rs12411980 single-nucleotide polymorphism related to PRTFDC1 expression is significantly associated with phantom tooth pain.

Phantom tooth pain (PTP) is one type of non-odontogenic neuropathic toothache, which rarely occurs after appropriate pulpectomy or tooth extraction. The cause of PTP is unknown. We investigated pain-related genetic factors that are associated with PTP. Four pain-associated genes, including G protein-coupled receptor 158 (GPR158) and phosphoribosyl transferase domain containing 1 (PRTFDC1), are adjacent to each other on the human genome. Some of these four genes or their genomic region may be related to PTP. We statistically analyzed associations between single-nucleotide polymorphisms (SNPs) in the genomic region and PTP in patients with PTP (PTP group), other orofacial pain (OFP group), and healthy control subjects. We then performed a database search of expression quantitative trait loci (eQTLs). For the seven SNPs that were significantly associated with PTP even after Bonferroni correction, we focused on the rs12411980 tag SNP (P = 9.42 × 10-4). Statistical analyses of the PTP group and healthy subject groups (group labels: NOC and TD) revealed that the rate of the GG genotype of the rs12411980 SNP was significantly higher in the PTP group than in the healthy subject groups (PTP group vs. NOC group: P = 2.92 × 10-4, PTP group vs. TD group: P = 5.46 × 10-4; percentage of GG: 30% in PTP group, 12% in NOC group, 11% in TD group). These results suggest that the GG genotype of the rs12411980 SNP is more susceptible to PTP. The rs2765697 SNP that is in strong linkage disequilibrium with the rs12411980 SNP is an eQTL that is associated with higher PRTFDC1 expression in the minor allele homozygotes in the healthy subject groups of the rs2765697 SNP. Thus, PRTFDC1 expression similarly increases in the minor allele homozygotes (GG genotype) in the healthy subject groups of the rs12411980 SNP, which would lead to greater susceptibility to PTP.

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.

Effects of Myostatin on Nuclear Morphology at the Myotendinous Junction.

Myostatin (Myo) is known to suppress skeletal muscle growth, and was recently reported to control tendon homeostasis. The purpose of the present study was to investigate the regulatory involvement of Myo in the myotendinous junction (MTJ) in vivo and in vitro. After Achilles tendon injury in mice, we identified unexpected cell accumulation on the tendon side of the MTJ. At postoperative day 7 (POD7), the nuclei had an egg-like profile, whereas at POD28 they were spindle-shaped. The aspect ratio of nuclei on the tendon side of the MTJ differed significantly between POD7 and POD28 (p = 4.67 × 10-34). We then investigated Myo expression in the injured Achilles tendon. At the MTJ, Myo expression was significantly increased at POD28 relative to POD7 (p = 0.0309). To investigate the action of Myo in vitro, we then prepared laminated sheets of myoblasts (C2C12) and fibroblasts (NIH3T3) (a pseudo MTJ model). Myo did not affect the expression of Pax7 and desmin (markers of muscle development), scleraxis and temonodulin (markers of tendon development), or Sox9 (a common marker of muscle and tendon development) in the cell sheets. However, Myo changed the nuclear morphology of scleraxis-positive cells arrayed at the boundary between the myoblast sheet and the fibroblast sheet (aspect ratio of the cell nuclei, myostatin(+) vs. myostatin(-): p = 0.000134). Myo may strengthen the connection at the MTJ in the initial stages of growth and wound healing.

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

Head injuries caused by contact with teeth during sports and exercise activities in Japanese schools during the period 2012-2018.

