Opinion

A critical appraisal of human

genotyping for pain therapy
Jorn Lotsch and Gerd Geisslinger
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe - University, Theodor Stern Kai 7, 60590 Frankfurt am
Main, Germany

Despite intensive research, genetics-based personalized

pain therapy has yet to emerge. Monogenetic heredity
seems to be restricted to very rare and extreme phenotypes, whereas common phenotypes are very complex
and multigenetic. Many common variants, of which only
a fraction have been identified so far, produce only minor
effects that are sometimes partly cancelled out. For most
clinical settings and analgesic drug effects, common
genetic variants cannot yet be used to provide a relevant
prediction of individual pain and analgesic responses.
However, genetics has some potential practical uses:
CYP2D6, MC1R and potentially PTGS2 could provide
guidance on the right choice of analgesics. After more
than a decade of identifying genetic associations, the
current challenge is to intensify compilation of this
information for precisely defined clinical settings for
which improved pain treatment is possible.
Introduction
Increasing awareness of genetic modulators of pain and
analgesia has raised expectations that genotyping information could be used to guide analgesic choice and dosage
for individual patients before initiation of their therapy.
This has been successfully applied in other fields; for
example, basing warfarin therapy on the individual cytochrome P450 (CYP) 2C9 genotype accelerated achievement
of stable anticoagulation, increased the duration of effective blood concentrations and reduced side effects [1].
Similar improvements are desired in pain treatment.
Reasonable scientific and clinical interest in this issue
was reflected in 159 publications according to a PubMed
search for genetics & pain therapy & human studies on 25
February 2010. However, genotyping-based pain therapy
has not yet entered clinical practice. By contrast, the
clinical utility of genotyping in pain control has been
questioned [2]. After more than a decade of intensive
research into the genetics of common clinical pain and
rare pain syndromes, the body of knowledge is large
enough for a critical evaluation of the role of genotyping
in pain treatment.
Genetics of nociceptive processing
The genetic control of nociception has been systematically
studied in mice using several approaches, such as null
mutants, gene knockdown and selective breeding. For
example, mouse strains varied 1.2- to 54-fold in their
Corresponding author: Lotsch, J. (j.loetsch@em.uni-frankfurt.de).

312

nociceptive sensitivity in various pain models and differed

with respect to the antinociceptive effects of morphine [3].
Many inbred strains were examined for pain phenotypes
and pain variability genes were identified by performing
genome-wide linkage mapping or quantitative trait locus
mapping that searched for DNA variants associated
with trait variability [4]. So far, 299 pain-relevant genes
have been identified (PainGenes Database, http://www.
jbldesign.com/jmogil/enter.html) [5].
Extreme pain phenotypes
Very rare cases of absent pain have been genetically
explained so far. Reasons identified have been loss-offunction mutations of the a-subunit of the voltage-gated
sodium channel Nav1.7 gene (SCN9A) that lead to inactive
channels [6]. Increased-function mutations in the same
gene cause primary inherited erythromelalgia, which consists of episodic symmetric skin redness, vasodilatation
and a burning pain in the feet and lower legs on exercising,
standing for long periods or exposure to warmth [7]. A
further five rare syndromes characterized by absent pain
(hereditary sensory and autonomic neuropathy, HSAN,
types IV) are caused by loss-of-function mutations in
genes (SPTLC1, HSN2, IKBKAP, NTRK1 and NGFB) that
control components important for the development, functioning and homeostasis of the nervous system [8].
Common pain phenotypes
Twin studies on pain phenotypes have emphasized that
genetic factors contribute to sensitivity to pain-producing
stimuli in humans [912]; however, particular functional
genes have not yet been identified by such studies. Based
on candidate approaches or translation of information
obtained from mice, genetic modulations affecting human
average pain have been identified in a few genes [8]
(Table 1). These code for structural components of the
nociceptive system, enzymes producing or degrading
nociceptive transmitters, or other components of the pathogenesis of pain. Although the role of an altered function of
their gene products is reasonable and positive evidence is
available, the functionality of variants in these genes is
often based on just a single positive report (TRPA1) [13], on
two positive reports (OPRM1) [14,15], on two positive
(GCH1) [16,17] versus two negative [18,19] reports, on
four or more positive (COMT) [2023] versus one negative
report [24], or one positive (OPRD1, MC1R) [24,25] versus
one negative [13,26] finding. To date, almost every genetic
association with common human nociception has been

0165-6147/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.04.002 Trends in Pharmacological Sciences 31 (2010) 312317

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Table 1. Genetic modulations affecting common human pain phenotype.

