Pharmacogenetic influences in obstetric anaesthesia

Pharmacogenetic influences in obstetric anaesthesia

Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 277–287 Contents lists available at ScienceDirect Best Practice & Research Cl...

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Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 277–287

Contents lists available at ScienceDirect

Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn

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Pharmacogenetic influences in obstetric anaesthesia Ruth Landau, MD, Virginia and Prentice Bloedel Professor of Anesthesiology, Director of Obstetric Anesthesia and Clinical Genetics Research * Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, 1959 NE Pacific Street, Suite BB 1415B Seattle 98195, Washington, USA

Keywords: pharmacogenetics genomics polymorphism SNP adrenergic receptor m-opioid receptor pregnancy preterm labour vasopressors b-blockers anaesthesia analgesia pain opioids fentanyl

Genomic discoveries in the field of perioperative medicine and anaesthesia have generated multiple publications and some hope that pharmacogenetic testing may guide clinicians to provide safe and effective medicine in a ’tailored’ manner. Within the field of anaesthesia, many consider that ‘titration of drugs to the desired effect works just fine’ and wonder if pharmacogenomics will ever impact on their daily practice. This review will cite practical examples of relevant candidates genes and common polymorphisms that have shown to alter the response to medication prescribed in the peripartum period by obstetricians and anaesthesiologists. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction Pharmacogenetics is the study of the variability in drug response due to genetic variability. The first observations that genetic factors may impact on the response to various pharmacological agents occurred in the mid-50’, with Werner Kalow’s report of prolonged postoperative muscle relaxation following the administration of succinylcholine, an anaesthetic drug used to facilitate orotracheal intubation. This report described how an inherited variation of drug metabolism involving the enzyme butyrylcholinesterase affects the response to succynilcholine and may cause prolonged apnoea. 1

* Tel.: þ1 206 543 2187; Fax: þ1 206 543 2958. E-mail address: [email protected] 1521-6934/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpobgyn.2009.11.009

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Recent developments in genomic research have opened vast opportunities to expand and improve our understanding of how genetic variability may not only affect the efficacy in response to medication we administer on a daily basis, but may also allow to improve patient safety in helping predict risks of adverse outcomes. The ultimate goal of pharmacogenetics research is to offer ‘tailored personalized medicine’. In the field of anaesthesia and peri-operative medicine, numerous clinical trials and reviews have surfaced in the recent years 2–10, and clinicians often wonder about the relevance of genetic research and consider that ‘titration of drugs to the desired effect works just fine’. Nonetheless, the challenges of translating pharmacogenetics to clinical practice are hopefully on their way. The goal of this review is to highlight examples of genetic variants relevant to obstetric anaesthesia with the hope to convey the message that the ‘trial and error pharmacotherapy’ and ‘one size fits all’ dogmas are bound to die. This review will focus on pharmacokinetic and pharmacodynamic polymorphisms affecting the response to (a) vasopressors for spinal hypotension during caesarean delivery, (b) bblockers to treat hypertension and provide myocardial protection, (c) bronchodilators for management of asthma, (d) tocolytics for preterm labour, and (e) pain management during labour and delivery and post-caesearean analgesia. Polymorphisms with clinical relevance Within the field of obstetric anaesthesia, several clinical issues have triggered a myriad of randomized clinical trials to identify the optimal dose of various pharmacological therapies. Genetic variability of a variety of drug receptors (adrenergic receptors, m-opioid receptor) or drug-metabolizing enzymes (Cytochrome P450) may explain the wide variability in observed therapeutic response and phenotype. Vasopressor requirement during spinal anaesthesia for caesarean delivery Numerous clinical trials have evaluated the response to vasopressors to prevent and or treat hypotension during spinal anaesthesia for elective caeserean delivery. 11 For decades, ephedrine has been considered a safe option based on classic studies in sheep that suggested deleterious effects of pure a-adrenergic agonists on uteroplacental blood flow. Ephedrine has been widely used in a variety of regimens (different bolus doses, infusions and in combination with phenylephrine) although no consensus has ever been achieved as to which of these modes of administration provides the most reliable and effective response. Ephedrine is a sympathomimetic amine, the principal mechanism of its action relies on its direct and indirect actions on the adrenergic receptor system (both an a- and badrenergic agonist). Several single nucleotide polymorphisms (SNPs) that have been described in the gene encoding the human b2-adrenergic receptor (b2AR) affect the function of the receptor in vitro. Substitution of glycine for arginine at residue 16 (Arg16Gly) has been associated with enhanced agonist-induced desensitization, while substitution of glutamic acid for glutamine at position 27 (Gln27Glu) has been associated with resistance to desensitization. 12 Significant differences in the response of individuals to b2AR therapeutic manipulation related to the particular genotype/haplotype of the b2AR have been demonstrated. A pharmacogenetic study in an obstetric population showed that the incidence and severity of maternal hypotension after spinal anaesthesia for caesarean delivery and the response to treatment is clearly affected by b2AR genotype/haplotype. 13 Women Gly16 homozygous, carrying one or two Glu at position 27 (heterozygous or homozygous for the Glu27 variant) were found to require significantly less vasopressors (ephedrine) for treatment of hypotension during spinal anaesthesia. The two haplotypes that seem to ‘protect’ women from requiring higher doses of ephedrine are relatively common in Caucasians, and in this study 20% of the women carried either one of these haplotypes. This pharmacogenetic effect may explain in part why the numerous studies trying to prevent or treat hypotension during spinal anaesthesia for caesarean section failed to define one single optimal strategy (fluid loading, ephedrine or phenylephrine) that would ‘fit all’. Since the incidence of spinal hypotension and vasopressor use is reduced in preeclampsia 14,15, we further hypothesized that haplotypes of b2AR gene influence haemodynamics during spinal anaesthesia for caesarean delivery in women diagnosed with severe pre-eclampsia. In a prospective case-