BACKGROUND/AIM: During sports activities, teeth-related contact can cause injury to both ally and opponent players, which can lead to potential infections and aesthetic problems. However, the extent of such injuries remains unclear. This study aimed to clarify the frequency and situation of head injuries caused by teeth (HICBT) occurring under the supervision of schools in Japan. MATERIAL AND METHODS: HICBT records were extracted from the Japan Sport Council data on head injuries occurring reported during the 7-year period from 2012 to 2018 under the supervision of schools in Japan. RESULTS: Of the total 463,527 head injury cases during the study period, 4495 cases (approximately 1%) were HICBT. Of the HICBT cases, 3650 (81.20%) were related to sports and athletic activity. Such injuries were reported to occur most often during basketball with a rate of 57.07% and 50.43%; soccer/futsal was the next most common sport with a rate of 13.38% and 24.01% in junior high school and high school students. Tag games were responsible for a similar number of HICBT cases at 22.73% and 39.03% in kindergartens and elementary school students. CONCLUSIONS: A total of 4495 cases of HICBT were identified, accounting for about 1% of all head injuries under the supervision of schools in Japan during the study period. This result reminds us that our teeth could be the weapon against the players during sports events. HICBTs occurring during basketball and soccer/futsal, in which mouthguards are not mandatory, were conspicuous among junior and senior high school students. Active use of mouthguards in various sports will protect players as well as their teammates and opponents. Sports dentists should encourage the revision of rules, such as mandating the use of mouthguards, in popular sports with a high incidence of HICBT, such as basketball and soccer/futsal.

Improving light-cured intermediate resin for hard and space mouthguard using a glass fiber.

BACKGROUND/AIMS: A light-cured intermediate material is useful for fabricating a hard insert and a buffer space mouthguard (H&SMG). However, it requires improvement in its mechanical properties and shock-absorbing capacity. The aim of this study was to evaluate the mechanical properties of two prototype light-cured intermediate materials reinforced with glass fibers, and the impact absorption capacity and durability of H&SMGs made with the prototype intermediate materials. MATERIALS AND METHODS: Two prototype materials containing long and microlength glass fibers in a light-cured intermediate material, Innerframe LC®, for H&SMG, were fabricated and tested. A three-point bending test was performed for evaluation of the mechanical properties. In addition, a shock absorption test was conducted using a customized pendulum impact testing machine to evaluate the H&SMGs' impact absorption capacity and durability. RESULTS: Long and microlength glass fibers significantly improved flexural modulus and strength. H&SMGs made with these two glass fiber-containing materials had high impact absorption capacity against both low and high impact forces, while the mouthguards made with long glass fiber materials had the best results. CONCLUSION: Long and microlength glass fibers with the prototype materials improved the mechanical properties of Innerframe LC® and the impact absorption capacity and durability of H&SMGs. H&SMGs made with the long glass fiber prototype materials had the best performance.

Single-nucleotide polymorphisms of the SLC17A9 and P2RY12 genes are significantly associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. We focused on solute carrier family 17 member 9 (SLC17A9)/vesicular nucleotide transporter (VNUT) and purinergic receptor P2Y12 (P2RY12), both of which have been associated with neuropathic pain and pain transduction signaling in the trigeminal ganglion in rodents. We sought to corroborate these associations in humans. We investigated gene polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 150 patients with orofacial pain, including PTP, and 500 healthy subjects. We found that the rs735055 polymorphism of the SLC17A9 gene and rs3732759 polymorphism of the P2RY12 gene were associated with the development of PTP. Carriers of the minor allele of rs735055 and individuals who were homozygous for the major allele of rs3732759 had a higher rate of PTP. Carriers of the minor allele of rs735055 reportedly had high SLC17A9 mRNA expression in the spinal cord, which may increase the storage and release of adenosine triphosphate. Individuals who were homozygous for the major allele of rs3732759 may have higher P2RY12 expression that is more active in microglia. Therefore, these carriers may be more susceptible to PTP. These results suggest that specific genetic polymorphisms of the SLC17A9 and P2RY12 genes are involved in PTP. This is the first report on genes that are associated with PTP in humans.

Jaw-Clenching Intensity Effects on Masseter Oxygen Dynamics and Fatigue: A NIRS Oximetry Study.

