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Abstract Aim Abundant data are available on the effect of the A118G (rs1799971) single‐nucleotide polymorphism (SNP) of the μ‐opioid receptor OPRM1 gene on morphine and fentanyl requirements for pain control. However, data on the effect of this SNP on intraoperative remifentanil requirements remain limited. We investigated the effect of this SNP on intraoperative remifentanil requirements. Methods We investigated 333 Japanese women, aged 21–69 years, who underwent laparoscopic gynecological surgery for benign gynecological disease under total intravenous anesthesia at Juntendo University Hospital. Average infusion rates of propofol and remifentanil during anesthesia and the average bispectral index (BIS) during surgery were recorded. Associations among genotypes of the A118G and phenotypes were examined with the Mann–Whitney U test. Results The average propofol infusion rate was not different between patients with different genotypes. The average remifentanil infusion rate was significantly higher in patients with the AG or GG genotype than the AA genotype (p = 0.028). The average intraoperative BIS was significantly higher in patients with the GG genotype than the AA or AG genotype (p = 0.039). Conclusions The G allele of the A118G SNP was associated with higher intraoperative remifentanil requirements and higher intraoperative BIS values but was not associated with propofol requirements. Given that remifentanil and propofol act synergistically on the BIS, these results suggest that the G allele of the A118G SNP is associated with lower effects of remifentanil in achieving adequate intraoperative analgesia and in potentiating the sedative effect of propofol on the BIS.

Abstract Background We report a case in which veno-venous extracorporeal membrane oxygenation (V-V ECMO) saved the life of a patient who developed severe hypoxemia due to unusual unilateral pulmonary edema (UPE) after cardiopulmonary bypass (CPB). Case presentation A 69-year-old man underwent aortic valve replacement and coronary artery bypass grafting. Following uneventful weaning off CPB, he developed severe hypoxemia. The ratio of arterial oxygen tension to inspired oxygen fraction (PaO2/FiO2) decreased from 301 mmHg 5 min after CPB to 42 mmHg 90 min after CPB. A chest X-ray revealed right-sided UPE. Immediately established V-V ECMO increased PaO2/FiO2 to 170 mmHg. Re-expansion pulmonary edema (REPE) was likely, as the right lung remained collapsed during CPB following the accidental opening of the right chest cavity during graft harvesting. Conclusions V-V ECMO was effective in improving oxygenation and saving the life of a patient who had fallen into unilateral REPE unusually developing after conventional CPB.

Abstract Background Postoperative pneumothorax is a well-known but relatively rare complication after laparoscopic surgery. There has been no report describing pneumothorax that persisted for a week or more after laparoscopic surgery. Herein, we report a case of bilateral pneumothorax after laparoscopic surgery, which appears to have occurred by a different mechanism than previously described. Case presentation A 65-year-old male, with a past history of esophagectomy and retrosternal gastric tube reconstruction 4 months earlier, underwent a robotic-assisted inguinal hernia repair. Postoperative chest x-rays revealed the development of bilateral pneumothorax, which became worse on postoperative day (POD) 1 and took more than 9 days to resolve spontaneously. We assumed that intra-abdominal gas replaced by the air after pneumoperitoneum might have migrated into thoracic cavities through an opened esophageal hiatus or along the retrosternal route. Conclusions Laparoscopic surgery after radical esophagectomy may be associated with an increased risk of postoperative pneumothorax.

Key Clinical Message In a patient with Parkinson's disease (PD) who underwent spine surgery 13 h after the last anti‐Parkinson medications, negative pressure pulmonary edema from upper airway obstruction developed immediately after extubation. Although oxygenation improved with high‐flow nasal cannula therapy, such complications might develop due to abrupt discontinuation of medication for PD.

Abstract Background Whole lung lavage (WLL) is an effective therapy for pulmonary alveolar proteinosis. We report a rare dilutional acidosis following WLL in a female patient. Case presentation Under general anesthesia, a left-sided double-lumen tube was inserted with its bronchial lumen connected to the saline delivery system. Preoperatively, arterial blood gases were within normal limits. During 14 l of fluid was instilled into the lung for 2.5 hours, a decrease in pH, K+, and base excess, alongside an increase in Na+ and Cl−, indicated a strong ion difference; the diagnosis was dilutional hyperchloremic metabolic acidosis. Although she remained hemodynamically stable and had no indicators of massive absorption, she stayed in the ICU for mechanical ventilation for one night out of concern of pulmonary edema. Conclusions Inappropriate irrigating fluid pressure might lead to absorption of normal saline. Continuous monitoring and careful observation during WLL can help prevent intraoperative dilutional acidosis.