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control study, we compared the incidence of hypotension and vasopressor requirements in a predominantly African-American cohort. 16 Despite a trend towards fewer pre-eclamptic women requiring vasopressors, the total vasopressor dose was higher in those in whom treatment was indicated, which was contrary to our expectations. However, no woman in the pre-eclamptic group carried the Gly16Gly/Glu27Glu haplotype, and since this was one of the two haplotypes that predicted less vasopressor requirement in normotensive women 13, this might provide an explanation for our unexpected results. Whether our findings are specific to African-American women remains to be determined in larger studies in all ethnic groups. These findings illustrate the importance of ethnicity when assessing genetic associations, and similar interactions between ethnicity and genetics have been suggested for other SNPs presented in this review (b1AR, m-OR). In the long term, if these findings are confirmed, clinical implications could involve using haplotype of b2AR to predict spinal hypotension and to guide haemodynamic management in women with compromised cardiovascular function and altered uteroplacental perfusion. Meanwhile, the effects of ephedrine on the foetus have been revisited recently. 17 Evidence that ephedrine crosses the placenta to a greater extent and undergoes less early metabolism and redistribution than phenylephrine (a direct a-adrenergic agonist) causing direct foetal metabolic acidosis has made ephedrine less desirable as a first-line treatment. 18 The proposed mechanism is that direct foetal b-adrenergic stimulation increases anaerobic glycolysis and causes a hypermetabolic state. It is possible that the response of the foetus to b-adrenergic manipulation may also be genetically mediated and that foetal haplotype may impact on the response to ephedrine given to the mother. This hypothesis is currently under investigation and may provide some insight on foetal acidosis and metabolic responses in neonates born to mothers who have received b-agonists (ephedrine and/or other b-stimulants prescribed for tocolysis or bronchodilation) prior to delivery.

