function due to genetic

polymorphism protected against pain

Tegeder et al. (2008)

Weak or negligible association between thermal and

cold pain responses and GCH1 genetic

polymorphism in healthy volunteers

Kim and Dionne (2007)

CLIN Kim and Dionne (2007)

(continued )

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Table 1 Continued

Gene Gene product Genotype Study populationa Study outcomes References

Role of GCH1 polymorphism in nociceptive pain

after third molar surgery is weak or negligible

2� Significant associations

Pain protective haplotype

1. Shows high threshold to mechanical pain

2. Longer time between cancer diagnosis andopioid

initiation therapy for homozygous carriers

Tegeder et al. (2006),

Lotsch et al. (2010)

COMT Catechol-O-methyl

transferase

COMT 158 EXP No significant association between the val158met

polymorphism and sensitivity to cold pain

Birklein et al. (2008)

CLIN Individuals homozygous for the met158 allele

showed diminished m-opioid responses when

compared with heterozygotes. The opposite effects

were observed for val158 homozygotes

Zubieta et al. (2003)

COMT polymorphisms do not appear to be

implicated in the genetic liability to migraine or to

increased susceptibility to neuropathic pain.

There was no association between Val158Met

polymorphism and migraine. For women with the

Val/Val genotype, nonmigrainous headache tended

to be less likely than for those with other genotypes

Cevoli et al. (2006),Hagen

et al. (2006), Armero et al.

(2005)

2 � Significant associations with comparable results

1. Individuals with Val/Val and Val/Met genotypes

required 63% and 23% higher morphine doses

respectively relative to carriers of the Met/Met

genotype

Reyes-Gibby et al. (2007),

Rakvag et al. (2005)

COMT 158 and

haplotypes

EXP 3� Significant associations

Following application of standardizsed thermal,

mechanical and ischaemic pain stimuli to healthy

female subjects, three major COMT haplotypes

(LPS, APS and HPS) encompassing 96% of the

examined genotypes appeared to determine COMT

enzymatic activity.

1. The LPS, APS and HPS haplotypes were

associated with low, average and high pain

sensitivity respectively The LPS haplotype was

associated with much higher levels of COMT

activity compared with the APS and HPS

haplotypes.

Diatchenko et al. (2005,

2006), Nackley et al.

(2009)

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2. TheVal158Met genotypewas associatedwith the

rate of temporal summation of heat but not other

types of pain. Individuals with low COMT

activity appeared to have an increased risk of

developing chronic pain.

3. Presence of a single LPS haplotype appeared to

diminish the risk of developing myogenous

temporomandibular joint disorder by 2.3-fold

13 SNPs from

COMT

EXP There were no differences among Val/Val, Val/Met,

andMet/Met populations in contrast to the findings

of Zubieta et al. (2003), andDiatchenko et al. (2006),

who reported higher pain ratings for met/met

homozygotes and that the levels of pain sensitivity

were correlated with LPS,APS andHPS haplotypes,

respectively

Kim et al. (2006b)

15 SNPs from

COMT

CLIN SNPs in intron 1 of the COMT gene at positions -

4873G and -4871G appeared to be protective against

morphine-related drowsiness, confusion and

hallucinations. However, there was no association

between COMT genotype and morphine dose or

serum morphine or metabolite concentrations.

Ross et al. (2008)

SNPS from MAO

A and MAO B

CLIN In females only, there was a weak association

between relief of postoperative pain and SNPs in

MAO A but not MAO B

Kim et al. (2006a)

MAO A and

MAO B

Monoamine

oxidase

SNPS from MAO

A and MAO B

CLIN Significant association between A/G polymorphism

in intron 13 of the MAOB and average intensity of

postoperative pain in male subjects.

Sery et al. (2006)

aCLIN, clinical pain; EXP, experimental pain.Source: Adapted and updated from Muralidharan and Smith (2011).

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mechanisms may have a role in the development of opioid-induced hyperalgesia (Doehring et al., 2013).