Abstract Background Opioids are widely used as effective analgesics, but opioid sensitivity varies widely among individuals. The underlying genetic and nongenetic factors are not fully understood. Based on the results of our previous genome‐wide association study, we investigated the effects of single nucleotide polymorphisms (SNPs) of the astrotactin 2 (ASTN2) gene on pain‐related phenotypes in surgical patients. Methods We investigated the effects of two SNPs, rs958804 T/C and rs7858836 C/T, of the ASTN2 gene on eight and seven pain‐related phenotypes in 350 patients who underwent laparoscopic colectomy (LAC) and 358 patients who underwent mandibular sagittal split ramus osteotomy (SSRO), respectively. In both surgical groups, intravenous fentanyl patient‐controlled analgesia (PCA) was used for postoperative analgesia, and 24‐hour postoperative PCA fentanyl use was the primary endpoint. Results The association analyses among the two SNPs and pain‐related traits showed that 24‐hour fentanyl use was significantly associated with the two SNP genotypes in both surgical groups. The Mann‐Whitney test showed that 24‐hour fentanyl use was lower in patients with the C allele than in patients with the TT genotype of the rs958804 T/C SNP (P = .0019 and .0200 in LAC and SSRO patients, respectively), and it was lower in patients with the T allele than in patients with the CC genotype of the rs7858836 C/T SNP (P = .0017 and .0098 in LAC and SSRO patients, respectively). Conclusion The two SNPs of the ASTN2 gene were consistently associated with fentanyl requirements after two different types of surgery. These findings may contribute to personalized pain control.

Abstract Background The indications for robot-assisted urologic surgeries have expanded due to their low invasiveness. However, complicated surgical procedures lead to prolonged surgical duration, requiring patients to remain in the lithotomy position for an extended time. Well leg compartment syndrome (WLCS) is a known severe postoperative complication related to the lithotomy position. Case presentation We report a case of WLCS after robot-assisted radical cystectomy (RARC), in which the patient recovered without neurological sequelae. A 55-year-old, obese male who underwent RARC complained of right leg pain and paresthesia 3 h after the surgery that lasted for 481 min. Emergency evaluation revealed unilateral WLCS in the anterior and lateral compartments. Urgent fasciotomy was performed 4 h after symptom onset. He thereafter recovered completely and was discharged without any neuromuscular dysfunction. Conclusions Early detection of WLCS, surgical treatment, and additional measures are crucial to prevent its life-threatening and/or disabling outcomes.

Abstract Background Giant anterior mediastinal tumor (GAMT) resection is a challenging procedure, for which anesthesiologist might take to need special precautions. Case presentation A 48-year-old male patient had been scheduled to undergo GAMT resection and superior vena cava (SVC) replacement. The tumor spread surrounding SVC and left main bronchus (LMB), resulting in small volume of his left lung. A soft left-sided double lumen tube (DLT) was selected to keep the patency of LMB during left one lung ventilation (OLV) against the tumor weight. Semi-awake intubation with spontaneous breathing was selected for DLT insertion to avoid lower airway occlusion. During left OLV after right open thoracotomy, his SPO2 decreased below to 90%. We performed selective right upper lobe bronchial blockade using the combination of DLT and bronchial blocker. The surgery was successfully completed with this strategy. Conclusions Although such cases are rare, they are informative for anesthesiologists, providing optional strategies.

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the CNR1, GRIN2A, PENK, and PDYN genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the CNR1, GRIN2A, and PENK genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman’s rank correlation coefficient ρ = 0.199, p = 0.002, ρ = 0.174, p = 0.006, and ρ = 0.135, p = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery (ρ = −0.200, p = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery (ρ = 0.143, p = 0.023), respectively. The associations between STRs in the CNR1 gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm’s multiple-testing correction. These findings indicate that STRs in the CNR1 gene influence analgesia in the orofacial region.

