Download pharmacogenetics of pain

29 August 2014
No. 27
PHARMACOGENETICS OF PAIN
A genetic based approach to personalized pain therapy
R Randolph
Moderator: A Dunpath
CONTENTS
INTRODUCTION ................................................................................................... 3
RARE HEREDITARY SYNDROMES OF COMPLETE INSENSITIVITY TO PAIN 4
THE GENETICS OF VARIABLE PAIN SENSITIVITY IN THE GENERAL
POPULATION....................................................................................................... 5
GENETIC MODULATION OF DRUGS USED IN PAIN TREATMENT .................. 6
PHARMACOGENETICS OF DRUG INTERACTIONS IN PAIN THERAPY ........ 10
GENETIC TESTING ............................................................................................ 12
CONCLUSION .................................................................................................... 14
REFERENCES.................................................................................................... 15
Page 2 of 18
INTRODUCTION
The inadequate treatment of acute and chronic pain remains a major cause of
distress and dissatisfaction among our patient population. It has been estimated
that one out of ten surgical patients develop chronic postoperative pain,
irrespective of the type of surgery.[1] Therefore, effective pain management
remains a key issue. Our awareness of the genetic modulation of pain and
analgesia has grown over the past decade, so too, has our hope of developing a
genetic based approach to pain management.
It has been our expectation that genotyping may provide a guide to analgesic
choice and dose before the commencement of treatment. Genotyping may also
provide a valuable insight into why certain individuals do not respond to
conventional therapy.
Genetic factors determine ones risk of developing a painful disease as well as its
severity from the varied expressive functioning of the nociceptive sensory system
(Figure1). Substances administered for pain are under distributional and metabolic
processes which involve genetic modulation. Finally, the interaction between the
drug and its target site are also under genetic influence.
Several foundation studies, mostly animal models, have provided a source of
candidate genes for genetic association studies in humans. Mice of 11 inbred
strains, showed variable nociceptive responses in 12 different pain models. These
differences in nociceptive sensitivity varied as much as 1.2- 54 fold [2]. Various
mice strains also showed a variation in their nociceptive response to morphine
administration [3]. This has also been seen in humans as opioid dose requirements
vary in the clinical setting by as much as 40 fold [4].
It is well recognised in humans that the risk of developing a painful disease varies
with certain genotypes. Several twin studies have evaluated the heritability of
various pain conditions and have indicated that migraines have a 39-58% genetic
contribution[5], lower back pain carries a 21-67% genetic contribution[6] and
menstrual pain a 55% genetic contribution [7].
Common phenotypes, like those identified in the average population, are highly
complex and multi-genetic. On the other hand, monogenetic heredity have been
restricted to rare and extreme phenotypes.[8] A patient’s phenotype may be
regarded as the sum or balance of synergistic or antagonistic effects of several
genetic variants concomitantly present in an individual.
At present, common genetic variants have not been reliably used to predict an
individual’s pain and analgesic response. The aim of this review is to highlight the
human genetic variants that have been identified in the pharmacotherapy of pain
with the focus on the mechanisms involved and the altered clinical effects of
analgesics.
Page 3 of 18
Figure 1. Pain sensitivity graph [9]
RARE HEREDITARY SYNDROMES OF COMPLETE INSENSITIVITY TO PAIN
The complete inability to sense pain is an extremely rare phenotype. It involves
the interruption of transmission and processing of nociception. Channelopathy
associated insensitivity to pain syndrome results from the loss of functional
mutations in the alpha subunit of the voltage gated sodium channel Na(v)1.7.
These changes are encoded by the gene SCN9A at the locus 2q24.3. [10] It is
exclusively expressed in primary nociceptive sensory neurons where it is
responsible for the amplification of small depolarisations. A further five rare
syndromes are characterized by the absence of pain. Hereditary Sensory and
Autonomic Neuropathy, HSAN (types I-V) results from the loss of functional
mutations in genes which control the development and homeostasis of the
nervous system.[10]
Unfortunately, these syndromes have no practical significance in terms of
pharmacotherapy as they are extremely rare and those that are affected do not
require pain treatment. However, in defining their molecular basis for insensitivity,
new target sites may be considered in the development of novel analgesic drugs.
