Abstract Postoperative nausea and vomiting (PONV) continues to be a most common complication of surgery and anesthesia. It has been suggested that the inherited factors may play a significant role in the background sensitivity to both PONV and also chemotherapy-induced nausea and vomiting (CINV), including resistance to antiemetic prophylaxis and/or therapy. This notion could be best exemplified by occurrence of PONV in several generations of families and concordance of PONV in monozygotic twins. The most frequently addressed issue in the research on genomic background of PONV/CINV relates to the inherited resistance to the antiemetic treatment (pharmacogenomics), and in lesser degree to their genomic background. The most common group of antiemetics consists of 5HT3 receptor antagonists, and this group was an initial target of pharmacogenomic research. Most research approaches have been based on the investigation of polymorphic variations in the target for the antiemetic 5HT3 receptor antagonists, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). The other area of pharmacogenomic investigations includes metabolic pathways of 5HT3 antagonists, in particular polymorphic variants of the CYP450 2D6 isoform (CYP2D6) because most of them are metabolized in various degrees by the CYP2D6 system. The results of targeted genomic association studies indicate that other genes are also associated with PONV and CINV, including OPRM1, and ABCB1. In addition, genes such as DRD2 and CHRM3 genes have recently been associated with PONV. The new genome-wide association studies
P. K. Janicki (*) · S. Sugino Laboratory of Perioperative Genomics, Department of Anesthesiology, Penn State College of Medicine, 500 University Drive, H187, Hershey, PA 17033‑0850, USA e-mail: [email protected]
seem also to indicate that the background genomic sensitivity to PONV and CINV might be multifactorial and include several genomic pathways. Keywords Postoperative · Nausea · Vomiting · Chemotherapy-induced nausea and vomiting · Genomics · Genetic polymorphism · PONV · CINV · Genetic variants
Significance of PONV for patient care Postoperative nausea and vomiting (PONV) continues to be a most frequent complication of surgery performed under general anesthesia worldwide. It is a limiting factor in the early discharge after ambulatory surgery, as well a leading cause of unanticipated hospital admission (Gan et al. 2014). Unresolved PONV can lead to increased recovery room time, expanded nursing care, and potential hospital admission—all factors that may increase total health care costs. Equally important are the high levels of patient discomfort and dissatisfaction associated with PONV. Approximately 30 % of all patients continue to experience PONV, and in subset of high-risk patients, the PONV rate can be as high as 80 % (Gan et al. 2014). The most important risk factors for PONV in adults include female sex, previous history of PONV and motion sickness (including family history), nonsmoking, duration of anesthesia, postoperative opioids, use of general anesthesia with nitrous oxide, type of surgery, and younger age. Apfel et al. (1999) created a simplified risk factor chart identifying four primary risk factors for PONV in patients receiving balanced inhaled anesthesia: female sex, nonsmoking status, history of PONV, and opioid use. The incidence of PONV with the presence of none, one, two, three, or all four of these risk factors was approximately 10, 20, 40, 60, and 80 %, respectively. The
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Table 1 Known human genes and their polymorphisms (as referenced in the manuscript) associated with occurrence of PONV, CINV, and motion sickness Target protein
Muscarinic receptor type 3 Neurokinin 1 receptor Transporter adenosine triphosphate-binding cassette subfamily B member 1 Dopamine receptor type 2 Serotonin transporter gene
CHRM3 TACR1 ABCB1
SNP in HTR3A: 1377A>G SNP in HTR3B: rs1176744, rs1672717, rs3782025, rs3758987, Tyr129Ser, Ala223Thr, Y129S; -100_-102delAAG deletion, c5+201_+202delCA, c6-137C>T SNP in HTR3C: K163 N, A405G SNP in HTR3D: rs6443930 SNP: rs1799971, haplotypes SNP: rs16947 (CYP2D6*2), rs35742686 (CYP2D6*3A), rs1135824 or rs35742686 (CYP2D6*3B), rs3892097 (CYP2D6*4), rs5030655 (CYP2D6*6), rs5030867 (CYP2D6*7), rs5030865 (CYP2D6*8), rs5030656 (CYP2D6*9), rs1065852 (CYP2D6*10), rs5030863 (CYP2D6*11) further genotypes listed at http://snpedia.com/ index.php/CYP2D6 SNP: rs685550, rs10802789, rs2165870 SNP: rs3755468, haplotypes SNP: rs1045642, rs2032582 and rs1128503, 3435C>T, 2677G>T/A Taq IA SNP: rs1176713 LA/SA polymorphism
effect of inherited factors for the incidence of PONV (i.e., history of PONV in mother, father of siblings) has also been acknowledged in pediatric PONV risk score by Eberhart et al. (2004). The identification of individuals at high risk for PONV (through medical history and/or molecular testing when available) can narrow the pool of potential candidates for specific type of the prophylactic antiemetic therapy, indicating those most likely to benefit and reducing antiemetic side effects and costs for patients unlikely to benefit.