b-blockers and management of cardiovascular disease and hypertension b-adrenergic receptors (b-AR) mediate chronotropic and inotropic responses to catecholamines, which is of particular interest to anaesthesiologists. b-blockade is recommended to treat hypertensive disorders and provide myocardial protection either peri-operatively or after acute myocardial infarction (MI). Indeed administration of b-blockers after an acute ischemic event has become a quality measure by which hospitals are judged. In a large prospective cohort study in patients receiving b-blockers after an acute coronary event, four common b1 and b2AR SNPs were examined. 19 Increases in mortality rates were found with possession of certain variants in the b2AR, rising to 20% mortality at 3 years according to the haplotype combination of Arg16Gly and Gln27Gly. It appears from this study that patients with variants impairing b2AR downregulation (Gly16/Glu27), where receptor function does not undergo desensitization, benefit from b-blocker therapy. Conversely, those with genotypes enhancing downregulation (Arg16/ Gln27) do not benefit from b-blockers, most likely because less receptor is present at the cell surface, which mimics bAR antagonist activity. In fact, the administration of b-blockers to such patients appears to unmask negative effects. Also of interest, the authors report no association of the b1AR variants with mortality regardless of b-blocker therapy. Pending replication, this study provides compelling evidence that genetic variability of the b2AR has direct clinical relevance. A common polymorphism of b1AR, Arg389Gly, has been extensively evaluated both in vitro and in clinical studies. The Arg389 variant been shown in vitro to display a greater response to agonist stimulation, and individuals with the Gly389 allele have a decreased response to b-blockade. 20,21 Based on recently accumulated evidence in the literature, a large randomized clinical trial (INVESTGENES, n ¼ 5,892 hypertensive patients with coronary artery disease) tested the hypothesis that patients with a combination of the Ser49/Arg389 haplotype of b1AR or a combination of the Arg16/ Gln27 haplotype of b2AR would be at relatively higher risk for cardiovascular events and that atenolol would be more beneficial as compared with a calcium-channel antagonist (verapamil sustained release) in patients carrying the Ser49/Arg389 b1AR haplotype. 22 The increase in mortality risk among patients with one or two copies of the Ser49/Arg389 haplotype was highly significant in patients randomly assigned to verapamil SR but not in patients assigned to atenolol. These findings suggest that atenolol offsets the mortality risk associated with the b1AR haplotype, consistent with prior

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observations that patients bearing the wild-type alleles are more responsive to b-blocker therapy in settings of blood pressure lowering, improvement in ejection fraction, and survival in heart failure. Findings related to b2AR haplotype did not allow to draw any firm associations and given the inconsistencies in the literature, these findings require independent replication. The authors concluded that b1AR haplotype variation is associated with mortality risk, and b-blockers may be preferred in subgroups of patients defined by adrenergic receptor polymorphisms. Of interest, the Gly389 allele is more frequent in African-Americans (42%) compared with Caucasians (28%) 23 and this has been suggested to in part explain the decreased sensitivity to b-blockade reported in African-Americans. This specific question has since then been reevaluated, and may be of particular interest for obstetric anaesthesiologists and obstetricians involved with management of hypertension in pregnancy and pre-eclampsia. One study specifically sought to determine whether ethnic differences in response to b-blockade could be attributed to distribution of genetic variants in the b1AR. Exercise-induced tachycardia was evaluated before and after atenolol response, and atenolol resulted in a greater reduction in exercise heart rate in whites than in blacks. 24 b1AR Arg389 was independently associated with a greater reduction in heart rate, however ethnic differences in response to atenolol remained significant after adjustment for genotype. Therefore, ethnic differences in sensitivity to atenolol persist even after accounting for different distributions of genetic variants of b1AR, suggesting that additional factors, yet to be identified, most likely contribute to these ethnic differences. Another study suggested that b1AR genotype contributes significantly in the observed differences in b-blocker response between Caucasians and African-Americans patients with heart failure. 25 Taken together, these results suggest that treatment response should take into account both ethnicity and genotype. A recent review summarizes the effect of relevant polymorphisms affecting pharmacodynamics and pharmacokinetics of medication prescribed for the management of cardiovascular disease. 26 Further evaluation of the effect of bAR haplotypes in the context of hypertensive management in pregnancy will be of interest. There has been to date no clinical trial examining the response to b-blockers in pre-eclamptic women according to genotype of b1AR, which may provide in part an explanation for the observed ineffectiveness of labetalol in some hypertensive/pre-eclamptic women. Bronchodilators for management of asthma There have been numerous studies assessing the association between asthma phenotypes and genetic variability of b2AR. A meta-analysis concluded that neither the Gly16 nor the Glu27 allele contributes to asthma susceptibility overall or to bronchial hyper-responsiveness. 27 Gly16 homozygotes however did have a much higher risk for nocturnal asthma and asthma severity than Arg16 homozygotes. Therefore, SNPs of b2AR gene are not major risk factors for the development of asthma, rather they are ‘disease modifiers’ and are important in determining drug response (pharmacogenetic effect). Initial studies described an enhanced response to b2-agonist bronchodilators in asthmatic subjects homozygous for the wild-type allele (Arg16) compared to patients homozygous for Gly16, 28 which would appear to be consistent with the prediction of the in vitro findings that demonstrated increased receptor down-regulation in presence of the Gly16 variant. However, recent genotype-stratified studies on treatment outcome in patients with mild asthma determined that patients homozygous for Gly16 improved in the long term with albuterol 29 or long-acting b2-agonists while those homozygous for Arg16 did not 30. With several studies showing that asthmatic patients who are Arg16 homozygous do not benefit from short-acting b-agonists in either the absence or presence of concurrent inhaled corticosteroid use, investigation of alternate treatment strategies that may help this group is on its way. Pharmacogenetics should influence the clinical management of asthma in a very near future. 31 Tocolytics for management of preterm labour and delivery Stimulation of the b2AR results in uterine smooth muscle relaxation, and thus the b2AR has long been a therapeutic target for the treatment of preterm labour. b2-agonist therapy, in common with

