Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

The influence of COMT and ABCB1 gene polymorphisms on sufentanil analgesic effect for postoperative pain in children with fracture.

The aim of this observational study was to investigate the effects of catechol-O-methyltransferase (COMT) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on the postoperative analgesic effect of sufentanil in Chinese Han pediatric patients with fractures. A total of 185 pediatric patients who underwent fracture surgery were included. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of COMT and ABCB1 genes. Sufentanil was used for postoperative analgesia. The pain level of the patients was evaluated using the face, legs, activity, cry, and consolability scale before surgery, during awakening, at 2, 6, 12, and 24 hours after surgery. The postoperative Ramsay sedation score, sufentanil consumption, and incidence of adverse reactions were also recorded. Pediatric patients with different genotypes of ABCB1 and COMT showed no statistically significant differences in general data such as age, gender, weight, height, surgical duration, and American Society of Anesthesiologists classification (P > .05). There were no statistically significant differences in sedation scores after surgery between different genotypes of ABCB1 and COMT (P > .05). Among patients with CC genotype in ABCB1, the pain scores and total consumption of sufentanil at awakening, 2 and 6 hours after surgery were higher compared to TT and CT genotypes (P < .05), while there were no statistically significant differences between TT and CT genotypes (P > .05). Among patients with AA genotype in COMT, the pain scores and total consumption of sufentanil at awakening, 2, 6, 12, and 24 hours after surgery were higher compared to AG and GG genotypes (P < .05), while there were no statistically significant differences between AG and GG genotypes (P > .05). There were no statistically significant differences in adverse reactions between different genotypes of ABCB1 and COMT (P > .05). The polymorphisms of COMT gene rs4680 and ABCB1 gene rs1045642 are associated with the analgesic effect and consumption of sufentanil in pediatric patients after fracture surgery.

Impact of pharmacogenomic profiles on post-surgical pain following laparotomy for gynecologic pathology.

OBJECTIVES: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism. METHODS: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests. RESULTS: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups. CONCLUSIONS: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology.

Risk factors and related miRNA phenotypes of chronic pain after thoracoscopic surgery in lung adenocarcinoma patients.

Chronic postsurgical pain may have a substantial impact on patient's quality of life, and has highly heterogenous presentation amongst sufferers. We aimed to explore the risk factors relating to chronic pain and the related miRNA phenotypes in patients with lung adenocarcinoma after video-assisted thoracoscopic lobectomy to identify potential biomarkers. Our prospective study involved a total of 289 patients with early invasive adenocarcinoma undergoing thoracoscopic lobotomy and a follow-up period of 3 months after surgery. Blood was collected the day before surgery for miRNA detection and patient information including operation duration, duration of continuous drainage of the chest, leukocyte count before and after operation, and postoperative pain scores were recorded. Using clinical and biochemical information for each patient, the risk factors for chronic postsurgical pain and related miRNA phenotypes were screened. We found that chronic postsurgical pain was associated with higher body mass index; greater preoperative history of chronic pain; longer postoperative drainage tube retention duration; higher numerical rating scale scores one, two, and three days after surgery; and changes in miRNA expression, namely lower expression of miRNA 146a-3p and higher expression of miRNA 550a-3p and miRNA 3613-3p in peripheral blood (p < 0.05). Of these factors, patient body mass index, preoperative history of chronic pain, average numerical rating scale score after operation, and preoperative peripheral blood miRNA 550a-3P expression were independent risk factors for the development of chronic postsurgical pain. Identification of individual risk markers may aid the development and selection of appropriate preventive and control measures.

Does Preoperative Pharmacogenomic Testing of Patients Undergoing TKA Improve Postoperative Pain? A Randomized Trial.