Neurobiology of nausea and vomiting The so-called vomiting center lies in the medulla oblongata and comprises the reticular formation and the nucleus of the vestibular nuclei (Vnu), tractus solitaries (NTS), and area postrema (AP) (Horn et al. 2014). When activated, motor pathways descend from this center and trigger vomiting. These efferent pathways travel within the 5th, 7th, 9th, 10th, and 12th cranial nerves to the upper gastrointestinal tract, within vagal and sympathetic nerves to the lower tract, and within spinal nerves to the diaphragm and abdominal muscles. The vomiting center can be activated directly by irritants or indirectly following input from 4 principal areas: gastrointestinal tract, cerebral cortex and thalamus, vestibular region, and chemoreceptor trigger zone (CRTZ). The CRTZ is closest in proximity, lying
SNP: rs4680, rs4633, rs165722
between the medulla and the floor of the fourth ventricle. Unlike other brain centers, it is not protected by the blood– brain barrier. This is to say that the endothelium of its capillaries is not tightly joined or surrounded by glial cells and is permeated easily by irritants regardless of their lipid solubility or molecular size. The principal receptors, ligands, and their associate polymorphisms linked to nausea and/ or vomiting sensitivity or pharmacology are provided in Table 1. Antiemetic targets for drug interventions are predicated on their ability to block the referenced receptor sites (Gan 2007). Receptors along with their conventional ligands are as follows: H1 histamine, M1–3 acetylcholine, 5-HT3 serotonin, D2 dopamine, NK1 (neurokinin or substance P), and μ-type opioid receptor (MOR). Transmitter mediators in the cerebral cortex and thalamus are poorly understood, although cortical cannabinoid (CB1) pathways have been characterized.
Patient‑related factors in sensitivity to PONV and CINV PONV is multifactorial in its origin. In addition to wellestablished emetogenic agents used during anesthesia such as opioids and inhalation anesthetics, a large number of factors appear to render patients more susceptible including female gender, nonsmoking history, anxiety and prior history of PONV, motion sickness, and migraine. No
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explanation has been offered for the increased incidence in female patients, but this increased risk persists throughout life, even following menopause, which obviates any role for estrogen as a factor. It is speculated that smokers may have developed some tolerance because of the chronic emetogenic influence of nicotine, which is lacking in the nonsmoker. A history of motion sickness suggests a more susceptible vestibular component. Nevertheless, it is surprising that none of these factors is a reliable predictor independently. It has been suggested that the inherited factors can play significant role in the background sensitivity to PONV and CINV, and/or resistance to antiemetic prophylaxis and/ or therapy. This notion is exemplified by multiple observations of increased frequency of PONV in the several generation of the same family (up to three generations in some cases) and almost 100 % concordance of PONV in monozygotic twins (Janicki, observation unpublished), as well as established increased risk of PONV in children with the history of PONV in family (Eberhart et al. 2004). This seems to be particularly true for intractable PONV, which is either resistant to conventional antiemetic medication and/ or have severe and protracted duration.
Genetic background of PONV: animal models of genetic background of PONV Susceptibility to motion sickness is an important predictor of PONV, and studies in humans suggest that genetic factors determine sensitivity to motion sickness. The focus of the recently performed studies has been to selectively breed an animal model of motion-induced emesis that could be applied to future molecular-genetic studies. In this respect, laboratory shrews and ferrets have recently been used for these experiments because, unlike mice and rats, they are capable of vomiting and are a well-characterized species for motion-induced emesis using standardized behavioral test conditions (Horn et al. 2012). Further analysis of the inhalation anesthetics-induced PONV in these animal species indicates that ferrets are probably not useful for delineating mechanisms responsible for isoflurane-induced emesis. In contrast to ferrets, musk shrews have been very sensitive to isoflurane-induced emesis (0.5–3 %, 10-min exposure; up to 11.8 ± 2.4 emetic episodes), whereas ferrets failed to induce vomiting (Horn et al. 2012). Musk shrews may therefore become a model animal for the investigations of vomiting after inhalation of volatile agents. In the most recent paper, Horn et al. (2013) showed that highresponse strain musk shrews demonstrated significantly more emetic episodes to motion exposure compared to low-response strain animals in the F1 and F2 generations. In F2 animals, there were no significant differences in total
emetic responses or emetic latency between strains after nicotine injection or CuSO4 gavage. However, isoflurane exposure stimulated more emesis in F1 and F2 high versus low strain animals, which suggests a relationship between vestibular- and inhalational anesthesia-induced emesis. Overall, these results indicate genetic determinants of motion sickness in a preclinical model and a potential common mechanism for motion sickness and inhalational anesthesia-induced emesis. Future work may include genetic mapping of potential “emetic sensitivity genes” to develop novel therapies or diagnostics for patients with high risk of nausea and vomiting.