The purpose of this study was to clarify the effects of jaw-clenching intensity on masseter muscle oxygen dynamics during clenching and recovery and masseter muscle fatigue using the spatially resolved method of near-infrared spectroscopy. Pulse rate, mean power frequency from electromyography in the masseter and visual analogue scale for masseter fatigue were also examined as related items. The 25% and 50% maximum voluntary contractions were determined using electromyography before the experiment and used as visual feedback on the screen. Twenty-three healthy adult male subjects volunteered for this study. Clenching decreased oxygen and oxygenated haemoglobin, and increased deoxygenated haemoglobin in the masseter muscle. The higher the intensity of clenching, the more prominent the effect. The oxygen dynamics tended to return to normal after clenching, but the change was slower with higher clenching intensity. Pulse rate increased with clenching, and the increment was more prominent with higher clenching intensity. Clenching caused a shift of mean power frequency to a lower range, an increase in subjective fatigue, an early appearance of a breakpoint appearance time and a prolongation of a 1/2 recovery time. All of these effects were more evident with increasing clenching intensity. In conclusion, clenching intensity influenced the oxygen dynamics of the masseter muscle and fatigue state during clenching and recovery. The higher the intensity, the greater the impact.

Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/F2RL1 and TRPM8.

Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the PAR2 gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the TRPM8 gene. Carriers of the minor A allele of the rs2243057 polymorphism of PAR2 and minor C allele of the rs12992084 polymorphism of TRPM8 exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both PAR2 and TRPM8 are involved in individual differences in cold pain sensitivity.

The effect of light-cured resin with a glass fiber net as an intermediate material for Hard & Space mouthguard.

BACKGROUND/AIMS: Despite the use of conventional mouthguards, preventable sports-related dental injuries continue to occur. The authors have developed a two-layered ethylene polyvinyl acetate (EVA) mouthguard with a hard polyethylene terephthalate (PET) insert and a buffer space (H&SMG). However, adapting the PET onto the EVA layer requires skill. A light-cured Splint Resin (SRLC) and a glass fiber net (NET) reinforcement appear to resolve this issue. The aim of this study was to investigate whether SRLC with NET could replace PET and find a more practical application for NET. MATERIALS AND METHODS: A pendulum impact testing machine and a dental model with strain gages were used. Six types of mouthguards were made: one with two laminated EVA blanks (LAM-MG), a three-layer type with a PET insert and an intermediate space (PET-H&SMG), a H&SMG with SRLC insert (LC-H&SMG), and three other types with differential NET-SRLC reinforcement; NET on the outer surface of SRLC, NET on the inner surface of SRLC, and NET on both the outer and inner surfaces. Five mouthguards of each type were fabricated and tested ten times with impact distances of 15 and 30 cm. Forty more impacts were applied to all H&SMGs to confirm the durability of the hard inner layer. RESULTS: All H&SMGs showed significant strain reduction compared to the LAM-MG. PET-H&SMG and the four types of LC-H&SMG exhibited an equally slight strain (approximately 95% shock absorbing ability) in all conditions. During the test against the smaller impact, all H&SMGs showed no cracks. When tested against the stronger impact, only the LC-H&SMG with the reinforced inner surface, the double NET-reinforced LC-H&SMG, and the PET-H&SMG remained intact. CONCLUSION: The NET-reinforced SRLC can replace PET as an intermediate mouthguard material. The NET application, at least on the internal surface, is indispensable for the LC-H&SMG reinforcement.

Parental Satisfaction with Ambulatory Anesthesia during Dental Treatment for Disabled Individuals and Their Preference for Same in Future.