Gene
Reported effects b
Shown or postulated key mechanisms
Genetic variants in the average population with altered but no loss of activity for the gene product
Increased opioid effects
Opioid accumulation due to decreased outward transporter expression
ABCB1
Increased opioid effects,
Decreased dopamine degradation, enkephalin downregulation and compensatory
COMT
changes in nociception
opioid receptor upregulation, decreased norepinephrine degradation and
upregulation of b-adrenergic nociceptive pathways
Decreased codeine and
Inactive enzyme required for prodrug activation
CYP2D6
tramadol effects
Increased codeine and
Hyperactive enzyme with increased active drug formation
tramadol effects
Increased pain
Decreased enzyme activity would be expected to increase endocannabinoid signaling
FAAH
and decrease pain; increased pain is not yet explained by a molecular mechanism
Decreased or delayed pain
Decreased tetrahydrobiopterin production leading to decreased NO, norepinephrine
GCH1
and serotonin synthesis
Increased pain
Increased transcription of the interleukin 1 gene
IL1A
Increased interleukin 1 levels
IL1B
Enhanced production of pro-inflammatory interleukin 1
IL1RN
Increased interleukin 6 levels
IL6
Increased interleukin 8 production [51,52]
IL8
Decreased opioid effects
Decreased expression of postsynaptic potassium channels [53,54]
KCNJ6
Increased opioid analgesia and
Modulation of descending modulatory systems in the periaqueductal grey region
MC1R
decreased pain sensitivity
and altered opioid tone
Increased pain
Decreased d-opioid receptor signaling
OPRD1
Decreased spontaneous pain
Increased binding of endogenous opioids and decreased signaling efficiency of
OPRM1
and decreased opioid analgesia
exogenous opioids at m-opioid receptors
Decreased effects of
Decreased COX-2 expression [40]
PTGS2
selective COX-2 inhibitors
Decreased pain
Difference in the voltage-dependent slow inactivation of sodium channels [55]
SCN9A
Decreased pain
Decreased nociceptor activity
TRPA1
Increased pain
Increased nociceptor activity
TRPV1
Rare variants, often in a few families with loss-of-function or greatly increased activity of the gene product
HSAN-II
Defective development and maintenance of peripheral sensory neurons or their
HSN2
supporting Schwann cells
HSAN-III
Dysregulation of neuronal exocytosis
IKBKAP
HSAN-V
Decrease in unmyelinated nerve fibers and moderate loss of thin myelinated nerve fibers
NGFB
HSAN-IV
Defective target of the nerve growth factor with altered neuronal survival
NTRK1
Channelopathy-associated
Absence of conduction due to inactive sodium channels
SCN9A
insensitivity to pain
Autosomal dominant
Increased conduction due to hyperactive sodium channels
erythromelalgia
HSAN-I
Decreased sphingolipid synthesis, perturbing neuronal development and functioning
SPTLC1
a

For full details about genetic variants, phenotype effects and original references, see [8].
The majority of reports of effects or a general tendency, without single reports of the opposite effect, are of absent effects.

disputed. Moreover, several variants statistically associated with pain phenotypes still lack a demonstration of
consequences at the molecular level. Effect sizes are generally small, such as those of OPRM1 118A>G, with a Cohen
d value of 0.3 1 for modulation of heat and ischemic pain
[14].
Genetics of analgesic effects
Extreme phenotypes in analgesic treatment
An extreme phenotype is displayed by pain patients who
need excessively large opioid doses of >2 g/day of oral
morphine. A rare monogenetic reason for this might be
the OPRM1 802T>C variant, because this leads to virtually absent signaling of the S268P m-opioid receptors
[27]. However, this single-nucleotide polymorphism (SNP)
has been found in only a single family and the hypothesized
phenotype has not been assessed yet. Some additional rare
variants could provide further confirmation of this phenotype [28,29]. Among common variants, OPRM1 118A>G
1
The accepted interpretation is that d=0.2 is indicative of a small, 0.5 of a medium
and 0.8 of a large effect.