Genetic background of PONV and CINV in humans: clinical studies History of clinical research on inherited factors involved in the pathogenesis of PONV and related chemotherapyinduced nausea and vomiting (CINV) or motion sickness is relatively new, with oldest papers in this area published <10 years ago. The incidence of nausea and vomiting in medical settings can reach 80 %, particularly in individuals at highest risk, such as patients with a history of sensitivity to motion sickness, and a twin study estimates that motion sickness has a heritability of 57–70 % (Reavley et al. 2006). The most frequently addressed issue in the research related to genetic background of PONV and CINV is the inherited resistance to antiemetic treatment (pharmacogenomics), and in lesser degree the genomic background to sensitivity to PONV or CINV. In 2009, Candiotti published editorial in Anesthesia and Analgesia entitled Anesthesia and Pharmacogenomics: Not ready for prime time, in which he suggested that current costs and knowledge basis of the genomic screening were not justified to prevent PONV. Five years later, it becomes obvious that the area of the perioperative genomics has expanded significantly through both increased number of discovered polymorphisms associated with PONV or CINV, and by clinical verification already known polymorphisms. What is currently needed are new pharmacogenomic implementation guidelines and strategies associated with therapeutic use of antiemetics which can be applied directly to the care of surgical patients undergoing anesthesia and surgery. As an example, similar pharmacogenomic guidelines were published recently by the Clinical Pharmacogenetics Implementation Consortium for CYP2D6 genotype and codeine therapy (Crews et al. 2014). 5‑Hydroxytryptamine type 3 (5‑HT3) receptor The concept that 5-hydroxytryptamine (5-HT; serotonin) is involved in the emetic reflex was revealed using drugs that
interfere with its synthesis, storage, release, and metabolism ahead of the discovery of selective tools to modulate specific subtypes of receptors (Johnston et al. 2014). The most common group of antiemetic used in both PONV and CINV consists of 5HT3 receptor antagonists (so-called ‘setrons’ including dolasetron, granisetron, ondansetron, palonosetron, and tropisetron) have similar mechanisms of action but different pharmacokinetic and pharmacodynamic properties (Janicki 2005). Genetic polymorphism in the cytochrome P450 mono-oxygenase system (CYP450), drug efflux transporter adenosine triphosphate-binding cassette subfamily B member 1, and subunits also contribute to the interindividual variation in response to different 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RA). It is therefore no surprise that pharmacogenomics of the antiemetics from 5-HT3RA group has been an initial target of pharmacogenomic research. The most developed approached has been based on the investigation of polymorphic variations in the target for the antiemetic 5-HT3RA, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). Tremblay et al. (2003) sequenced the entire length of the 5-HT3B receptor gene, including the 5′ flanking region and at least a 20-base pair intronic sequence of each intron–exon splice site in 242 cancer patients on their first day of chemotherapy. Approximately 30 % of patients suffered from nausea and vomiting. This analysis revealed 13 polymorphisms: Two of them were amino acid exchanges (Tyr129Ser, Ala223Thr), and two were deletion variants. In both observation periods, patients homozygous for the -100_-102delAAG deletion variant of the promoter region experienced vomiting more frequently than did all the other patients. The authors concluded that only a small fraction of the therapeutic failure is explained by the -AAG deletion variant of the 5-HT3B receptor gene. A similar approach to the investigation of the pharmacogenomics of 5-HT3RA in PONV patients was undertaken by the Rueffert et al. (2009) who similarly investigated the genes of the serotonin receptor subunits A and B for genetic variants. They screened the entire HTR3A and HTR3B receptor types coding regions, the 5′ flanking regions, and exon/intron boundaries for genetic variants in 95 patients with history of PONV and 95 controls. They subsequently identified 16 different variants in the HTR3A gene and 19 in the HTR3B gene. By using a multivariate logistic regression model that also included classical risk factors, the HTR3A variant 1377A>G was associated with a significantly higher risk (odds ratio [OR] 2.972 and the HTR3B variants c5+201_+202delCA (OR 0.421) and c6-137C>T (OR 0.034) were associated with a lower risk for PONV). All significant genetic variants were located in noncoding regions of the investigated genes. The authors concluded that genetic variations in the HTR3A and
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HTR3B gene seem to be associated with the individual risk of developing PONV. In addition, Sugai et al. (2006) investigated the effect HTR3A and HTR3B gene polymorphisms on nausea induced by paroxetine in 78 Japanese psychiatric patients. They demonstrated that Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea. Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold higher risk of developing nausea than patients with the Ser allele. They also reported that HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea in this group of patients. The effect of yet another commonly occurring singlenucleotide polymorphisms (SNP) in HTR3 was reported by Fasching et al. (2008) [nonsynonymous SNPs: Y129S (HTR3B), K163N (HTR3C) and A405G (HTR3C)]. All patients received epirubicin, with or without cyclophosphamide, and preventive medication with ondansetron and dexamethasone. The patients documented every vomiting event on an hourly basis. The overall proportion of patients (total n = 110) who reported vomiting in the first 24 h after chemotherapy was 31.8 %. The variant genotype of K163N (HTR3C) was associated with vomiting, which occurred in 50.0 %. The authors concluded that polymorphisms in the HTR3C gene could serve as a predictive factor for CINV in patients undergoing moderately emetogenic chemotherapy. In the subsequent paper, the same group (Hammer et al. 2010) reported results of an investigation in 110 previously characterized chemotherapy-naive women with primary breast cancer treated with anthracycline-containing chemotherapy which served as a study group for mutational analysis by direct sequencing. Eight common SNPs in HTR3 genes (HTR3A, HTR3B, HTR3D, and HTR3E) were selected for association analysis. A nonsynonymous variant in HTR3D, G36A (rs6443930), was found to be over-represented in nonresponders. In addition, Cox proportional regression analysis resulted in a hazards ratio of 0.36 for homozygous carriers of the C allele to vomit within 24 h after first chemotherapy administration. These data support again hypothesis that 5-HT3 receptors play an important role in the pathogenesis of CINV. Along with previously identified HTR3 polymorphisms, the HTR3D G36A variant could also contribute to facilitating individual risk predictions. Finally, in the most recent multicenter study in cancer patients receiving opioids, Laugsand et al. (2011) included patients from 17 centers in 11 European countries. Intensities of nausea and vomiting were reported by 1,579 patients on four-point categorical scales. In stratified regression models including demographical and disease-related factors as covariates, 96 SNPs in 16 candidate genes related to opioid- or nausea/vomiting signaling pathways (ABCB1,