The purpose of this study was to survey parental satisfaction with ambulatory anesthesia during dental treatment in disabled patients. Factors associated with parental preference for general anesthesia during future dental treatment in such patients were also investigated. A questionnaire was mailed to the parents of 181 disabled individuals who underwent dental treatment under ambulatory anesthesia at Tokyo Dental College Suidobashi Hospital between 2012 and 2016. A total of 71 responses were received (39.2%). The mean patient age was 18 years, and disabilities included autism spectrum disorder, intellectual disability, cerebral palsy, and epilepsy. The items surveyed included dental treatment details, number of times patients received general anesthesia, type of anesthetic used, anesthesia induction method, durations of treatment and anesthesia, and the presence or absence of intraoperative or postoperative complications. Questionnaire items queried problems related to dental care, anesthesia history, preoperative anxiety, length of fasting period, induction of general anesthesia, nursing and hospital room environment, postoperative anxiety, overall evaluation, and whether the parent would prefer general anesthesia during future dental treatment. The patients were divided into 2 groups: those whose parents preferred general anesthesia during future dental treatment and those whose parents did not. The results revealed that, where disabled individuals had previously received general anesthesia during dental treatment, the parents were more likely to prefer general anesthesia during future dental treatment.

Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test.

Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control.

Association between UGT2B7 gene polymorphisms and fentanyl sensitivity in patients undergoing painful orthognathic surgery.

Background Fentanyl is often used instead of morphine for the treatment of pain because it has fewer side effects. The metabolism of morphine by glucuronidation is known to be influenced by polymorphisms of the UGT2B7 gene. Some metabolic products of fentanyl are reportedly metabolized by glucuronate conjugation. The genes that are involved in the metabolic pathway of fentanyl may also influence fentanyl sensitivity. We analyzed associations between fentanyl sensitivity and polymorphisms of the UGT2B7 gene to clarify the hereditary determinants of individual differences in fentanyl sensitivity. Results This study examined whether single-nucleotide polymorphisms (SNPs) of the UGT2B7 gene affect cold pain sensitivity and the analgesic effects of fentanyl, evaluated by a standardized pain test and fentanyl requirements in healthy Japanese subjects who underwent uniform surgical procedures. The rs7439366 SNP of UGT2B7 is reportedly associated with the metabolism and analgesic effects of morphine. We found that this SNP is also associated with the analgesic effects of fentanyl in the cold pressor-induced pain test. It suggested that the C allele of the rs7439366 SNP may enhance analgesic efficacy. Two SNPs of UGT2B7, rs4587017 and rs1002849, were also found to be novel SNPs that may influence the analgesic effects of fentanyl in the cold pressor-induced pain test. Conclusions Fentanyl sensitivity for cold pressor-induced pain was associated with the rs7439366, rs4587017, and rs1002849 SNPs of the UGT2B7 gene. Our findings may provide valuable information for achieving satisfactory pain control and open to new avenues for personalized pain treatment.

Recovery Profile and Patient Satisfaction After Ambulatory Anesthesia for Dental Treatment-A Crossover Comparison Between Propofol and Sevoflurane.

The purpose of this study was to determine which anesthetic was preferable for ambulatory anesthesia: propofol alone or sevoflurane alone. A crossover study was performed to compare the recovery profile and patient satisfaction after 2 anesthesia methods. Twenty healthy patients with severe anxiety toward dental treatment undergoing 2 sessions of day-case dental treatment received either propofol or sevoflurane anesthesia. The order of these methods was randomized. The depths of anesthesia were kept constant using bispectral index (BIS) monitoring. Observations on recovery profiles were performed in the emergence phase, in the recovery phase, and 24 hours after discharge. Patient satisfaction and preference were obtained by a questionnaire. Most of the recovery profiles in the emergence phase such as time to eye opening to respond to verbal command, time to BIS ≥ 75, and time to extubation were shorter in the sevoflurane group than in the propofol group. All recovery profiles in the recovery phase showed no differences between the 2 groups. Based on the subject's satisfaction and preference, propofol was evaluated as a better anesthetic for ambulatory anesthesia than sevoflurane. Higher patient satisfaction and a greater preference for future dental treatment were revealed for propofol anesthesia. Propofol may be more suitable for ambulatory anesthesia for dental treatment.

Remifentanil in Combination With Propofol Is Suitable for Use in the Dental Outpatient Setting.