BACKGROUND: Pharmacogenomics is an emerging and affordable tool that may improve postoperative pain control. One challenge to successful pain control is the large interindividual variability among analgesics in their efficacy and adverse drug events. Whether preoperative pharmacogenomic testing is worthwhile for patients undergoing TKA is unclear. QUESTIONS/PURPOSES: (1) Are the results of preoperative pharmacogenetic testing associated with lower postoperative pain scores as measured by the Overall Benefit of Analgesic Score (OBAS)? (2) Do the results of preoperative pharmacogenomic testing lead to less total opioids given? (3) Do the results of preoperative pharmacogenomic testing lead to changes in opioid prescribing patterns? METHODS: Participants of this randomized trial were enrolled from September 2018 through December 2021 if they were aged 18 to 80 years and were undergoing primary TKA under general anesthesia. Patients were excluded if they had chronic kidney disease, a history of chronic pain or narcotic use before surgery, or if they were undergoing robotic surgery. Preoperatively, patients completed pharmacogenomic testing (RightMed, OneOME) and a questionnaire and were randomly assigned to the experimental group or control group. Of 99 patients screened, 23 were excluded, one before randomization; 11 allocated patients in each group did not receive their allocated interventions for reasons such as surgery canceled, patients ultimately undergoing spinal anesthesia, and change in surgery plan. Another four patients in each group were excluded from the analysis because they were missing an OBAS report. This left 30 patients for analysis in the control group and 38 patients in the experimental group. The control and experimental groups were similar in age, gender, and race. Pharmacogenomic test results for patients in the experimental group were reviewed before surgery by a pharmacist, who recommended perioperative medications to the clinical team. A pharmacist also assessed for clinically relevant drug-gene interactions and recommended drug and dose selection according to guidelines from the Clinical Pharmacogenomics Implementation Consortium for each patient enrolled in the study. Patients were unaware of their pharmacogenomic results. Pharmacogenomic test results for patients in the control group were not reviewed before surgery; instead, standard perioperative medications were administered in adherence to our institutional care pathways. The OBAS (maximum 28 points) was the primary outcome measure, recorded 24 hours postoperatively. A two-sample t-test was used to compare the mean OBAS between groups. Secondary measures were the mean 24-hour pain score, total morphine milligram equivalent, and frequency of opioid use. Postoperatively, patients were assessed for pain with a VAS (range 0 to 10). Opioid use was recorded preoperatively, intraoperatively, in the postanesthesia care unit, and 24 hours after discharge from the postanesthesia care unit. Changes in perioperative opioid use based on pharmacogenomic testing were recorded, as were changes in prescription patterns for postoperative pain control. Preoperative characteristics were also compared between patients with and without various phenotypes ascertained from pharmacogenomic test results. RESULTS: The mean OBAS did not differ between groups (mean ± SD 4.7 ± 3.7 in the control group versus 4.2 ± 2.8 in the experimental group, mean difference 0.5 [95% CI -1.1 to 2.1]; p = 0.55). Total opioids given did not differ between groups or at any single perioperative timepoint (preoperative, intraoperative, or postoperative). We found no difference in opioid prescribing pattern. After adjusting for multiple comparisons, no difference was observed between the treatment and control groups in tramadol use (41% versus 71%, proportion difference 0.29 [95% CI 0.05 to 0.53]; nominal p = 0.02; adjusted p > 0.99). CONCLUSION: Routine use of pharmacogenomic testing for patients undergoing TKA did not lead to better pain control or decreased opioid consumption. Future studies might focus on at-risk populations, such as patients with chronic pain or those undergoing complex, painful surgical procedures, to test whether pharmacogenomic results might be beneficial in certain circumstances. LEVEL OF EVIDENCE: Level I, therapeutic study.

Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype.

ABSTRACT: It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

The Effect of Genetic Variation on the Sensitivity to Opioid Analgesics in Patients With Postoperative Pain: An Updated Meta-analysis.

BACKGROUND: Responsiveness to opioid analgesics differs among patients with acute postoperative pain. OBJECTIVE: Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids. STUDY DESIGN: An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain. METHODS: PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021. RESULTS: Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human µ-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms. LIMITATIONS: Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis. CONCLUSIONS: In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia. KEY WORDS: Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis.

Descending Control of Nociception Poorly Predicts the Development of Persistent Postsurgical Pain-like Behavior in Consomic Dahl S Rat Strains.