(N40D) could only contribute to this phenotype in the

presence of other factors. A greater frequency of the G
allele in this extreme phenotype than in the average
population would hint at a form of genetic selection [30].
However, the allelic frequency of 16.7% (HapMap Project,
http://www.hapmap.org/) in Caucasians indicates that it
cannot be a sufficient monogenetic cause of this rare phenotype. By contrast, this variant is carried by many pain
patients requiring average opioid doses [31]. The 118G
genotype might thus only be a risk factor and could retrospectively offer an explanation for cases of high opioid
demands.
Common phenotypes in pain patients
A setting resembling CYP2C9-dependent warfarin therapy
is CYP2D6-dependent codeine analgesia. This polymorphic enzyme activates codeine transformation to morphine, which produces the analgesic effects. Its genetics is
well understood, at least in Caucasians, and absent or
reduced enzyme function can be predicted from the genotype. However, if the CYP2D6 genotype were the only
determinant of codeine analgesia, then therapy failure
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Opinion
could be expected in 7% of Caucasians, because this is the
percentage of carriers of non-functional CYP2D6. This
corresponds to a number needed to treat 2 (NNT) of 2 or
3 when assuming 20% or 50% placebo responders, respectively. When including the 15% of subjects with reduced
CYP2D6 function (intermediate metabolizers), the
expected NNT would be similar. However, the published
NNT for 60 mg of codeine is 50 or 9 [32] to obtain 50% relief
of dental or postsurgical pain, respectively, at best. To date,
a high degree of morphine formation with a risk of toxicity
can be predicted from CYP2D6 gene amplification in half of
cases, whereas there is still no identifiable genetic cause for
the rest of the 7% phenotypic ultrafast-metabolizers [33]. It
has not yet been assessed whether codeine toxicity could be
better predicted in North Africa, where 29% of the population carry alleles with multiple CYP2D6 genes [34].
Thus, CYP2D6 genotyping could serve to exclude the use
of codeine in approximately 10% of patients because of
ineffectiveness or toxicity, but would fail to identify many
patients who experience the same clinical problems.
Most pharmacogenetic evidence for opioid therapy is
available for m-opioid receptor polymorphisms, which are
prime candidates for opioid effect modulation [35]. The
OPRM1 118A>G (N40D) SNP leads to decreased receptor
signaling in a pain-relevant brain region (secondary somatosensory area) [36], although negative results [27] mean
that its biological function is less certain. Nevertheless, it
frequently produced decreased opioid potency in experimental settings controlling for many confounders. However, a meta-analysis of clinical studies revealed no effect
on opioid demands and pain scores [37], despite positive
single-study outcomes. Moreover, the clinical utility of this
genetic information has not strongly convinced physicians.
Analgesic therapy is rarely planned before pain occurs;
instead, dosing is quickly titrated according to the patients
response. The need to start with larger opioid doses in
carriers of the 118G genotype does not seem to be urgent
and the protection against respiratory depression conferred by OPRM1 118GG [38] cannot be used as an excuse
to neglect the supervision of patients under postoperative
opioid analgesia.
Common functional variants in other genes (ABCB1,
MC1R, COMT and KCNJ6) seem to produce effects of a
similar modest size. Moreover, because opioid therapy is
not started at the maximum dose, COMT or ABCB1 genotyping information that would indicate the suitability of a
lower dose is of restricted utility. Furthermore, there is
still no urgent clinical demand for disclosure of ABCB1
genotype information to avoid opioid-induced respiratory
depression [39]. Such small effects have been unconvincing
for incorporation of genotype information into opioid dosing guidelines.
Perhaps clinically more important than dose adaptations would be genetic guidance on the choice of analgesic. Besides CYP2D6 guidance for codeine prescription, the
ineffectiveness of a selective cyclooxygenase-2 (COX-2)
inhibitor in carriers of the PTGS2 variant rs20417 G>C
2
NNT=1/(A/n1C/n2), where A and C are the numbers of responders to codeine and
placebo treatment, respectively, and n1 and n2 are the total numbers of subjects
treated with the respective substance. For 7% poor metabolizers and with n1=n2=100,
A=100%7%=93%.