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virtually all tocolytics, has not been consistently successful at stopping preterm labour or prolonging pregnancy, in part due to the multifactorial nature of preterm labour, and possibly because of a wide variability in therapeutic response within the population. The mechanisms involved in regulation of myometrial smooth muscle contraction and relaxation in preterm labour or even at term are not yet fully elucidated. Polymorphisms of b2AR (Arg16Gly and Gln27Glu) have been associated in several studies with preterm labour and delivery. Arg16 homozygosity of b2AR genotype appears to confer a protective effect against preterm delivery while the Glu27 variant might increase the risk for preterm delivery. 32–34 Furthermore, we have shown a pharmacogenetic effect, with a better response to b2agonist therapy (hexoprenaline) for tocolysis in women Arg16 homozygous with idiopathic preterm labour between 24 and 34 weeks gestation. 35 This had a significant impact on neonatal outcomes, with higher birth weights and less neonatal ICU admissions for respiratory or other complications due to prematurity in babies born to mothers with that genotype. It remains to be determined whether b2AR genotype influences the severity of the disease (i.e. that Arg16 homozygote women present with a milder disease than women with other genotypes) or directly affects the response to therapy. Meanwhile, a variety of genomic studies have examined the influence of genetic variants on the incidence of preterm labour, 36 and proteomic studies to validate biomarkers that could identify women at risk for preterm delivery and serve as predictive tools is ongoing. 37,38 Analgesia and pain-related candidate genes Interindividual variability in pain perception and sensitivity to analgesic therapy with a large unpredictability in efficacy, side effects and tolerance profiles to opioids is well described. Numerous candidate genes have been considered as suitable targets for the study of the genetic basis of pain and or analgesia. 39 In addition, a genetic database of knock-out mice allowing the study of genetic variations in the context of specific pain phenotypes was made public. 40 Recently an extremely rare phenotype characterized by a total absence of pain perception (‘congenital indifference to pain’) with no associated neuropathy has been associated with the mutations in the gene SCN9A, encoding the a-subunit of the voltage-gated sodium channel, Nav1.7. 41–43 Individuals with loss-of-function mutations of the NaV1.7 lack protective mechanisms that allow tissue damage detection and suffer severe injuries because they do not learn pain-avoiding behaviors. This discovery opens new directions for development of novel generations of drugs with blocking Nav1.7 proprieties, which should provide more selective and safe analgesia. Meanwhile, we are still in the era of opioid therapy, and the analgesic effect may be influenced by alterations in the metabolism of analgesic drugs (cytochrome P450), variants coding for the m-opioid receptor (mOR) as well as other targets. The codeine ‘story’ Cytochrome P450 (CYP450) is a super-family of liver enzymes that catalyze phase 1 drug metabolism. The gene coding for this enzyme was found to be highly polymorphic, with more than 75 different CYP2D6 alleles (http://www.imm.ki.se/cypalleles), resulting in a variable enzymatic activity ranging from 1 to 200%. As a result, each individual can be classified as having an ‘‘ultra-rapid metabolism’’, an ‘‘extensive metabolism’’, a ‘‘normal metabolism’’ or a ‘‘poor metabolism’’ and microarray technology is available to classify individuals according to their metabolic phenotype. 44 Of note, CYP2D6 activity is absent in approximately 7–10% Caucasians. Codeine is a pro-drug and needs be converted into morphine to elicit its analgesic effect, therefore ‘poor metabolizers do not achieve analgesia with codeine while they do encounter side effects such as nausea and vomiting. Conversely, codeine intoxication can be anticipated with ultra-rapid CYP2D6 metabolism. 45 While codeine is undoubtedly not a wonder analgesic, it is still prescribed because of the belief that being a weak opioid, it is safe. There has been a recent FDA warning on codeine use in nursing mothers (http://www.fda.gov/bbs/topics/NEWS/2007/NEW01685.html) following the death of a breastfed 13 days old neonate thought to have suffered a morphine overdose because his mother was taking codeine and was a CYP2D6 ultra-rapid metabolizer. 46 Since that fatal report in 2006, numerous publications have addressed the issue of potential neonatal and pediatric codeine intoxications