To evaluate associations among coagulation-related variables, resolution of disseminated intravascular coagulation (DIC) and mortality, we retrospectively investigated 123 patients with sepsis-induced DIC treated with recombinant human soluble thrombomodulin (rTM). Changes in coagulation-related variables before and after treatment with rTM were examined. Further, associations between coagulation-related variables and DIC resolution were evaluated. The platelet count, prothrombin international normalized ratio (PT-INR), and fibrin/fibrinogen degradation products (FDP) significantly ( p

Abstract Background Blind epidural catheter placement can lead to inadvertent misplacement. We present a case of intercostal misplacement of a thoracic epidural catheter. Case presentation A 67-year-old male underwent left lung cancer surgery via thoracotomy with epidural analgesia via the Th 5–6 intervertebral space, although with some difficulty. We detected dermatomal cold sensory loss around Th five min after initial administration of local anesthetics through the catheter before general anesthesia induction. However, the epidural catheter was intraoperatively found below the fifth rib, running along the course of the intercostal nerve. The catheter was successfully withdrawn via his back, and we postoperatively performed paravertebral block under ultrasound guidance. He did not complain of complications at discharge. Conclusions Detailed bilateral assessment of sensory loss after initial local anesthetic administration might have facilitated preoperative detection of the misplacement. In cases requiring multiple catheter insertion attempts, switching to another analgesic method should be considered.

Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC50 values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists.

Considerable individual differences are widely observed in the sensitivity to opioid analgesics. We focused on rs12496846, rs698705, and rs10052295 single-nucleotide polymorphisms (SNPs) in the C3orf20, SLC8A2, and CTNND2 gene regions that we previously identified as possibly associated with postoperative analgesia after orthognathic surgery. We investigated associations between these SNPs and postoperative analgesia in 112 patients who underwent major open abdominal surgery in hospitals and were treated with analgesics, including opioids, after surgery. Total genomic DNA was extracted from peripheral blood or oral mucosa samples for genotyping each SNP. Effects of these potent SNPs on gene expression in the brain were also investigated in samples that were provided by the Stanley Foundation Brain Bank. In the association studies, carriers of the G allele of the rs12496846 SNP in the C3orf20 gene region were significantly associated with greater 24 h postoperative analgesic requirements among the three SNPs that were investigated (p = 0.0015), which corroborated a previous study of orthognathic patients (p < 0.0001). In the gene expression analysis, carriers of the G allele of the rs12496846 SNP were significantly associated with lower mRNA expression of the C3orf20 gene (p < 0.0001). These results indicate that this SNP could serve as a marker that predicts analgesic requirements.

Abstract Background Ventilation failure commonly occurs when a standard left-sided double-lumen tube is used in patients after left upper lobectomy having remarkable angulation of the left main bronchus. We present a female without remarkable angulation, in whom ventilation failure occurred after lateral jackknife positioning. Case presentation A 73-year-old female after lingula-sparing left upper lobectomy without remarkable angulation was scheduled for robot-assisted right upper lobectomy. Ventilation failure with a standard left-sided double-lumen tube occurred when she was placed not in the lateral position but in the lateral jackknife position required for robotic surgery. After replacement by the Silbroncho® left-sided double-lumen tube, adequate one-lung ventilation became possible. Conclusions Ventilation failure with a standard tube may occur more easily when patients with bronchial angulation are placed in the lateral jackknife than lateral position due to posture-induced exacerbations of bronchial angulation. The Silbroncho® tube seems useful in such situations.

Abstract Background Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects. Results In this study, 33 single nucleotide polymorphisms (SNPs) were selected, and a total of 2 linkage disequilibrium blocks with 6 Tag SNPs (rs1153702, rs7583431, rs2302663, rs3845744, rs268214, and rs1982235) were observed in the region within and around the ATF2 gene. We further analyzed associations between these Tag SNPs and clinical data. Even after multiple testing with Bonferroni adjustments, an increase in the analgesic effect of fentanyl in the cold pressor‐induced pain test was significantly associated with a greater number of the A allele of the rs7583431 SNP (linear regression, P = .001). Conclusions The present findings may contribute to adequate pain relief in individual patients. Although more research on the genetic factors that influence opioid sensitivity is needed, analgesic requirements may be predicted by analyzing ATF2SNPs, together with other polymorphisms of genes that are reportedly associated with opioid sensitivity, such as CREB1, OPRM1, and GIRK2.