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OPRM1, OPRK1, ARRB2, STAT6, COMT, CHRM3, CHRM5, HRH1, DRD2, DRD3, TACR1, HTR3A, HTR3B, HTR3C, CNR1) were analyzed for association with nausea and vomiting. Eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids (P < 0.01). The SNPs were rs1176744, rs3782025, and rs1672717 in HTR3B; rs165722, rs4680, and rs4633 in COMT; rs10802789 and rs685550 in CHRM3. Only the SNP rs1672717 in HTR3B passed the 10 % false discovery rate criteria. The authors concluded that clinical characteristics and SNPs within the HTR3B, COMT, and CHRM3 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids. Most of above genomic studies of the 5-HT3 receptor were performed in the patients suffering from CINV. Only very recently, Ma et al. (2013) investigated whether common genomic variations of the A and B subunits of HTR3 are associated with the incidence of postoperative vomiting in a Chinese Han population. Two hundred and thirty-one female Chinese Han patients undergoing gynecological surgery with standardized general anesthesia were recruited for the study. Five SNPs in HTR3A and HTR3B were found, with r2 >0.8 and minor allele frequency >10 %. One of these (rs3758987 in HTR3B) was statistically associated with vomiting, after adjusting for body weight, body mass index, and duration of general anesthesia in dominant and additive models. It was therefore concluded that the HTR3B rs3758987 SNP might serve as a predictor of postoperative vomiting in Chinese Han patients undergoing gynecological laparoscopic surgery. CYP450 2D6 system Other area of pharmacogenomic investigations includes metabolic pathways of clinically used 5HT3RA, in particular polymorphic variants of the Cyp450 2D6 isoform (CYP2D6). Most of the 5-HT3RA, so-called setrons, are metabolized in various degrees by the CYP2D6 system (with notable exception of granisetron) (Janicki 2005). Early in 2002, Kaiser et al. sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on CYP2D6 genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated. They included in the study 270 cancer patients receiving their first day of chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 h after drug administration was analyzed in a subgroup of 42 patients. Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients. Approximately 30 % of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined
ultrarapid metabolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 h (P < 0.001) and within the period 5–24 h (P < 0.03) after treatment than all the other patients; the tendency for nausea was similar. This difference was more pronounced in patients treated with tropisetron than in those treated with ondansetron. The authors concluded that antiemetic treatment with tropisetron or ondansetron could be improved by adjustment for the CYP2D6 genotype; approximately 50 subjects would have to be genotyped to protect one patient from severe emesis. Interestingly enough, these findings could not be replicated in 202 Indonesian cancer patients treated with cisplatin as monotherapy or as combined chemotherapy (Perwitasari et al. 2011). Ondansetron and dexamethasone intravenously were used as the standard antiemetic therapy for the prevention of acute chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582, and rs1128503; in 5-HT3B-R: rs45460698, rs4938058, and rs7943062; and in CYP2D6: rs16947 (CYP2D6*2), rs3892097 (CYP2D6*4), and rs1065852 (CYP2D6*10). Carriers of the CTG haplotype of the ABCB1 gene experienced chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase. No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes. This study showed that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting. The involvement of ABCB1 gene by Babaoglu et al. (2005) in patients with cancer (N = 216) treated with chemotherapeutic regimens composed of highly or moderately emetogenic agents who were examined for their antiemetic responses to tropisetron, ondansetron, or granisetron. The efficacy of antiemetic treatment was documented by self-report charts for 5 days after chemotherapy. ABCB1 3435C>T genotype was determined to analyze its association with the antiemetic efficacy of 5-HT3RAs. Within the first 24 h of chemotherapy, the complete control rate of nausea and vomiting was higher in subjects with the ABCB1 TT genotype as compared with those with the CC or CT genotype. The complete control rates were 92.9 % in TT subjects in comparison with homozygote or heterozygote carriers of the 3435 C allele in granisetron-treated patients. However, during the delayed phase of chemotherapy, the complete control rates did not differ across genotypes. The authors concluded that ABCB1 3435C>T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT3RA, particularly in
granisetron-treated patients, during the short-term phase of chemotherapy. The previously described involvement of the polymorphic CYP2D6 system in 5-HT3RA pharmacology was subsequently validated in surgical patients experiencing PONV and using ondansetron, dolasetron, or granisetron (as negative control) as primary prophylactic antiemetic regimen. Candiotti et al. (2005) examined two hundred and fifty female patients undergoing standardized general anesthesia who were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting and blood DNA analyzed for CYP2D6 polymorphism. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27 %), 27 in 198 (14 %), and 7 in 23 (30 %), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8 %), 5 in 30 (17 %), 26 in 176 (15 %), and 5 in 11 (45 %), respectively (P < 0.01 vs. all other groups). There were no differences between groups in the incidence of nausea based on CYP2D6 copy number or genotype. The authors concluded that patients with three copies of the CYP2D6 gene, a genotype consistent with ultrarapid metabolism, or both have an increased incidence of ondansetron failure for the prevention of postoperative vomiting but not nausea. Similar findings were reported by Janicki et al. (2006a, b), who investigated the efficacy of granisetron and dolasetron in preventing PONV. Because the metabolism of the various antiemetic 5-HT3RAs involves different isoforms of the hepatic cytochrome P450 system, they examined the relationship between the clinical efficacy of these drugs and polymorphic CYP2D6 genotype. This prospective, randomized, double-blind study involved 150 adult patients with a moderate to high risk for PONV. All subjects received dexamethasone at induction of anesthesia followed by either 12.5 mg of dolasetron or 1 mg of granisetron. They subsequently analyzed the number of complete responders (no vomiting or rescue medication) during the first 24 h after surgery. CYP2D6 genotyping was performed using a TaqMan real-time polymerase chain reaction. A complete response was more frequent in the granisetron group (54.7 %) compared with the dolasetron group (38.7 %, P < 0.05). In subjects receiving dolasetron, carriers of the duplication of the CYP2D6 allele predicting ultrarapid metabolizer status had more frequent vomiting episodes (P < 0.05) than patients in the granisetron group. Based on obtained results, the authors postulated that the difference in the antiemetic efficacy between two investigated 5-HT3RA
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may be associated with differences in the carrier status for the duplication of the CYP2D6 allele. Stamer et al. (2009) found that in the subpopulation of total of 92 surgical subjects, the subjects who possessed three or greater active CYP2D6 alleles (and were thus classified as UM) had reduced ondansetron plasma concentration compared to those subjects that had zero to two active alleles. The involvement of CYP2D6 system in the sensitivity to PONV was further confirmed by Wesmiller et al. (2013a, b) who presented data from 112 trauma patients with single extremity fractures, aged 18–70 years, The incidence of PONV was 38 % in the post-anesthesia care unit and increased to 50 % when assessed at 48 h. CYP2D6 classification results were 7 (6 %) poor metabolizers, 34 (30 %) intermediate metabolizers, and 71 (63 %) extensive metabolizers. No ultrarapid metabolizers were identified. Patients who were classified as poor metabolizers had less PONV and higher pain scores. These findings suggest variability in CYP2D6 impacts susceptibility to PONV. Because ondansetron and its metabolites consist of the mixture of optical isomers, Stamer et al. (2011) evaluated the hypothesis that genotype-dependent CYP2D6 and CYP3A activity selectively influence plasma concentrations of ondansetron enantiomers. In this study, 141 patients received IV ondansetron 4 or 8 mg for emesis prophylaxis before emergence from anesthesia. The CYP2D6-dependent activity score representing no, decreased, normal, or increased CYP2D6 enzyme activity as well as CYP3A low (CYP3A5*3/*3) and high expressor status (CYP3A5 wt/wt or wt/*3) were determined. Plasma concentrations of R- and S-ondansetron enantiomers were measured by liquid chromatography–tandem mass spectrometry. Area under the plasma concentration– time curves (AUCs) of R- and S-ondansetron was associated with CYP2D6 and CYP3A5 genotype-dependent enzyme activity. It was observed that concentrations of S-ondansetron differed between CYP2D6 activity groups with highest values in patients with no CYP2D6 activity compared with subjects displaying genotypes resulting in reduced or normal CYP2D6 activity. AUC of R-ondansetron was 2 times higher in CYP3A5 low expressors compared with high expressors. Doubling the ondansetron dose increased plasma concentrations only in individuals with low CYP3A activity, but not in individuals with high enzyme activity. The authors concluded that the metabolism of ondansetron seems to be enantioselective. CYP2D6 activity scores correlated with concentrations of S-ondansetron, whereas CYP3A5 expressor status mainly influenced concentrations of R-ondansetron. It is therefore possible that genetically and environmentally determined CYP2D6 and CYP3A enzyme activity might have implications for antiemetic efficacy.
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Neurokinin 1 (NK1, substance P) receptors Multiple reports concluded that neurokinin 1 (NK1) receptors are involved in nausea and vomiting. In clinical trials, there is a singular success: NK1 receptor antagonists to treat nausea and vomiting (Steinhoff et al. 2014). Several preliminary reports (mostly in the abstract form, so far) aimed to determine the genetic influence of SNPs in the TACR1 gene, which encodes NK1 receptors, including gender difference in PONV. Hayase et al. (2012) reported the results of the study in which two hundred patients who were scheduled to undergo lower abdominal surgery were enrolled in this study. The incidence and severity of PONV were evaluated after surgery. Twenty-seven selected SNPs were genotyped by the Sanger sequencing method. Transcription factor binding sites were predicted and compared with the locations of both the 27 SNPs and DNase I hypersensitivity sites in the TACR1 gene. The authors observed that SNP rs3755468 showed significant association with the incidence and severity of PONV. The GTTC haplotype of the TACR1 gene constructed by four SNPs, including the rs3755468, reduced the incidence and severity of PONV in female patients. The SNP rs3755468 is located within the predicted estrogen response element and a DNase I hypersensitivity site. The authors concluded that they found novel SNPs in the TACR1 gene that were associated with PONV. A haplotype constructed by four SNPs significantly decreased the incidence and severity of PONV to a greater extent in females than in males. SNPs in the TACR1 gene are associated with gender differences in PONV and may help to elucidate mechanisms underlying the differences. Adenosine triphosphate‑binding cassette subfamily B member 1 (ABCB1) gene polymorphism ABCB1 gene encodes protein involved in the transmembrane transport of endogenous substance or drugs (e.g., antiemetics). As far as the role of the ABCB1 polymorphism in PONV is concerned, Choi et al. (2010) investigated whether the 2677G>T/A, and 3435C>T polymorphisms ABCB influence the efficacy of ondansetron to prevent PONV in 198 patients undergoing general anesthesia. The incidence of PONV was compared between genotypes in the 2677G>T/A, and 3435C>T polymorphisms of ABCB1. The incidence of PONV was lower in patients with the 2677TT during the first 2 h after surgery. There were no significant differences in the incidence of PONV between the different genotype groupings during period between 2 and 24 h after surgery. In conclusion, the authors concluded ABCB1 genotypes may be a clinical predictor of responsiveness for ondansetron.