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according to pharmacokinetic phenotype. 47-52 This case exemplifies very precisely the irrefutable input of diagnostic pharmacogenetic testing and carries direct clinical implications for obstetric anaesthesiologists, obstetricians and neonatologists. Similarly, the effect of tramadol, a centrally acting m-opioid agonist that has a dual mechanism of action, binding to the mORs and weakly inhibiting the neuronal reuptake of norepinephrine and serotonin, is also influenced by the CYP2D6 genotype and interactions with any other co-administered medication undergoing CYP2D6 metabolism should be anticipated. 53,54 Neuraxial labour analgesia and post-caesarean analgesia The mOR, encoded by genetic locus OPRM1, has been the focus of several genetic studies because this receptor is the primary site of action for many endogenous opioid peptides and the major target for opioid analgesics, such as morphine, heroin (diamorphine), fentanyl, and methadone. The mOR is a GPCR, and a number of SNPs have been described for OPRM1. At nucleotide position 118, an adenine substitution by a guanine (A118 G), has been reported to occur with an allelic frequency of 10–30% among Caucasians 55 with a higher prevalence among Asians. 56 The major interest for this particular SNP is due to its pharmacological and physiological consequences. In vitro, the presence of at least one G118 allele has been shown to increase the binding affinity and potency of b-endorphin. 57 Thus, individuals carrying the variant receptor gene could show differences in some of the functions mediated by b-endorphin action at the altered mOR, such as higher thresholds to pain. Consistent with this laboratory finding, one in vivo study in a human experimental pain model demonstrated that volunteers carrying a G118 allele exhibited lower sensitivity to pressure pain compared with A118 homozygotes. 58 The exact relationship of this polymorphism with the responses to oral opioids for treatment of chronic pain, 59,60 post-operative requirements of intravenous alfentanil 61 or morphine 62–65 or the adverse effects and toxicity profiles 66–69 appear to go ‘in the opposite direction’. Individuals carrying the variant G118 allele may actually require higher doses of morphine, 71 which is in contrast with what is expected if the variant mOR is truly associated with an increased endogenous opioid activity. Our group has demonstrated that the A118 G polymorphism impacts on the median effective dose (ED50) of intrathecal fentanyl in labour; nulliparous women carrying the variant G118 allele required substantially lower doses of intrathecal fentanyl to achieve adequate analgesia early in labour (with a 1.5 to 2 fold difference between genetic groups). 70 Of note, cervical dilatation at the time of analgesia request was significantly less in women homozygous for the wild-type variant (A118) than that in women carrying one or two variant alleles (G118). This is of interest, since women received combinedspinal epidural (CSE) analgesia by their own request, at the time they experienced painful contractions. Since, it has been demonstrated previously that epidural analgesic requirements increase with progress of labour and cervical dilatation, the expectation would be that women carrying the mutant G allele should have greater analgesic requirements due to the greater cervical dilatation at which they requested analgesia; our finding that these women require less fentanyl therefore may actually underestimate the true effect of genotype. This is consistent with the premise that women carrying the G allele may have higher pain tolerance and therefore request epidural analgesia at a later stage in labour. Our finding of a significant difference in the median effective dose (ED50) according to genotype is clinically relevant, because provision of optimal labour analgesia remains an ongoing challenge for obstetric anaesthesiologists. A major goal of labour analgesia is minimal motor impairment, emphasizing the need to minimize local anaesthetic use. Similarly, there is a need to reduce opioid doses in order to minimize opioid-related side effects such as pruritus and foetal bradycardia (which appear to be dose-dependant). Therefore, according to our findings, genotyping may well help improve the delivery of labour analgesia because a 1.5–2 fold increase in fentanyl dose is not trivial. We have also evaluated the effect of the A118 G polymorphism on the duration of intrathecal fentanyl analgesia in early labour and did not find any difference between genotypic groups. 72 While the A118 G polymorphism may influence drug potency, there may be no pharmacokinetic effect altering duration of drug action. As mentioned above, our findings in labouring women are in disagreement with studies looking at post-operative intravenous consumption of morphine after general or orthopedic surgery. In addition,