BACKGROUND: Chronic postsurgical pain is a poorly recognized outcome of surgery where patients experience pain long after healing from the surgical insult. Descending control of nociception, a phenomenon whereby application of a strong nociceptive stimulus to one part of the body of animals inhibits pain in remote body regions, offers one strategy to identify a propensity to develop chronic postsurgical pain-like behavior. Here, consomic rat panel was used to test the hypothesis that pain persistence is mechanistically linked to ineffective descending control of nociception. METHODS: Male and female Brown Norway, Dahl S, and eight consomic strains (SS-xBN) were used to determine the presence of chronic postsurgical pain-like behaviors by using paw-withdrawal threshold evaluation (von Frey method) in the area adjacent to a hind paw plantar incision. Descending control of nociception was assessed by measuring hind paw-withdrawal thresholds (Randall-Selitto method) after capsaicin (125 µg) injection into a forepaw. Consomic rats were developed by introgressing individual Brown Norway chromosomes on the Dahl S rat genetic background, as Dahl S rats lack preoperative descending control of nociception. RESULTS: Substitution of several chromosomes from the "pain-resistant" Brown Norway to the "pain-prone" Dahl S/Medical College of Wisconsin reduced mechanical nociceptive sensitivity and increased endogenous pain modulation capacity by differing degrees. Statistical modeling of these data revealed that descending control of nociception is a poor general predictor of the propensity to develop chronic postsurgical pain-like behavior (poor fit for model 1). However, a significant strain-by-descending control of nociception interaction was revealed (model 3, -2*log likelihood; 550.668, -2ll change; 18.093, P = 0.034) with SS-13BN and SS-15BN strains showing a negative descending control of nociception relationship with chronic postsurgical pain-like behavior. CONCLUSIONS: Descending control of nociception poorly predicted which rat strains developed chronic postsurgical pain-like behavior despite controlling for genetic, environmental, and sex differences. Two consomic strains that mimic clinical chronic postsurgical pain criteria and display a strong negative correlation with descending control of nociception were identified, offering novel candidates for future experiments exploring mechanisms that lead to chronic postsurgical pain.

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.

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.

Association between single nucleotide variants and severe chronic pain in older adult patients after lower extremity arthroplasty.

BACKGROUND: Hip or knee osteoarthritis (OA) is one of the main causes of disability worldwide and occurs mostly in the older adults. Total hip or knee arthroplasty is the most effective method to treat OA. However, severe postsurgical pain leading to a poor prognosis. So, investigating the population genetics and genes related to severe chronic pain in older adult patients after lower extremity arthroplasty is helpful to improve the quality of treatment. METHODS: We collected blood samples from elderly patients who underwent lower extremity arthroplasty from September 2020 to February 2021 at the Drum Tower Hospital Affiliated to Nanjing University Medical School. The enrolled patients provided measures of pain intensity using the numerical rating scale on the 90th day after surgery. Patients were divided into the case group (Group A) and the control group (Group B) including 10 patients respectively by the numerical rating scale. DNA was isolated from the blood samples of the two groups for whole-exome sequencing. RESULTS: In total, 661 variants were identified in the 507 gene regions that were significantly different between both groups (P < 0.05), including CASP5, RASGEF1A, CYP4B1, etc. These genes are mainly involved in biological processes, including cell-cell adhesion, ECM-receptor interaction, metabolism, secretion of bioactive substances, ion binding and transport, regulation of DNA methylation, and chromatin assembly. CONCLUSIONS: The current study shows some variants within genes are significantly associated with severe postsurgical chronic pain in older adult patients after lower extremity arthroplasty, indicating a genetic predisposition for chronic postsurgical pain. The study was registered according to ICMJE guidelines. The trial registration number is ChiCTR2000031655 and registration date is April 6th, 2020.

Effects of oxycodone pharmacogenetics on postoperative analgesia and related clinical outcomes in children: a pilot prospective study.