Page 4 of 18
THE GENETICS OF VARIABLE PAIN SENSITIVITY IN THE GENERAL
POPULATION
The genetics of variable pain sensitivity are influenced by various factors which
have been identified in the general population (Table 1). These include the large
number of genes which encode for the structural components of the nociceptive
system, enzymes producing or degrading nociceptive transmitters and
components that regulate pain pathogenesis.
Mu - opioid receptors
Opioid receptors provide a natural site of action for endogenous ligands such as
endorphin, dynorphin and encephalin. Variable pain sensitivity in the general
population has been associated with common variants of the mu opioid receptor
gene. A variant, exon 1 of the mu opioid receptor gene (OPRM1,
118A>Grs1799971) has been associated with a 0.8 fold lower pressure pain
intensity, especially in females[11]. A 0.5 fold smaller amplitude of pain related
cortical potentials following stimulation of specific nasal nociception to carbon
dioxide, has also been noted.[12] Another study found lower intrathecal fentanyl
dose requirements for labour analgesia in females carrying this variant.[13]
Melanocortin 1 receptors (MCR1)
Kappa agonists , nalbuphine and pentazocine produce pronounced analgesia in
females carrying melanocortin 1 receptor gene variant on chromosome
16q24.3.[14] This variant is known to abolish MC1R functionality and is seen in red
hair, fair skin phenotypes. It has been suggested that the activation of the MC1R
by endogenous neuromodulators exerts anti -opioid activity. This has been
demonstrated by the binding of kappa opioid receptor ligand, dynorphin, to nonmutated MCR1s.The greater effect of Kappa agonists in those carrying this
mutation may be attributed to the omission of this anti –opioid activity due to
mutated nonfunctional MCR1s.
Guanosine triphosphate cyclohydrolase1 (GCH1)
A haplotype of the GCH1 gene on chromosome 14q22.1-q22.2 was found to have
an allelic frequency of 15.4%. GCH1 is a rate limiting enzyme in the production of
tetrahydrobiopterin (BH4) an essential cofactor of nitric oxide synthase. The
accumulation of excessive amounts of BH4 in peripheral nerves following axonal
injury (increase in calcium influx and nitric oxide production), is associated with
the development of neuropathic pain.[15] A decrease in pain has been
demonstrated with reduced GCH1 function in defined cohorts after lumbar disc
surgery.[16]
Transient receptor potential cation (TRPV1)
At least 6 polymorphisms in human TRPV1 gene have been discovered. TRPV1
integrates a number of noxious stimuli such as capsaicin, heat, protons and
leukotrienes. People with complete insensitivity to capsaicin showed several point
mutations in the second intron of their TRPV1 gene. [17]
Page 5 of 18
Table 1: Genetic modulations affecting common human pain phenotype
[8]
GENETIC MODULATION OF DRUGS USED IN PAIN TREATMENT
Pharmacokinetics
Genetic variations may regulate the uptake, transport, metabolism and excretion
of a drug. However, due to the wide therapeutic range of analgesics not all
measurable fluctuations in drug concentration have clinical consequences.
Therefore, focus must be given to variants that have demonstrated an altered
clinical effect.
Drug metabolising enzymes
There are several enzymes that are responsible for the metabolic clearance of
analgesics. It is important to note that if the compound concerned is an active
principle drug then decreased metabolism should result in a greater clinical effect
due to slower systemic elimination. On the other hand, if the compound in
question is a pro-drug then the opposite is true due to the decreased production of
its active metabolite.
Page 6 of 18
Pro-drug activation
A pro-drug is a substance that is administered in an almost inactive from and
requires metabolic activation before its clinical effects are recognised.
Codeine, tilidine, parecoxib, metamizole, and tramadol(less typical) are all
examples of pro-drugs.
Codeine is extensively metabolised by the cytochrome P450 isoenzyme 2D6.