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three studies specifically evaluated post-caesarean analgesia with intrathecal or intravenous morphine. One study did not find a difference in the duration of intrathecal morphine analgesia or need for analgesic supplementation in women carrying the G118 allele; however, among these women, pruritus was less frequent during the first 24 h post-operatively. 73 The two other studies, both from Singapore, reported that Asian women with at least one G118 allele exhibited increased post-caesarean morphine consumption with intravenous patient-controlled analgesia. 74,75 These differences may be due to the fact that spinal and systemic opioid pharmacokinetics and pharmacodynamics may be different; enhanced analgesia in response to intrathecal fentanyl in the presence of the G118 allele may not exist in response to intravenous fentanyl or other opioids via the intravenous route. Or one could speculate that human spinal cord receptor function and signal transduction is selectively more altered by the G118 variant than supraspinal receptors. Another potential explanation and factor to bear in mind is the different nature of the nociceptive stimulus in labour versus other painful syndromes. Indeed, similar disparate results in human genetic studies of pain sensitivity have been shown to occur with other polymorphisms commonly assessed in pain studies. A polymorphism of the catechol-O-methyltransferase gene (Val158Met) has been inconsistently found to be associated with altered nociception and response to analgesic; 76 while one study found a significant genetic association, 77 another did not, 78 a third described a significant effect but not for that polymorphism, 79 and a fourth reported that findings depended on stimulus modality. 80 This illustrates the challenges in evaluating a genotype-phenotype association when the underlying genetic susceptibility is clearly polygenic and the phenotype is complex in itself (multifactorial, subjective, involving pain perception and/or response to analgesics). Last, a relatively unexpected candidate gene has been suggested to modulate the perception of pain in labouring women in an ongoing study. 81 Women who were Gly16 homozygous for the b2AR reported less pain in early labour compared to others. Whether haplotypes of b2AR predict more rapid and less painful labour remains to be confirmed. Undeniably, numerous candidate genes as well as elaborate models have been suggested for the study of the genetic component of pain and several excellent reviews on the pharmacogenetics of opioids and analgesia were recently published. 82–86 Nonetheless, due to the inherent complexity of studying pain (different nociceptive modalities, gender differences, limitations in extrapolating data from animal models to the response in humans, interethnic and environmental differences) in addition to the obvious polygenic nature of this, it is the design and execution of large clinical studies analyzing multiples haplotypes simultaneously that remains to be the true challenge to date. Meanwhile, genome wide association studies (GWAS) in the context of acute post-operative pain are published 87 and researchers are actively working on gene therapies for pain. 88,89 It will also be of interest to see the new insights and developments brought by more research on the SCN9A gene in the near future. 90 Practice points Despite remarkable achievements and promises that discoveries from the Human Genome Project will translate into tangible clinical tests that would change drug prescriptions, numerous obstacles have prevented the widespread development and implementation of pharmacogenetic testing. 91 Nonetheless, a handful of recently developed pharmacogenetic tests have become available 92 and the Food and Drug Administration (FDA) has approved numerous drug label modifications to contain pharmacogenetic information. For a test to be approved and become commercially available robust evidence that (a) the test is associated with outcomes is required and (b) it can predict the need for a change in dose or in drug. If no other drug is available or no alternative dose has been studied then the test is unlikely to provide any useful information. Warfarine (testing of CYP2C9 and VKORC1), tamoxifene (testing of CYP2D6) and herceptine (testing of HER2) are among the list of drugs for which pharmacogenetic testing is now available. 92 From the clinician’s perspective, while it is still too early to foresee immediate implications of pharmacogenetics in general and pharmacogenetic diagnostic tests specifically, advances in the field of genomics will certainly aid anaesthesiologists and other clinicians in predicting efficacy or toxicity for some drugs. These discoveries should allow to target anaesthetic and analgesic drugs, hypertensive