Melanocortin-1 receptor (MC1R)

MC1R is a GPCR encoded by theMC1R gene that is bestknown for its role in pigmentation as 75% of individualswith red hair or fair skin have two to three inactivatingvariants (R151C, R160W and D294H) in MC1R (Mogilet al., 2005). Mice with nonfunctional MC1Rs exhibiteddecreased pain sensitivity across a broad range of noci-ceptive modalities and this was mirrored by the higherelectrical pain tolerance of healthy subjects with two orthree of the aforementioned inactivating MC1R variants(Liem et al., 2005; Mogil et al., 2005). By contrast in otherwork, there were no significant differences in electrical painperception or threshold in red-haired compared with dark-haired women (Liem et al., 2005). However, in the samestudy, red-haired women were more sensitive to heat painas well as cold pain perception and tolerance, comparedwith their dark-haired counterparts (Liem et al., 2005). InMC1Rknockoutmice ormicewith amutatedMC1R gene,female but notmale animals exhibited a higher tolerance toinflammatory and thermal pain (Delaney et al., 2010)suggesting a possible sex-specific role for the MC1R innoxious thermal and inflammatory pain.

Genetic determinants: ion channels�pain sensitivity

SCN9A (Nav1.7 sodium channel)

Antiarrhythmic drugs such as lidocaine and mexiletineproduce analgesia by blocking voltage-gated sodiumchannels expressed on sensory nerve fibres (Dib-Hajj et al.,2013).Of the nine voltage-gated sodiumchannels identifiedto date, Nav1.3, Nav1.7, Nav1.8 and Nav1.9 are expressedprimarily in sensory nerves that transduce nociception(Dib-Hajj et al., 2013). See also: Evolution of Voltage-Gated Sodium ChannelsThe Nav1.7 channel is encoded by SCN9A and it is

predominantly expressed in dorsal root ganglion (DRG)neurons (Dib-Hajj et al., 2013). Studies in knockout miceconfirmed the essential role of Nav1.7 in nociceptive neu-rotransmission (Nassar et al., 2004). Additionally, indivi-duals with nonsense mutations in SCN9A are unable tosense pain (channelopathy associated insensitivity to pain)(Cox et al., 2010) whereas those with rare gain-of-functionmutations suffer from primary erythromelalgia and par-oxysmal extreme pain disorders (familial pain syndromes)(Reimann et al., 2010). Hence, these genetic findings inhumans serve to validate Nav1.7 as a suitable target forpain therapeutics discovery programmes.However, using a genetic association study approach to

evaluate the influence of the rs6746030 SNP in SCN9A onclinical pain outcomes, there are conflicting results. In amixed cohort of 1277 patients with sciatica, osteoarthritis,pancreatitis, lumbar disectomy and phantom limb pain,there was a significant association between pain score andthe rs6746030 SNP such that individuals with the rarer Aallele reported higher pain scores (Reimann et al., 2010). In

other work, there was a significant correlation of thers6746030 SNP in patients with multiple regional pain butnot osteoarthritic pain (Valdes et al., 2011).

KCNS1 (Kv9.1 potassium channel)

Voltage-gated potassium channels (Kv), like voltage-gatedsodium channels, are key physiological regulators ofmembrane potentials in excitable tissues such as DRGsensory neurons (Takeda et al., 2011). Activation of K+

channels leads to hyperpolarisation of the cell membraneand a consequent decrease in cellular excitability (Takedaet al., 2011). See also: Voltage-gated Potassium ChannelsAnalysis of global gene expression profiles in the DRGs

from three different rat models of neuropathic pain identi-fied the KCNS1 gene (encoding Kv9.1) as being of impor-tance in neuropathic pain (Costigan et al., 2010). Asubsequent genetic association study by the same groupshowed that the V allele of a nonsynonymous polymorph-ism (rs734784 (1489V)) in KCNS1 was correlated sig-nificantly with higher pain severity ratings in four of fivecohorts ofpatientswith chronicpain, andagroupofhealthysubjects subjected to acute noxious nociceptive stimuli in alaboratory setting (Costigan et al., 2010). On this basis, theauthors proposed that the ‘valine risk allele’ ofKCNS1maybe a prognostic indicator for chronic pain risk. However, inblack (n=158, 78% female) South Africans with humanimmunodeficiency virus-associated sensory neuropathy,significant associations between individual SNPs inKCNS1and pain intensity were lacking (Hendry et al., 2013).Nevertheless, there were significant correlations betweenseveral haplotypes of population-specific tag SNPs andpainintensity after correction for age, gender and CD4 T-cellcount, suggestive that the haplotypes incorporate thecausative SNPs (Hendry et al., 2013).