After the ingestion of 30mg of codeine, 81% was transformed into codeine 6
glucuronide, 2.2% into norcodeine, 0.6% transformed into free morphine, 2.1%
into morphine 3 glucuronide, 0.8% into morphine 6 glucuronide and 2.4%
transformed into normorphine.[18] Of interest only 6% of codeine is transformed
into morphine and its glucuronides. Codeines clinical effect is determined by its
conversion to morphine as morphine has a 200 fold higher affinity and 50 fold
higher intrinsic activity at the mu receptor compared to codeine.[19]
As the CYP2D6 system which metabolizes codeine is genetically polymorphic, the
effects of codeine are under pharmacogenetic infleunce.[20] Genetically
determined codeine effects may result from absent, decreased or highly increased
CYP2D6 activity when compared with the population average.
The decreased effects of codeine can be seen in 7-11% of the Caucasian
population as they display a poor metabolizer phenotype (PM) as very low levels
or no morphine is formed after the administration of codeine. [21] On the other hand
7% of the Caucasian population has an extremely active CYP2D6 ultrafast
metabolizer phenotype (UM) with very high levels of morphine being formed.[22]
Therefore, one in seven Caucasians are at risk of treatment failure or toxicity from
codeine.[23]
Tramadol a mu receptor agonist has a lower receptor affinity than its metabolite odesmethyltramadol. However, tramadol is not without effect should the CYP2D6
display a poor metabolizer phenotype.[24] This is because non-opioid dependent
mechanisms involve serotonin and noradrenaline pain inhibition in the brain stem.
Tilidine is metabolized to nortilidine and paraecoxib to valdecoxib via CYP3A. This
enzyme system is genetically polymorphic. Individuals with at least one
CYP3A5*1 allelele copy produce high levels of full CYP3A5 MRnA and display
active CYP3A5 functionality.[25] 95% of the Caucasian population have no active
CYP3A5 due to a premature stop cordon.[26] Positive associations between prodrug activation and analgesic activity have not been reported.
Drug inactivation
Morphine, codeine and buprenorphine undergo glucuronidation which is mediated
by UDP glucuronosyl transferase (UGT)2B7.[27] A couple of genetic
polymorphisms have been discovered. In the case of morphine, the main
metabolites are morphine 3 glucuronide and morphine 6 glucuronide. Both
metabolites are active, but seem to display opposite effects.
Page 7 of 18
Morphine 3 glucuronide has an anti-analgesic and excitatory effect when
compared to the opioid agonistic effects of morphine 6 glucuronide. Functional
polymorphisms at the UGT2B7 gene have been associated with a change in
plasma concentration ratios of opioids and their glucuronide metabolites[28]
The Tyr268 UGT2B7 glucuronidates buprenorphine at a 10 fold higher rate in vitro
than the His268 isoform.[28] In vivo variants of the 5 untranslated region of
UGT2B7 are associated with reduced morphine 6 glucuronide to morphine
ratio.[29] UGT variants are restricted to alterations in plasma concentrations and
none of the variants alone have been associated with altered analgesic effect.
Increased enzyme activity associated with the CYP3A581 allele may cause the
accelerated elimination of CYP3A substrates.[30] These include alfentanil,
fentanyl and sufentanil. Positive associations between CYP3A polymorphisms and
analgesic activity have not been reported.
Transmembrane transporters
P – glycoprotein ( P-gp) a transmembrane transporter is located in organs that
have an excretory function like the liver, kidney and gastrointestinal tract. At the
blood brain barrier it forms an outward tract. P-gp is coded by the ABCB1 gene.[31]
Functional impairment of P-gp may lead to the increased bioavailability of orally
administered drugs, decreased renal clearance and increased brain
concentrations. One would therefore expect an increased clinical effect and
decreased dose requirements for P-gp substrates if its functionality were impaired.
Methadone dosing in heroin substitution may be decreased in carriers ABCB1
variant.[32]
Loperamide an opioid used for its antidiarrheal properties does not produce high
CNS concentrations because of its poor absorption and rapid elimination.
However, in the ABCB1 343577 variant it produced significant CNS opioid effects
due to the inhibition of P-pg.[33] Those individuals that carry the ABCB1 345C>T
variant are at increased risk of fentanyl associated respiratory depression. [34]
Pharmacodynamics
Genetic factors may decrease the effects of analgesics. They can result in
inadequate receptor binding, activation and signalling.