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[40], which decreases COX-2 expression, could serve to

exclude COX-2 inhibitors from analgesic choice for an
individual, although this ineffectiveness has been disputed
[41] . Better analgesia of k-opioid agonists in red-haired
fair-skinned women carrying MC1R variants could also
serve to incorporate k-opioid analgesics otherwise considered weak into a wider choice of stronger pain relief
options.
Extreme and common phenotypes and genotypes
Studies on human pain genetics have shown that the
effects of common polymorphisms in average subjects
are small, although a genetic component remains undisputed. By contrast, large genotype effects are exerted by
extremely rare variants, mainly identified for hereditary
syndromes with greatly altered pain perception [27] (see
above) but that suggest monogenetic pain traits. It is
reasonable that this is conferred by rare genotypes when
considering that distinct and extreme pain phenotypes are
very rare too. If common pain and analgesic effects, which
exhibit a unimodal distribution over a wide range (i.e.
single-peak histograms), were modulated monogenetically
by a variant with a large effect, then the causal variant
would have to be carried by most subjects, otherwise the
phenotype would not be common or the distribution would
be bi- or multimodal. However, too many people would then
carry an extreme phenotype, which contradicts the definition of extreme in a unimodal distribution.
A further problem in identifying relevant variants
arises from the fact that one or more common functional
variants are carried by almost all individuals. The probability of not carrying at least one mutation is very small
for five example variants assumed to be functional. For
OPRM1 118A>G (G allele frequency of 10% in 246 randomly chosen unrelated Caucasians), COMT 472G>A
(51.8%), TRPV1 rs8065080A>G (36.8%), FAAH
rs4141964 T>C (39%) and a GCH1 haplotype (13.6%),
the probability of not carrying any of these variant alleles
is equal to the joint probability for the wild-type subjects
for each variant. For the five variants, the joint probability
of carrying none is 2%. The probability will approach zero
when including many more pain genes that have yet to be
identified (Figure 1). By contrast, the concomitant presence of variants is also likely. Because this could include
variants with opposite phenotypic effects on pain of comparable size, the effect of a single variant is masked in most
people by the effects of other variants [42], although statistically significant effects could be identifiable in large
samples. However, for prospective phenotype prediction,
the exact combination of pain-relevant variants would be
required. This includes the few known variants that comprise less than one-tenth of the 299 pain genes identified
in mice [5] and probably many more variants yet to be
identified. Ideally, collection of all the information about all
the functional variants should facilitate prediction of a
pain or analgesia phenotype as a combined effect. In this
context, Goldstein has identified a major problem [43]: by
explaining only small parts of the common variance,
genetics provides little guidance because most genes will
contribute to the variance and thus, in pointing at everything, genetics would point at nothing. This view might be

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Figure 1. Concommitant presence of functional polymophisms. Left: Closed circles show the decreasing probability (closed symbols, left ordinate) of not carrying any
mutated allele with increasing numbers of functional gene variants. This is calculated as the product of the probabilities of carrying only wild type alleles of each
polymorphic gene locus. The latter is obtained according to the Hardy-Weinberg law as the square of the wild-type allelic frequency given by 1 minus the variant allelic
frequency, which is depicted at the bottom of the figure as open symbols (right ordinate). For OPRM1 118A>G (rs1799971), COMT 472 G>A (rs4560), TRPV1 rs8065080 A>G,
FAAH rs4141964 T>C, and a GCH1 haplotype 16, shown as triangles, the minor allelic frequencies of 0.1,0.52, 0.37, 0.39 and 0.14, respectively, were taken from 246
randomly selected unrelated Caucasian subjects were. The following 45 minor allelic frequencies (circles) are random numbers between 0.1 and 0.5. Right: Genotypes for
five variants observed in 246 unrelated Caucasian subjects and the number of subjects carrying 05 mutated genes. The cell plot has 246 lines, each representing one
subject, and five columns, each representing one gene variant, resulting in five cells per subject, together showing the grayscale-coded individual genotype with respect to
the five loci selected.