Genetic determinants: neurotransmitters�painsensitivity

There is compelling evidence that the development andmaintenance of the so-called ‘central sensitisation’ that iscausative in the pathobiology of neuropathic pain isunderpinned by increased excitatory and decreased inhibi-tory neurotransmission in the dorsal horn of the spinal cord(Vranken, 2012). Hence, tricyclic antidepressants (TCAs)that augment descending noradrenergic and serotoninergicsignalling in the central nervous system (CNS) are oftenused as first-line agents for the relief of neuropathic pain(Vranken, 2012). Thus, SNPs in genes encoding nor-epinephrine, serotonin, one or more receptors (e.g. ser-otonin (5HTR)), transporters such as the norepinephrinetransporter (NET) and the serotonin transporter (SERT),the enzyme, guanosine triphosphate cyclohydrolase 1(GCH1) involved in their biosynthesis, and metabolicenzymes including, catchol-O-methyl-transferase (COMT)and monoamine oxidase (MAO), have the potential tomodulate nociception as well as analgesic drug out-comes (Svetlik et al., 2013). See also: Amine Transporters;Neurotransmitter Transporters; Neurotransmitters

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Pharmacogenetics of Pain

5HTR

There are seven families of 5-HT receptors (5-HT1–7)comprising 15 subtypes (Nichols and Nichols, 2008). Allare members of the superfamily of seven transmembranedomain spanning GPCRs except for the ionotropic 5-HT3

receptor (Nichols and Nichols, 2008), and they modulateligand-gated and voltage-gated ion channels (Gentile et al.,2011). Triptans, mainly used for the treatment ofmigraine,exert their actions by binding primarily to 5HT1B/1Dreceptors (Gentile et al., 2011). Although several poly-morphisms have been described in the 5HT1B gene, themajority of association studies have focused on three mainSNPs, viz. T-261G, A-161T and G861C. However, thereare no significant associations between the clinical responseto triptans and these three SNPs in 5HT1B (Gentile et al.,2011). See also: Serotonin Receptors

Monoamine reuptake transporters

NET (SLC6A2)TCAs and selective noradrenaline reuptake inhibitorsexert their pain-relieving actions by acting as NET inhibi-tors to augment descending noradrenergic inhibitorymechanisms in the CNS. Although SNPs in the SLC6A2gene encoding NET are weakly associated with pain sen-sitivity in patients with postoperative pain (Kim et al.,2006a), the influence of these SNPs on the modulation ofchronic pain remains to be investigated.

SERT (SLC6A4)TheSERT regulates serotoninergic neurotransmission andis encoded by the 5HTT gene (also known as SERT orSLC6A4). The 5HTT gene has two main functional var-iants, viz. 5-HTTLPR and STin2 VNTR (Gentile et al.,2011).The 5-HTTLPR variant is due to a 44 base-pair (bp)

insertion/deletion in the 5’ promoter region to generateeither a long (L) or a short (S) allele (Gentile et al., 2011).Although several groups reported positive correlations forthe 5-HTTLPR polymorphism with attack frequency ofmigraine, a large cohort study (Wieser et al., 2010) as wellas a systematic review and meta-analysis of 10 studiesconducted in European and Asian patients concluded thatthe 5-HTTLPR polymorphism is not significantly asso-ciated with migraine (Schurks et al., 2010a). Contrary toinitial reports that the 5-HTTLPR polymorphism is asso-ciated with a higher risk for tension-headache (Park et al.,2005) andfibromyalgia (Buskila et al., 2007),meta-analysisfound that the 5-HTTLPR S/L allele was not significantlyassociated with susceptibility to fibromyalgia (Lee et al.,2012). By contrast, there was reportedly a significantassociation between the 5-HT2A receptor 102T/C poly-morphism and susceptibility to fibromyalgia (Lee et al.,2012).The STin2 VNTR is a 17 bp variable number of tandem

repeats located in intron 2 of the 5HTT gene resulting inalleles carrying 9-, 10- or 12-repeats (Gentile et al., 2011).Despite the biological function of this polymorphismbeing

unclear, the STin2.10 allele is associated with lower tran-scriptional activity than the STin2.12 allele (Fiskerstrandet al., 1999). The STin2 VNTR polymorphism in theSLC6A4 gene of patients with migraine reportedly con-ferred a higher risk of inconsistent response to triptans(Terrazzino et al., 2010), but there are also reports to thecontrary (Yilmaz et al., 2001; Todt et al., 2006). Meta-analysis of 5 studies suggested a protective effect of the 10/12 and 10/10 genotypes cf. the 12/12 genotype formigrainein people of European descent (Schurks et al., 2010b).