Opioid receptors
OPRM1 gene is highly polymorphic and so far 1799 Human SNPs have been
identified.[35] Of consequence, genetic mutations that code for the 3 rd intracellular
loop of the mu receptor have resulted in decreased G protein coupling, signalling
and desensitization.
OPRM1 variant 118A>G SNP is present in >5% of the population. Carriers of this
variant display decreased clinical effects to various opioids in experimental and
clinical models.[36]
Page 8 of 18
G protein coupled receptor kinase (GRK) and G protein coupled inwardly
rectifying potassium channels (GIRK) are involved in intracellular opioid receptor,
signalling cascade. GIRKs are the primary post synaptic effectors of opioids in the
CNS while GRK are involved with opioid receptor desensitization. GRK2,3,6 have
shown to modulate opioid tolerance[37].GRK2 and 6 may play a role in
inflammation and allodynia.[38] GIRK1 and GIRK2 are involved in opioid induced
analgesia.[39] GIRK3 are modulators of pain sensitivity.[40] GIRK and GRK are
currently being examined as candidates in experimental models for the genetic
modulation of pain and opioid effect.
Catechol-o-methyl transferase
As mentioned earlier, COMT degrades catecholamine neurotransmitters.
Reduced COMT functionality increases dopamine concentrations that suppress
the production of endogenous opioid peptides.[41] As a result, opioid receptors are
up regulated. This has been demonstrated with the V158M variant of COMT.
Patients with cancer pain carrying the variant V158M needed less morphine than
those that did not.[42]
Cyclooxygenases
Prostaglandin endoperoxide synthase 2 gene (PTGS2) codes for cycloxygenase 2
(COX2). COX2 modulates inflammation and provides a target site for antiinflammatory drugs especially COX2 inhibitors. PTGS2-765G>C SNP resulted in a
twofold decrease in COX2 expression[43]. Not surprisingly carriers of the -765G
variant lacked the analgesic effects of Rofecoxib.[44].
Co analgesics
Co analgesics are often used in the treatment of chronic pain. Several
antidepressants used in the treatment of chronic neuropathic pain are substrates
of polymorphic CYP2D6 or CYP2C19.[45] It terms of their pharmacodynamics,
antidepressant target structures, are norephinephrine (SLC6A2) and
serotonin(SLC6A4) transporters.[46] These have been found to display genetic
variability. This has led to a specific genotype dependant dosage
recommendation. Unfortunately, these are based on psychiatric response rather
than analgesic.
Page 9 of 18
PHARMACOGENETICS OF DRUG INTERACTIONS IN PAIN THERAPY
There are three main types of enzyme interactions. A substrate (Table 2) is any
drug that is metabolized by an enzyme. An inducer (Table 3) is a drug that
accelerates the metabolism of another.
This results in the increased breakdown and clearance as well as a decreased
duration of action. However, if the drug is a pro-drug, accelerated metabolism
would lead to an increase in activity. An inhibitor (Table 4) is a medication that
reduces the metabolism of another drug.
This may result in excessively high concentrations, increased effect and toxicity. If
the drug in question is a pro-drug there may be a decreased effect as a result of
its inhibition.
The incidence of potential drug interactions increase with the number of
medications being used by an individual. There are 7 clinically relevant enzymes
responsible for the metabolism of commonly used drugs. These include CYP1A2,
CYP2C8, CYP2C9,CYP2C19, CYP2D6,CYP2E1 and CYP3A4.
St. John’s wort, used in the treatment of depression induces CYP1A2, 2C9 and
3A4. The induction of CYP2C9 and CYP1A2 leads to the accelerated metabolism
of warfarin with decreased blood concentration and a greater risk of clot
development.[47] Smoking is a potent inducer of CYP1A2 resulting in decreased
caffeine levels. This may explain the increased agitation experienced when
smoking stops and caffeine levels begin to rise.[47]
Many of the drugs commonly used are substrates, inhibitors or inducers of
medication used in pain therapy. Due to genetic variability many enzymes lose
their compensatory capacity when additional drugs are added which target the
same pharmacological system.