unilateral because it has been shown that body height,

given as an example of a multigenetic trait, is influenced by
identifiable genetic factors [44]. Much larger numbers of
variants of smaller effect, rarer variants with possibly
larger effects that are poorly detected by current genotype
association strategies and low power for detection of gene
gene interactions are reasons proposed for the low genotypephenotype predictive value called missing heritability in genome-wide association studies [45]. The detection
of relevant genotypes will benefit from identification of
variants in rate-limiting steps of the various cellular pathways of nociception and analgesia, thus reducing the
number of genotypes needed to predict phenotype.
Genotyping as a tool
Rodent models [4,46,47] have been used to identify molecular pathways of nociception and new target proteins.
Genotyping for rare and common variants has also been
used in humans to explain familial syndromes and identify
indispensable components of the human nociceptive system. Functional common variants were used to prove the
role of nociceptive pathways in humans in the absence of
other means to manipulate the pathway of interest. The
focus was on the modulation of biological mechanisms
rather than on genetics. For example, the role of GCH1
activity in pain, first identified in laboratory animals, was
confirmed in humans using GCH1 genetic variants shown
to decrease enzyme upregulation and tetrahydrobiopterin
production at the molecular level [17]. However, the geno-

type associated with altered pain itself does not yet have
predictive clinical value in pain therapy personalization;
rather, it is used as a vehicle to translate a molecular
principle to humans. Finally, genetic association studies
could be used as a tool to generate such hypotheses but this
requires molecular proof and replication of the findings.
Genetics has also contributed to the identification of functionally relevant portions of a gene product, as in the case
of the m-opioid receptor, for example [27].
Conclusions
The genetics of pain is valuable as a research tool in
elucidating the role of molecular pathways in human
nociception and analgesia [4,46]. However, the multigenetic heredity of common pain and the small effect of each
variant mean that pain and analgesia are a particularly
challenging target for genetics-based personalized medicine. In contrast to other fields, such as anti-cancer therapy
[48] and warfarin anticoagulation [1], genotyping has not
yet provided significant clinical benefits in pain management. For most clinical settings and analgesics, common
genetic variants cannot yet provide a relevant prediction of
individual analgesic response [33,37]. The multigenetic
nature of pain has characteristics that currently limit
higher expectations for genotyping information [43]. However, genetics has potential practical uses. CYP2D6 and
MC1R, and possibly PTGS2, are examples for which current pharmacogenetic knowledge might guide choice of the
correct analgesic drug.
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Opinion
Several functional common genotypes in several common pain phenotypes have been proven as a concept,
raising the issue of their clinical utility [49]. A precise
definition of the clinical settings in which pharmacogenetic
information could improve pain management should
precede future research directions. Currently, the variants
about which most information has been acquired modulate
opioid doses by pharmacokinetic or pharmacodynamic
mechanisms. If individualized opioid dosing were the
major clinical need, then research should focus on developing genetics-based dosing regimens. If, however,
titration of opioid doses suffices in clinical practice, then
greater benefits would arise from the possibility of choosing the optimum individual analgesic before therapy
initiation. In this case, research should be focused on
identifying patients who will suffer from severe opioid side
effects, such as drug dependency, or will most or least
benefit from an analgesic class, before such information
is revealed after months of therapeutic trial. Prospective
studies will increase in importance and biomathematical
methods will be increasingly required to process this complex information; several of the pitfalls of genetics association studies should thus be avoided [50]. The challenge
will be to compile this and additional information into
clinically practicable therapy guidance.
Acknowledgement
Our work is supported by the Deutsche Forschungsgemeinschaft. We
thank Mark Sellen for English language editing.

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