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therapies and vasopressors as well as to personalize strategies aimed at improving perioperative and peripartum outcomes outcomes according to our patients’ genetic profiles, because ‘one size does not fit all’ anymore.

Practice points  Pharmacogenetic testing is available for selected polymorphisms  CYP2D6 testing may be recommended when prescribing drugs undergoing CYP2D6 metabolism (e.g. codein, tramadol)  Response to b-blockers and b-agonists is influenced by b-adrenergic genotype/haplotypes  Response to opioids is influenced by polymorphisms of m-OR and numerous other selected candidate genes

Research agenda  GWAS to unravel the genetic determinants of preeclampsia and the effect of genetics on severity of hypertension in pre-eclampsia  Pharmacogenetics of anti-hypertensive therapy in pre-eclampsia (including b-AR haplotypes and response to labetalol)  Pharmacogenetics of vasopressors used for spinal hypotension during caesarean delivery  Proteomic and pharmacogenomic studies to predict preterm labour and improve therapy and outcomes  Response to neuraxial opioids for labour analgesia according to m-OR genotype and other selected candidate genes  Response to neuraxial and parenteral opioids for post-caeserean analgesia according to m-OR genotype and other selected candidate genes  GWAS to predict individual susceptibility to acute pain, labour pain, chronic pain and response to analgesics

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Table glossary Pharmacogenetics: Study of the variability in drug response due to genetic variability Pharmacogenomics: Similar to pharmacogenetics but incorporates sophisticated genomic tests and a genome wide approach to define the inherited nature of drug response. Genotype: Genetic identity of an individual, with a particular set of alleles (variants of genes). Three possible genotypes for each polymorphism: wild-type homozygote (wt/wt), heterozygote (wt/v) or variant homozygote (v/v) Phenotype: Observable traits or characteristics of an individual (ex. hair color, presence or absence of disease). Usually the product of the genotype and all environmental effects. Polymorphism(poly¼several; morph¼form): Naturally occurring variation, present in more than 1% of population, with several genetic variants (DNA sequences) in individuals at a certain position (locus) of the genome. Most polymorphisms are SNPs. SNP single nucleotide polymorphism: A common variation in the sequence of DNA involving 1 nucleotide. The average frequency is 1 variation for 1000 bases. More than 1.4 Mio SNPs have been identified, but only 1% appear to be functional. Nucleotide: One of the structural components of DNA and RNA. Consists of a base (one of four chemicals: adenine (A), thymine (T), guanine (G), and cytosine (C)) and a molecule of sugar and one of phosphoric acid. Codon: Three bases (nucleotides) in a DNA or RNA sequence which specify a single amino acid. Among the 64 possible combinations, 61 codons have a sense and 3 codons are non-sense; multiple codons code for the same amino acid (degeneration of the genetic code), hence only 20 amino acids Wild-type: First genetic variant cloned (regardless of frequency) Variant (or mutant): The other genetic variant Allele and allelic distribution: One of the variant forms (wild-type or variant) of a gene at a particular locus on a chromosome. Different alleles produce variation in inherited characteristics such as hair color or blood type. Both alleles need to be known to determine the genotype. The allelic distribution takes into consideration that there are 2 alleles in homozygotes, and 1 allele in heterozygotes. Linkage disequilibrium: Situation in which 2 alleles in 2 different loci on the same chromosome are more frequently associated in the population than expected. Such an association is favored by: 1) proximity of the loci; 2) the recent character of the mutation producing one of the alleles; 3) a selective advantage CHIP chromatin immunoprecipitation: Technique allowing massive sequencing of DNA fragments (up to 400’000 nucleotides), on a silicone plate. For more information on GeneChip Technology, see www.affymetrix.com/technology/index.html