Coulbault et al. (2006) performed an investigation of several genomic factors, including ABCB1 polymorphism, involved in PONV. Seventy-four patients who planned to undergo colorectal surgery were included in this pilot study. The cumulative 24-h postoperative dose of morphine and PONV requiring the antiemetic ondansetron was the 2 clinical end points. The association of patient characteristics, A118G mu-opioid receptor (OPRM1) SNP; T802C uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) SNP; and ABCB1 (also known under alternative names as multidrug resistance 1 [MDR1] gene) exonic SNPs (G2677T/A, and C3435T) with study end points, was investigated. The homozygous ABCB1 diplotype (GG-CC) conferred an odds ratio of 0.12 with regard to the use of ondansetron for PONV. Multivariate analysis identified that the ABCB1 GG-CC diplotype was the only borderline predictive factor of morphine side effects. Another study that examined the association of the ABCB1 and µ-opioid genes and adverse opioid drug reactions focused on oxycodone. In this study, Zwisler et al. (2009) recruited 33 healthy volunteers who were exposed to experimental pain. In this small sample, there were no significant differences between the genotypes for the µ-opioid A118G; however, they observed a significant difference in adverse reactions (nausea and vomiting) based on the ABCB1 genotype. Morphine (μ) opioid receptor gene Because of the direct association of opioid analgesic with the incidence and severity of PONV in surgical patients, a significant number of previous pharmacogenomic investigations have focused on the polymorphism in the mu-opioid receptor gene (OPRM1) which serves as the main target of all clinically used opioid agonists. The major target of these investigations was focused on the common, nonsynonymous polymorphism in OPRM1– A118G (rs179991). The results and conclusions from the studies published so far remain controversial. Several studies reported the association of the µ-opioid receptor gene (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty and after total abdominal hysterectomy (e.g., Chou et al. 2006a, b. In both studies, they reported a higher incidence of PONV in patients who were the homozygous (AA) variants. The strong trend reported was based on observing 22 % of subjects in the AA group with PONV, as compared to 12 and 7 % in the heterozygous (AG) and homozygous variant (GG) groups, respectively. This trend was confirmed by the work of Sia et al. (2008). In their study of women post-cesarean section, they report that genetic variation at A118G of the µ-opioid receptor is associated with individual differences in pain score, amount of
self-administered morphine, and the incidence of postoperative nausea. Specifically, results showed that those subjects who carried the AA (wild type) for A118G had significantly more PONV, despite a lower consumption of PCA morphine postoperatively. They concluded that a greater sensitivity to morphine may be attributed to the AA allele and thus lead to the increased PONV that was observed in the wild-type group. As far as Caucasian population is concerned, several studies did not confirm any association between A118G polymorphism and the incidence of PONV (Janicki et al. 2006a, b; Wesmiller 2013-unpublished). In fact, association of A118 SNP was recently questioned in the study Chen et al. (2013) who directly investigated whether this polymorphism prevents PONV associated with patient controlled intravenous opioid analgesia (IV-PCA) in 179 Taiwanese patients. They observed no significant difference between the severity and incidence of IV-PCA morphine-induced side effects and SNP A118G genotype or between the associations between morphine consumption versus genotype. The genetic analysis for the severity and incidence of IVPCA morphine-induced nausea or vomiting showed no association between phenotype and genotype. They concluded that SNP A118G does not protect against IVPCA morphine-induced nausea or vomiting. In the recent meta-analysis performed by Song et al. (2013), six clinical studies were included with a total 838 women who received epidural analgesia with fentanyl during labor. The meta-analysis results indicated that there were no statistically significant differences between an AA homozygote and a G carrier (AG + GG) in the incidence of nausea and vomiting. In addition, it was recently postulated that the altered sensitivity for PONV in relation to the OPRM1 polymorphism might be related not so much to the presence of single OPRM1 SNP variant but rather combination of several variants (haplotypes). In this respect, Sugino et al. (2013) examined the incidence and severity of PONV during 24 h after surgery in 85 Japanese patients who received IV- PCA fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene were genotyped for haplotype analysis and its association with postoperative pain and PONV outcome data. The four most common haplotypes with a frequency of >10 % which were observed in the investigated groups included GGGAACAC (33 %), AGGGACAC (19 %), GGGAACGC (12 %), and AGAGACAC (10 %). The severity of PONV in carriers of GGGAACGC haplotype was significantly lower than in the carriers of other haplotypes (P < 0.05). Variations in eight SNPs within the OPRM1 gene locus might be involved in the incidence and severity of PONV associated with general anesthesia and opioid administration.
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Dopamine D2 receptor (DRD2) polymorphism Dopamine receptors, specifically D2 and D3, are known to play a role in nausea and emesis, most likely through inhibition of adenylate cyclase (Sanger and Andrews 2006) which alters the amount of cAMP within neurons located in the NTS and AP (Hyde et al. 1996). The competitive antagonism of D2, and possibly D3 receptors, provides explanation for the antiemetic activity of metoclopramide, droperidol, as well as other D2 receptor antagonists. Nakagawa et al. (2008) described recently the relationship between DRD2 Taq IA polymorphism and the occurrence of PONV in Japanese population. They enrolled 1,070 patients who were scheduled to undergo elective surgery under general anesthesia. Patients who vomited or required rescue antiemetics for severe nausea at two time points (within 6 and within 24 h after surgery) were defined as having early and total PONV, respectively. Genotyping was performed for DRD2 allele (A1A1, A1A2, or A2A2). The relationship between DRD2 Taq IA polymorphism and the occurrence of PONV was examined by multivariate logistic regression analysis. The observed incidences of early PONV were 9.0, 9.3, and 14.4 % in patients with the A1A1, A1A2, and A2A2 alleles, respectively. On multivariate analysis, the relative risk associated with the A2A2 allele in comparison with the A1A1 or A1A2 allele was 1.58 for early PONV. The incidences of total PONV were 12.5, 13.6, and 17.2 % in patients with the A1A1, A1A2, and A2A2 alleles, respectively. On multivariate analysis, the relative risk associated with the A2A2 allele in comparison with the A1A1 or A1A2 allele was 1.27 for total PONV. It appears therefore that the DRD2 Taq IA polymorphism affected the occurrence of early PONV. Catechol‑O‑methyltransferase (COMT) polymorphism COMT polymorphism may influence nausea and vomiting as the COMT enzyme modulates neurotransmission by metabolizing the catecholamine dopamine. Dopamine D2 receptors blockade in the area postrema and vomiting center has an antiemetic effect, and enhanced dopaminergic activity in patients receiving COMT inhibitors leads to more nausea/vomiting. The SNP rs4680 (G472A) is a missense variant leading to an amino acid exchange (Val158Met). COMT polymorphism may influence nausea and vomiting as the COMT enzyme and a three-to fourfold reduction in the COMT enzyme activity (158Met) (Andersen and Skorpen 2009). In migraine without aura, patients with the Met-allele had an increased incidence of nausea/vomiting, most likely due to the elevated levels of dopamine (Park et al. 2007). In line with this hypothesis, patients carrying the Val-allele reported less intense symptoms. Kolesnikov et al. (2011) investigated whether