Although several adjuncts to the general anesthetic propofol have been proposed, there is insufficient research identifying the ideal agent, and in what dosage, to combine with propofol in dental outpatient anesthesia. Here we examined the combination of remifentanil or nitrous oxide and propofol in patients with severe dental avoidance undergoing dental treatment in the outpatient setting. Eighty patients were randomized to 4 groups and administered propofol/saline solution (PS; n = 20), propofol/remifentanil 0.25 µg/kg/min (PRe-0.25; n = 20), propofol/remifentanil 0.125 µg/kg/min (PRe-0.125; n = 20), or propofol/66% nitrous oxide (PN; n = 20). During anesthesia, the bispectral index value was kept between 40 and 60. Body movements and hemodynamic changes during anesthesia, emergence, and recovery as well as anesthetic cost were compared between the combinations. Body movements were observed in all patients administered PS but in no patients administered PRe-0.25, PRe-0.125, or PN. Postoperative nausea was observed in 5 patients (25%) administered PRe-0.25 and in 1 patient (5%) administered PN. Although both PRe-0.125 and PN were useful clinically, PRe-0.125 was the least expensive combination.

Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements.

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.

Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl.

BACKGROUND: The P2X7 receptor is a member of the P2X family of adenosine 5'-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery. RESULTS: We first conducted linkage disequilibrium (LD) analyses for 55 reported single-nucleotide polymorphisms (SNPs) in the region within and around the P2RX7 gene using genomic samples from 100 patients. In our samples, 42 SNPs were polymorphic, and a total of five LD blocks with six Tag SNPs (rs2708092, rs1180012, rs1718125, rs208293, rs1718136, and rs7132846) were observed. Thus, we further analyzed associations between genotypes/haplotypes of these Tag SNPs and clinical data using a total of 355 samples. In the genotype-based association study, only the rs1718125 G>A SNP tended to be associated with higher pain scores on a visual analog scale 24 h after surgery (VAS24). The haplotype-based association study showed that subjects with homozygous haplotype No.3 (GTAAAC; estimated frequency: 15.0%) exhibited significantly higher cold pain sensitivity and lower analgesic effects of fentanyl for acute cold pain in the cold pressor test. Conversely, subjects who carried haplotype No.1 (ACGGAC; estimated frequency: 24.5%) tended to exhibit lower cold pain sensitivity and higher analgesic effects of fentanyl. Furthermore, subjects with homozygous haplotype No.2 (GCGGAC; estimated frequency: 22.9%) exhibited significantly lower VAS24 scores. CONCLUSIONS: Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5'-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl.

OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis.

BACKGROUND: Although a number of studies have investigated the association of the OPRM1 A118G polymorphism with pain response, a consensus has not yet been reached. METHODS: The authors searched PubMed, EMBASE, and the Cochrane Library to identify gene-association studies that explored the impact of the OPRM1 A118G polymorphism on postoperative opioid requirements through July 2013. Two evaluators independently reviewed and selected articles on the basis of prespecified selection criteria. The authors primarily investigated the standardized mean difference (SMD) of required amounts of opioids between AA homozygotes and G-allele carriers. The authors also performed subgroup analyses for race, opioid use, and type of surgery. Potential bias was assessed using the Egger's test with a trim and fill procedure. RESULTS: Three hundred forty-six articles were retrieved from databases, and 18 studies involving 4,607 participants were included in the final analyses. In a random-effect meta-analysis, G-allele carriers required a higher mean opioid dose than AA homozygotes (SMD, -0.18; P = 0.003). Although there was no evidence of publication bias, heterogeneity was present among studies (I(2) = 66.8%). In the subgroup meta-analyses, significance remained robust in Asian patients (SMD, -0.21; P = 0.001), morphine users (SMD, -0.29; P <0.001), and patients who received surgery for a viscus (SMD, -0.20; P = 0.008). CONCLUSIONS: The OPRM1 A118G polymorphism was associated with interindividual variability in postoperative response to opioids. In a subpopulation, identifying OPRM1 A118G polymorphism may provide valuable information regarding the individual analgesic doses that are required to achieve satisfactory pain control.