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.

Abstract Anesthesia for patient with large anterior mediastinal mass might induce life‐threatening complication. Maintaining the spontaneous breathing throughout the procedure and finding rescue position are the cornerstones of anesthetic management.

Abstract.: G-protein–activated inwardly rectifying potassium (GIRK) channels are expressed in many tissues and activated by several Gi/o protein–coupled receptors, such as opioid and dopamine receptors, and thus are known to be involved in the modulation of opioid-induced analgesia, pain, and reward. We focused on a GIRK-channel subunit that plays a pivotal role in the brain, GIRK2, and investigated the contribution of genetic variations of the GIRK2 (KCNJ6) gene to individual differences in the sensitivity to opioid analgesia. In our initial linkage disequilibrium analysis, a total of 27 single-nucleotide polymorphisms (SNPs) were selected within and around the regions of the KCNJ6 gene. Among them, the rs2835859 SNP, for which associations with analgesia and pain have not been previously reported, was selected in the exploratory study as a potent candidate SNP associated with opioid analgesic sensitivity. The results were corroborated in further confirmatory study. Interestingly, this SNP was also found to be associated with sensitivity to both cold and mechanical pain, susceptibility to nicotine dependence, and successful smoking cessation. The results indicate that this SNP could serve as a marker that predicts sensitivity to analgesic and pain and susceptibility to nicotine dependence. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.14189FP] Keywords:: G-protein–activated inwardly rectifying potassium (GIRK) channel, single-nucleotide polymorphism, opioid analgesia, pain, susceptibility to nicotine dependence

An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.

A previous study reported that low baseline cerebral oxygen saturation (ScO2) (≤50%) measured with near-infrared spectroscopy was predictive of poor clinical outcomes after cardiac surgery. However, such findings have not been reconfirmed by others. We conducted the current study to evaluate whether the previous findings would be reproducible, and to explore mechanisms underlying the ScO2-based outcome prediction.We retrospectively investigated 573 consecutive patients, aged 20 to 91 (mean ± standard deviation, 67.1 ± 12.8) years, who underwent major cardiovascular surgery. Preanesthetic baseline ScO2, lowest intraoperative ScO2, various clinical variables, and hospital mortality were examined.Bivariate regression analyses revealed that baseline ScO2 correlated significantly with plasma brain natriuretic peptide concentration (BNP), hemoglobin concentration (Hgb), estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) (p < 0.0001 for each). Baseline ScO2 correlated with BNP in an exponential manner, and BNP was the most significant factor influencing ScO2. Logistic regression analyses revealed that baseline and lowest intraoperative ScO2 values, but not relative ScO2 decrements, were significantly associated with hospital mortality (p < 0.05), independent of the EuroSCORE (p < 0.01). Receiver operating curve analysis of ScO2 values and hospital mortality revealed an area under the curve (AUC) of 0.715 (p < 0.01) and a cutoff value of ≤50.5% for the baseline and ScO2, and an AUC of 0.718 (p < 0.05) and a cutoff value of ≤35% for the lowest intraoperative ScO2. Low baseline ScO2 (≤50%) was associated with increases in intubation time, intensive care unit stay, hospital stay, and hospital mortality.Baseline ScO2 was reflective of severity of systemic comorbidities and was predictive of clinical outcomes after major cardiovascular surgery. ScO2 correlated most significantly with BNP in an exponential manner, suggesting that BNP plays a major role in the ScO2-based outcome prediction.