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combined COMT and μ-opioid receptor polymorphisms contribute to the morphine response in postoperative analgesia and PONV. One hundred and two surgical patients were enrolled in this prospective, observational study. All patients received general anesthesia and were screened for μ-opioid receptor polymorphism A118G (Asn40Asp) and COMT G1947A (Val158Met) polymorphism. The heterozygous patients with μ-opioid receptor A118G and catechol-O-methyltransferase G1947A mutation consumed significantly less morphine in the post-anesthetic recovery room and 48 h after surgery compared with homozygous patients of the A118 variant. Nausea and sedation scores were also significantly lower during all observed postoperative periods for heterozygous patients, and only 2 patients (18 %) from this group received nausea treatment. Cholinergic muscarinic receptor type 3 (CHRM3) polymorphism The muscarinic acetylcholine receptors including the M3 encoded by CHRM3 have been associated with the emetic pathway and opioid-induced nausea/vomiting (Sanger and Andrews 2006). In addition, M3 muscarinic antagonists impede motion sickness and opioid-induced nausea/vomiting (Pergolizzi et al. 2012). The involvement of another SNP in the promoter region of CHRM3 (rs2165870) was also recently confirmed by both genome-wide association study in Caucasian population (Janicki et al. 2011) and targeted genomic association study in Japanese patients as reported by Hayashi et al. (2012). Other candidate genes that could influence the occurrence of PONV The serotonin transport gene (SLC6A4), a critical element of regulation of the serotonin system, has been associated with nausea and vomiting, and there is evidence that serotonin receptor genes (HTR3A, HTR3B) are associated with variability of response to antiemetic medications. A preliminary prospective design by Wesmiller et al. (2013a, b) was employed to measure PONV in 87 women following breast cancer surgery. Thirty women (34 %) experienced PONV despite administration of ondansetron and dexamethasone as standard protocol during surgery. Women classified with increased serotonin transport activity were at greater risk for PONV. The wild-type allele (A) of the single-nucleotide polymorphism (SNP) within 5-HT3A, 14396A>G (rs1176713) showed a trend toward PONV. Higher anxiety and higher pain clustered with PONV, yet the PONV group consumed less opioids. Both SLC6A4 variable number (L/S alleles) tandem repeats (VNTR) LL and the wildtype A genotype of the SNP 14396A>G represent higher serotonin activity and are associated with increased PONV
in this sample. Common hepatic organic cation transporter 1 (OCT1; SLC22A1) loss-of-function polymorphisms may also affect pharmacokinetics and efficacy of 5HT3RA. Tzvetkov et al. (2012) demonstrated in vitro that both tropisetron and ondansetron inhibited aspartate uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations and higher clinical efficacy compared with carriers of fully active OCT1. This work may indicate that in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake. Opioids are commonly used in the perioperative period (and for cancer analgesia) to control pain. Opioids are well known to induce nausea and vomiting as an independent stimulus (i.e., opioid-induced nausea and vomiting—OINV). UDP-glucuronosyltransferase (UGT2B7) plays a role in the metabolism of morphine to its main metabolites. Fujita et al. (2010) examined the relation of morphine-related adverse events to polymorphisms in UGT2B7, ABCB1, and OPRM1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. The UGT2B7*2 genotype was associated with the frequency of nausea (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2,677 and 3,435 in ABCB1 was associated with the frequency of vomiting (grades 1–3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2,677 and 3,435 suffered from vomiting. The newly employed approach of next-generation sequencing of the whole exome was recently performed in patients suffering from hyperemesis gravidarum (HG). HG is severe nausea and vomiting of pregnancy that often results in dehydration and undernutrition and is the second leading cause of hospitalization in pregnancy after preterm birth. In the study of Fejzo et al. 2013, saliva samples and surveys have been collected on 716 HG cases, 643 unaffected controls, and 29 families with 3 or more affected individuals. Exome sequencing was performed on 5 families and included 15 affected and 3 unaffected individuals. An average of 125 rare nonsynonymous damaging variants shared by affected relatives was identified in each family using a series of filtering steps. Four variants were identified in the PKD1 gene in two of five families. Three variants in the related genes PKHD1, LAMA5, and HOXD9 were identified in the remaining families. Variants were confirmed to segregate with the disease in the families by Sanger sequencing. The authors concluded that all 5 HG families carry biologically related rare damaging variants in genes known to cause polycystic kidney disease. Thus, a common pathway may be responsible for the majority of
cases of familial HG. Screening of variants in additional families and in sporadic HG cases and controls will determine whether this pathway represents a major cause of HG. This novel discovery is the first step in understanding the biology of HG, may be relevant to understanding genetic susceptibility to nausea. Another rare syndrome associated with nausea and vomiting is called cyclic vomiting syndrome (CVC) and represents a chronic disorder that is characterized by episodic nausea and vomiting. It occurs mostly in pediatric population but is being recognized with increased frequency in adults. The pathophysiology of CVS is largely unknown, but extensive pedigree analysis of children with CVS has revealed a clustering of functional disorders in maternal side relatives. It was suggested recently by Venkatesan (2013) and Malik et al. (2013) that mitochondrial DNA polymorphism may confer significantly higher odds of developing CVS in comparison with controls.