Background: Variability in the pharmacokinetics and pharmacodynamics of oxycodone in children undergoing surgery could be due to genetic polymorphisms. Materials & methods: The authors studied the association between clinical outcomes and pharmacogenes in children undergoing major surgery. A total of 89 children (35 undergoing pectus excavatum repair and 54 undergoing spinal fusion) were recruited. Results: OPRM1 SNP rs6902403 showed an association with maximum pain score and total morphine equivalent dose (p < 0.05). Other polymorphisms in OPRM1 SNP, PXR, COMT and ABCB1 were also shown to be associated with average morphine equivalent dose, length of hospital stay and maximum surgical pain (p < 0.05). Conclusion: This study demonstrates novel associations between the above pharmacogenes and oxycodone's pharmacokinetics as well as postoperative outcomes in children. Clinical trial registration: NCT03495388 (ClinicalTrials.gov).

Effect of common OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 polymorphisms on perioperative analgesic and propofol demands on patients subjected to thyroidectomy surgery.

BACKGROUND: Perioperative anesthetic and/or analgesic demand present considerable variation, and part of that variation appears to be genetic in origin. Here we investigate the impact of common polymorphisms in OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 genes, on the intra-operative consumption of remifentanil and propofol, as well as the postoperative analgesic needs, in patients subjected to thyroidectomy surgery. METHODS: We conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of propofol and remifentanil. Postoperative analgesics were administered by protocol and on-demand by the individual patient. Genotyping was established by PCR-RFLP methods. Genotyping data, intra-operative hemodynamics, and total consumption of remifentanil and propofol, as well as postoperative analgesic needs and pain perception, were recorded for each individual. RESULTS: Patients with the ABCB1 3435TT genotype appeared to experience significantly less pain within one hour post-operatively, compared to C carriers [mean VAS (SD) = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment. Intra-operatively, homozygotes patients for the minor allele of OPRM1 A118G and CYP2B6 G516T appeared to consume less remifentanil [mean (SD) = 9.12 (1.01) vs. 13.53 (5.15), for OPRM1 118GG and A carriers] and propofol [median (range) = 14.95 (11.53, 1359.5) vs. 121.4 (1.43, 2349.4), for CYP2B6 516TT and G carriers, respectively] but the difference was not statistically significant in our sample. CONCLUSIONS: The ABCB1 C3435T polymorphism appears to affect the postoperative perception of surgical pain among patients with low pain threshold. The small number of minor allele homozygotes for the OPRM1 A118G and CYP2B6 G516T polymorphisms precludes a definitive conclusion regarding the inclusion of the latter in a TCI-programming algorithm, based on the results of this study. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12616001598471.

Predictive models for fentanyl dose requirement and postoperative pain using clinical and genetic factors in patients undergoing major breast surgery.

ABSTRACT: Fentanyl exhibits interindividual variability in its dose requirement due to various nongenetic and genetic factors such as single nucleotide polymorphisms (SNPs). This study aims to develop and cross-validate robust predictive models for postoperative fentanyl analgesic requirement and other related outcomes in patients undergoing major breast surgery. Data regarding genotypes of 10 candidate SNPs, cold pain test (CPT) scores, pupillary response to fentanyl (PRF), and other common clinical characteristics were recorded from 257 patients undergoing major breast surgery. Predictive models for 24-hour fentanyl requirement, 24-hour pain scores, and time for first analgesic (TFA) in the postoperative period were developed using 4 different algorithms: generalised linear regression model, linear support vector machine learning (SVM-Linear), random forest (RF), and Bayesian regularised neural network. The variant genotype of OPRM1 (rs1799971) and higher CPT scores were associated with higher 24-hour postoperative fentanyl consumption, whereas higher PRF and history of hypertension were associated with lower fentanyl requirement. The variant allele of COMT (rs4680) and higher CPT scores were associated with 24-hour postoperative pain scores. The variant genotype of CTSG (rs2070697), higher intraoperative fentanyl use, and higher CPT scores were associated with significantly lower TFA. The predictive models for 24-hour postoperative fentanyl requirement, pain scores, and TFA had R-squared values of 0.313 (SVM-Linear), 0.434 (SVM-Linear), and 0.532 (RF), respectively. We have developed and cross-validated predictive models for 24-hour postoperative fentanyl requirement, 24-hour postoperative pain scores, and TFA with satisfactory performance characteristics and incorporated them in a novel web application.