Monoamine biosynthesis

GCH1The enzyme, GCH1, regulates the biosynthesis of tetra-hydrobiopterin, an essential cofactor in the synthesis ofcatecholamines and nitric oxide (Tegeder et al., 2006). Insupport of a key role for GCH1 in the modulation of painsensitivity, a GCH1 haplotype and 15 SNPs in the GCH1gene were significantly associated with less pain in patientsfollowing discectomy for persistent radicular low backpain (Tegeder et al., 2006). In the same study, individualscarrying two copies of the pain-protective haplotype fromtwo cohorts of healthy subjects exposed to standardisednoxious heat, noxious pressure and ischaemic pain stimuliin an experimental setting, were significantly less sensitiveto mechanical pain (Tegeder et al., 2006). However, in alarge cohort of patients with postoperative pain after thirdmolar extraction, there were only weak or negligibleassociations between GCH1 variants and pain sensitivity(Kim and Dionne, 2007). It is possible that these appar-ently paradoxical findings may be explained by differencesin haploblock architecture between the two postoperativepain patient populations (Tegeder et al., 2008). In patientswith cancer, genotyping showed that individuals homo-zygous for noncoding and nonsplice site GCH1 variantsresulting in lowGCH1expression levels, hada longermeanperiod (78 months) from cancer diagnosis to initiation ofopioid therapy, when compared with heterozygous indi-viduals (37 months) or noncarriers (30 months) (Lotschet al., 2010). By contrast in 2294 patients with cancer pain,significant associations between GCH1 variants andopioid dosing requirements were not apparent (Klepstadet al., 2011).

COMTCOMT encoded by the COMT gene, is an enzyme thatdegrades catecholamines including epinephrine and nor-epinephrine (Muralidharan and Smith, 2011). Initialreports of a significant association of the COMT SNPV158M (also called rs4680), with various common chronicpain conditions including fibromyalgia, migraine andtemporomandibular joint disorder (Smith and Mur-alidharan, 2010;Young et al., 2012), were not replicated byothers (Table 1; Smith and Muralidharan, 2010; Younget al., 2012).

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Pharmacogenetics of Pain

MAOMAOare a family of enzymes that catalyse the oxidationofmonoamines (Kim et al., 2006a). The two isoforms,MAO-A and MAO-B, are encoded by the genes MAOA andMAOB, respectively, which share 70% amino acidsequence homology (Kim et al., 2006a). In female patientswith postoperative pain, there was a weak associationbetween pain sensitivity and SNPs in MAOA, but notMAOB (Kim et al., 2006a). By contrast, there was a sig-nificant relationship between the A/G polymorphism inintron 13 of MAOB and mean pain intensity in malepatients with postoperative pain (Sery et al., 2006). Forpatients with migraine, SNPs in MAOA and MAOB werenot significantly correlated with migraine risk (Gentileet al., 2011).

Conclusion

Genetic association studies conducted over the past 15years have failed to identify robust relationships betweenSNPs in candidate pain genes encoding various receptors,enzymes or ion channels that transduce or modulatenociceptive signalling and pain severity ratings in eitherdiscrete patient populations or healthy volunteers sub-jected to acute noxious heat, chemical or electrical painstimuli.Hence, future research aimed at elucidating geneticinfluences on pain phenotypes and analgesic responsive-ness need to utilise strategies other than the candidate geneapproach.

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Further Reading

Altman RB, Flockhart D and Goldstein DB (2012) Principles of

Pharmacogenetics and Pharmacogenomics. New York: Cam-

bridge University press.

Hirschhorn JN, Lohmueller K, Byrne E and Hirschhorn K

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ment – Clinical pharmacological implications. European Jour-

nal of Clinical Pharmacology 67(6): 541–551.

Lotsch J (2012) Pharmacogenetics of pain medication. In: Mait-

land-Van Der Zee A-H and Daly AK (eds) Pharmacogenetics

and Individualized Therapy. Hoboken: JohnWiley & Sons, Inc.

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