For example the effects of loperamide on the CNS are increased by the
administration of quinidine a P-gp blocker in carriers of the P-gp gene variant
ABCB1 3435C>T. [55] Non functional variants of CYP2C9 may increase the
plasma concentration of COX inhibitors like ibuprofen, diclofenac or celecoxib. As
these drugs have a broad therapeutic range, changes in clinical effect are unlikely
unless warfarin also a CYP2C9 substrate is added, then the risk of bleeding may
increase exponentially.[48]
Page 10 of 18
Table 2: Common substrates of CYP enzymes [50]
Table 3: Common Inducers of the CYP enzymes [50]
Page 11 of 18
Table 4: Common inhibitors of CYP enzymes [50]
GENETIC TESTING
Genetic polymorphism may cause absent or reduced enzyme activity, resulting in
drugs being metabolised slowly. These individuals are at increased risk of side
effects or treatment failure. Knowledge of an individual’s polymorphism could aid
in selecting the appropriate agent, at a safe dosage.
Patients can be classified according to how effectively they metabolize a drug.
This depends on the number of normal alleles they inherit. An extensive
metabolizer (EM) has two normal alleles where as an intermediate metabolizer
(IM) has 1 normal and 1 reduced allele or 2 partially deficient alleles.
A poor metabolizer (PM) has 2 mutant alleles leading to a limited or loss of
activity. Finally, Ultra rapid metabolizer (UM) may have multiple copies of
functional alleles leading to excessive activity.
There appears to be an ethnic distribution of polymorphism among metabolizes,
as 7 -10% of whites are PMs, with a CYP2D6 deficiency compared to 1-2 % of
Asians and 2-4% of blacks. Approximately 30% of Asians and blacks are IMs of
CYP2D6. Approximately 10% of Southern Europeans and 1-2% of Northern
Europeans are UMs.[51]
Page 12 of 18
Genotype based dose adjustment would offer a standard dose, for example of 2
tablets for an EM where as a PM could be offered a single tablet. An IM could
need 1.5 tablets and a UM three or more tablets to achieve the same clinical
effect.[52]
Quantitative urine drug screening may offer clues as to the genetic make-up of an
individual. If there is poor conversion of hydrocodone to hydromorphone or poor
conversion of oxycodone to oxymorphone, this would suggest a CYP2D6
inhibition or deficiency. If this patient were to complain of poor analgesia then
changing to hydromorphone or oxymorphone would bypass the CYP2D6 system
and improve analgesic response.
DNA testing has become economically feasible with several SNPs available,
these include CYP enzymes, 2D6, 2C9, 2C19 and 3A4. Testing can be used to
determine or explain ineffective or high opioids use. Patients with a CYP2D6
deficiency would be expected to display a poor response to tramadol, codeine,
hydrocodone and oxycodone.
On the other hand, patients with an UM, CYP2D6 enzyme may be at risk of
developing high levels of morphine from codeine metabolism. By changing to an
opioid not metabolised by that particular enzyme a more effective and better side
effect profile may be achieved. As mentioned previously, patients with an inactive
OPRM1 allele displayed a poor response to the mu agonist morphine and my
benefit from switching to a K agonist like buprenorphine.
Page 13 of 18
CONCLUSION
Genetic research has improved our understanding of the molecular pathways in
nociception and analgesia. Unfortunately, the multi genetic heredity of pain in our
population coupled with the small effect of each variant, remains a particularly
challenging target for genetic based personalized therapy.
The impact of pharmacogenetics for pain therapy may be further reduced by
additional factors, such as disease, environment and the concurrent use of
medication. However, there are some practical uses for genetic testing. Our
current pharmacogenetic knowledge of the CYP2D6, MC1R and PTGS2 may
guide our choice for the correct analgesic drug.
Currently, our patients are given a trial and error based analgesic challenge.
Further research is required to identify patients who are at risk of severe opioid
side effects and drug dependency, or those that will benefit from a particular class
of drug, before the initiation of therapy.
Page 14 of 18
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