Impact of Genetic Variants on Postoperative Pain and Fentanyl Dose Requirement in Patients Undergoing Major Breast Surgery: A Candidate Gene Association Study.

BACKGROUND: Postoperative analgesia is crucial for the early and effective recovery of patients undergoing surgery. Although postoperative multimodal analgesia is widely practiced, opioids such as fentanyl are still one of the best analgesics. The analgesic response of fentanyl varies widely among individuals, probably due to genetic and nongenetic factors. Among genetic factors, single nucleotide polymorphisms (SNPs) may influence its analgesic response by altering the structure or function of genes involved in nociceptive, fentanyl pharmacodynamic, and pharmacokinetic pathways. Thus, it is necessary to comprehensively ascertain if the SNPs present in the aforementioned pathways are associated with interindividual differences in fentanyl requirement. In this study, we evaluated the association between 10 candidate SNPs in 9 genes and 24-hour postoperative fentanyl dose (primary outcome) and also with postoperative pain scores and time for first analgesia (secondary outcomes). METHODS: A total of 257 South Indian women, aged 18-70 years, with American Society of Anesthesiologists (ASA) physical status I-III, undergoing major breast surgery under general anesthesia, were included in the study. Patients were genotyped for candidate SNPs using real-time polymerase chain reaction. All patients received a standardized intravenous fentanyl infusion through a patient-controlled analgesic (PCA) pump, and the 24-hour postoperative fentanyl dose requirement was measured using PCA. RESULTS: The median 24-hour postoperative fentanyl requirement was higher in rs1799971 carriers (G/G versus A/A + A/G-620 µg [500-700] vs 460 µg [400-580]) with a geometric mean (GM) ratio of 1.91 (95% confidence interval [CI], 1.071-1.327). The median 24-hour pain scores were higher in rs4680 carriers (A/G + A/A versus G/G-34 [30-38] vs 31 [30-38]) with a GM ratio of 1.059 (95% CI, 1.018-1.101) and were lower in rs1045642 carriers (A/A + A/G versus G/G-34 [30-38] vs 30 [30-34]) with a GM ratio of 0.936 (95% CI, 0.889-0.987). The median time for first analgesic was lower in rs734784 carriers [C/C versus T/T + C/T-240 minutes (180-270) vs 240 minutes (210-270)] with a GM ratio of 0.902 (95% CI, 0.837-0.972). Five of 9 clinical factors, namely, history of diabetes, hypertension, hypothyroidism, anesthesia duration, and intraoperative fentanyl requirement were associated with different outcomes individually ( P < .05) and were used to adjust the respective associations. CONCLUSIONS: The SNP opioid receptor mu-1 ( OPRM1 ) (rs1799971) was associated with higher postoperative fentanyl requirement in South Indian patients undergoing major breast surgery. Twenty-four hour postoperative pain scores were higher in catechol-O-methyl transferase ( COMT ) (rs4680) carriers and lower in ATP binding cassette subfamily B member 1 ( ABCB1 ) (rs1045642) carriers, whereas time for first analgesic was lower in potassium channel subunit 1 ( KCNS1 ) (rs734784) carriers. However, these exploratory findings must be confirmed in a larger study.

Acute postoperative pain and dorsal root ganglia transcriptomic signatures following total knee arthroplasty (TKA) in rats: An experimental study.

Total knee arthroplasty (TKA) is the final treatment option for patients with advanced knee osteoarthritis (OA). Unfortunately, TKA surgery is accompanied by acute postoperative pain that is more severe than arthroplasty performed in other joints. Elucidating the molecular mechanisms specific to post-TKA pain necessitates an animal model that replicates clinical TKA procedures, induces acute postoperative pain, and leads to complete functional recovery. Here, we present a new preclinical TKA model in rats and report on functional and behavioral outcomes indicative of pain, analgesic efficacy, serum cytokine levels, and dorsal root ganglia (DRG) transcriptomes during the acute postoperative period. Following TKA, rats exhibited marked deficits in weight bearing that persisted for 28 days. Home cage locomotion, rearing, and gait were similarly impacted and recovered by day 14. Cytokine levels were elevated on postoperative days one and/or two. Treatment with morphine, ketorolac, or their combination improved weight bearing while gabapentin lacked efficacy. When TKA was performed in rats with OA, similar functional deficits and comparable recovery time courses were observed. Analysis of DRG transcriptomes revealed upregulation of transcripts linked to multiple molecular pathways including inflammation, MAPK signaling, and cytokine signaling and production. In summary, we developed a clinically relevant rat TKA model characterized by resolution of pain and functional recovery within five weeks and with pain-associated behavioral deficits that are partially alleviated by clinically administered analgesics, mirroring the postoperative experience of TKA patients.