BACKGROUND:The analgesic efficacy of opioids is well known to vary widely among individuals, and various factors related to individual differences in opioid sensitivity have been identified. However, a prediction model to calculate appropriate opioid analgesic requirements has not yet been established. The present study sought to construct prediction formulas for individual opioid analgesic requirements based on genetic polymorphisms and clinical data from patients who underwent cosmetic orthognathic surgery and validate the utility of the prediction formulas in patients who underwent major open abdominal surgery. METHODS:To construct the prediction formulas, we performed multiple linear regression analyses using data from subjects who underwent cosmetic orthognathic surgery. The dependent variable was 24-h postoperative or perioperative fentanyl use, and the independent variables were age, gender, height, weight, pain perception latencies (PPL), and genotype data of five single-nucleotide polymorphisms (SNPs). To examine the utility of the prediction formulas, we performed simple linear regression analyses using subjects who underwent major open abdominal surgery. Actual 24-h postoperative or perioperative analgesic use and the predicted values that were calculated using the multiple regression equations were incorporated as dependent and independent variables, respectively. RESULTS:Multiple linear regression analyses showed that the four SNPs, PPL, and weight were retained as independent predictors of 24-h postoperative fentanyl use (R² = 0.145, P = 5.66 × 10⁻¹⁰) and the two SNPs and weight were retained as independent predictors of perioperative fentanyl use (R² = 0.185, P = 1.99 × 10⁻¹⁵). Simple linear regression analyses showed that the predicted values were retained as an independent predictor of actual 24-h postoperative analgesic use (R² = 0.033, P = 0.030) and perioperative analgesic use (R² = 0.100, P = 1.09 × 10⁻⁴), respectively. CONCLUSIONS:We constructed prediction formulas, and the possible utility of these prediction formulas was found in another type of surgery.

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca(2+) channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Ca(v)2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity.

Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean+/-SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45+/-9.27 mg, 10.84+/-2.24 mg, and 13.07+/-2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

Background: General anaesthesia is commonly conducted in surgeries for the treatment of cancer or other diseases. Whereas postoperative nausea and/or vomiting (PONV) is known as the most frequent side effect following anaesthesia, considerable individual differences have been widely observed in incidence of PONV. Although four major factors for PONV--female gender, a history of PONV and/or motion sickness, non-smoking status, and the use of postoperative opioids--were incorporated into a simplified risk score to predict PONV that was developed by Apfel et al. (1999) [1], even patients at low PONV risk according to their assigned Apfel score may experience PONV, suggesting a genetic predisposition [2]. Aims and Objectives: To explore potential candidate genetic variants responsible for the inter-subject differences in the incidence of PONV, we conducted genome-wide association study (GWAS) in patients who underwent general anaesthesia to identify potential genetic variants that may significantly contribute to individual differences in PONV. Method: The subjects in the association study were a total of 806 patients with written informed consent who underwent general anaesthesia by total intravenous anaesthesia (TIVA) with propofol and/or desflurane at The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR). The study protocol was approved by the Institutional Review Board at each related institute. Total genomic DNA was extracted from peripheral blood samples and genotyping was conducted using whole- genome genotyping arrays with more than 900,000 markers and iScan System (Illumina, San Diego, CA, USA). GWAS was conducted in the entire 806 patient subjects to identify potential candidate single nucleotide polymorphisms (SNPs) associated with frequency of nausea and presence/absence of nausea, vomiting, and both of nausea and vomiting (PONV) in trend/additive, dominant, and recessive genetic models. Genome-wide associations were also investigated only in patients with propofol, which was the most common type of anaesthesia in the subjects. Results: As a result of GWAS in all patients, several two SNPs, rs2776262 and rs140703637 (exm2274524) SNPs in the LOC100506403 and CNTN5 gene regions were significantly associated with frequency of nausea in additive or recessive and dominant models, respectively (P <7.812 × 10-8). In another GWAS only in patients with propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with frequency of nausea in additive model as well as the rs2776262 SNP in additive and recessive models, and rs1752136 and rs45574836 (exm1401859) SNPs in the LOC105370198 and ATP8B3 gene regions, respectively, were significantly associated with vomiting in trend model. Among these SNPs, clinical and SNP data were available only for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. Discussion and Conclusion: The results indicate that rs2776262, exm2274524, rs7212072, rs12444143, rs1752136, and exm1401859 SNPs could serve as markers that predict PONV [3]. Our findings will provide valuable information for achieving satisfactory prophylactic treatment for PONV. [ABSTRACT FROM AUTHOR]