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association remained significant after correcting for multiple testing (P < 0.0023) for one SNP (rs2165870), which is located upstream of the promoter for the muscarinic acetylcholine receptor 3 subtype (CHRM3) gene. Interestingly enough, the association of the same SNP in CHRM3 with PONV was recently confirmed in Japanese population by Hayashi et al. (2012). In this study, 70 Japanese patients were scheduled to undergo gynecological surgery under combined general and epidural anesthesia and the intensity of PONV, as well as the use of anitemetics was analyzed at 24 h after surgery. The minor allele frequency of this SNP in the Japanese population was 0.21. The incidence of PONV in homozygous carriers of major allele (G) of this polymorphism was 41 %, in hereozygotes 26 % and homozygotes for minor allele 33 %. Similarly, the use of postoperative antiemetics was more frequently observed in carriers of only A allele than G allele (52 vs. 26 %). This study further confirms that CHRM3 may be involved in the mechanism of PONV in more than 1 population.
Genome‑wide association strategy for investigating PONV and CINV Concluding remarks and future directions The described above investigations have been based on target gene/polymorphism association approach. In that approach, only selected genes and polymorphisms in these genes are interrogated for association with PONV. Taking into account the fact that our current knowledge about the genomic background of PONV remains very limited, the above-mentioned approach does not allow extending the investigation of genomic background beyond previously known genes presumably involved in the mechanism of PONV. One of the methods of overcoming this shortcoming has been genome-wide association studies (GWAS). This approach, used in the study of Janicki et al. (2011), remains the only example so far of studies using GWAS approach for investigating PONV. The authors performed GWAS involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to SNP microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verification cohort consisting of 208 subjects (104 PONV patients and 104 controls). The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification cohort, the association with PONV was observed for four SNPs. This
A number of genomic investigations were reviewed here in relation to the genetic backgrounds of nausea and vomiting. Most of these investigations focused on the well-established genes and polymorphisms previously documented to be associated with the pharmacogenomics of drugs used for the treatment of PONV or motion sickness. The conclusion that can be drawn from these studies is that multiple genes and polymorphisms in the metabolic pathways previously linked PONV or motion sickness may be involved in different response to antiemetic drugs. Unfortunately, so far, all observed associations are relatively week and do not sufficiently explain inter-individual differences in the severity or background sensitivity of PONV. This seems to be particularly true for the most severe, intractable forms of PONV which respond poorly to conventional antiemetic prophylaxis and/or treatment. Because this presentation of PONV is likely to have more inherited character than other, less troublesome, presentations of PONV, it is obvious that other, more significant, genetic, or epigenetic associations are still to be discovered. There are several research strategies that can be used for these investigations. First of all, it seems to be necessary to shift the research paradigm from the search for common, less relevant polymorphism into search the rare but more functionally important polymorphisms in the part of the genes more directly involved in the protein functions (promoter regions and/or exome). This hypothesis (rare variants, common disease) assumes that each individual possesses several rare genetic variants with strong impact on the investigated common phenotype. In contrast to the common variants–common disease
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hypothesis, these rare variants are seen in few individuals (so they cannot be detected just by genetic association studies or GWAS strategy, but rather through deep sequencing or gene of interest (if we can identify one) or even better through next-generation sequencing of the entire exome). This review reports about one of the first successful applications of this strategy for the discovery of rare genetic variants in HG. It is important to note that the rare variants were discovered by the whole exome next-generation sequencing strategy in several genes previously not suspected to be related to nausea and/or vomiting. Does this mean that in order to use a similar strategy for investigating the genomic background of PONV, we would expand significantly the number of genomic targets to investigate and go beyond the number of already known target genes involved in PONV or motion sickness. One of the strategies that could potentially help in this task is to employ linkage analysis in the families affected by frequent and severe PONV and/or motion sickness. Another more translational approach involves animal models with different background sensitivity to PONV (Horn et al. 2014). The selective breeding of animals with different sensitivity to motion sickness or PONV (e.g., musk shrews mentioned before in this review) may allow identification of differentially expressed pathways in these animals (e.g., through full transcriptome analysis in different tissues or sub-tissue structures) and consequently allow for identification of genetic (or epigenetic) alterations responsible for these differences.
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Postoperative nausea and vomiting (PONV) is a long-standing issue, not a new concept in anesthesiology. Despite many studies over the last several decades, PONV remains a significant problem due to its complex mechanism. This review presents a summar
Patients undergoing ambulatory surgery under general anesthesia experience considerable levels of postoperative nausea and vomiting (N/V) after their discharge. However, those complications have not been thoroughly investigated in hand surgery patien
Postoperative nausea and vomiting (PONV) remains a problem in the postoperative period. Previous PONV in oncology patients has recently been associated with chemotherapy-induced nausea and vomiting (CINV). We assessed if CINV could improve Apfel's he
Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) can negatively impact patient quality of life, functional performance and activities of daily living. Although the development of serotonin receptor antagoni
Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk predictors, including a young age, female sex, lack of smoki
There is a passive blood flow to the stomach during oral and nasal surgery. It may cause postoperative nausea and vomiting (PONV). We researched the relationship between gastric decompression (GD) and severity of PONV in ear, nose, and throat (ENT) s