LncRNA-GAS5 and its Promoter Region Polymorphism Associate with Helper Th17 Polarization and Predict Postoperative Pain and the Prognosis of the Patients with Hepatocellular Carcinoma Undergoing Hepatectomy.

BACKGROUND: The relationship between genetic polymorphism and postoperative pain and the prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is not fully understood. OBJECTIVE: To examine whether lncRNA-GAS5 and its promoter region rs145204276 polymorphism can predict postoperative pain and prognosis of the patients with HCC undergoing hepatectomy. METHODS: Seventy patients with HCC undergoing hepatectomy were enrolled. The lncRNA-GAS5 levels in CD4+ T cells from peripheral blood mononuclear cells (PBMC-CD4+ T cells) and tumor tissues were measured by qRT-PCR. Genotyping analysis of rs145204276 was performed using the TaqMan platform. PBMC-CD4+ T cells were isolated and the cytokine levels in helper T (Th) cells were determined by flow cytometry. Patients with Ins/Ins genotype carrying the rs145204276 polymorphism were allocated into the Ins group, and others were allocated into the Del group. RESULTS: The lncRNA-GAS5 level decreased significantly in PBMC-CD4+ T cells and tumor tissues compared with the healthy controls and corresponding adjacent non-tumor tissues. The patients with Del/Del genotype showed significantly higher lncRNA-GAS5 expression in PBMC-CD4+ T cells, lower postoperative pain scores, and better overall survival. LncRNA-GAS5 expression in PBMC-CD4+ T cells was negatively associated with IL-6, IL-17, and the RORγT/CD3 ratio (an indicator of Th17 polarization). CONCLUSION: LncRNA-GAS5 expression and its promoter region rs145204276 polymorphism are prognostic biomarkers that can predict postoperative pain of patients with HCC undergoing hepatectomy.

Pain predict genetics: protocol for a prospective observational study of clinical and genetic factors to predict the development of postoperative pain.

INTRODUCTION: Postoperative pain remains a challenging medical condition impacting the quality of life of every patient. Although several predictive factors for postoperative pain have been identified, an adequate prediction of postoperative pain in patients at risk has not been achieved yet.The primary objective of this study is to identify specific genetic risk factors for the development of acute and chronic postoperative pain to construct a prediction model facilitating a more personalised postoperative pain management for each individual. The secondary objectives are to build a databank enabling researchers to identify other risk factors for postoperative pain, for instance, demographic and clinical outcome indicators; provide insight into (genetic) factors that predict pharmacological pain relief; investigate the relationship between acute and chronic postoperative pain. METHODS AND ANALYSIS: In this prospective, observational study, patients who undergo elective surgery will be recruited to a sample size of approximately 10 000 patients. Postoperative acute and chronic pain outcomes will be collected through questionnaires at different time points after surgery in the follow-up of 6 months. Potential genetic, demographic and clinical risk factors for prediction model construction will be collected through blood, questionnaires and electronic health records, respectively.Genetic factors associated with acute and/or chronic postoperative pain will be identified using a genome-wide association analysis. Clinical risk factors as stated in the secondary objectives will be assessed by multivariable regression. A clinical easy-to-use prediction model will be created for postoperative pain to allow clinical use for the stratification of patients. ETHICS AND DISSEMINATION: The Institutional Review Board of the Radboud university medical centre approved the study (authorisation number: 2012/117). The results of this study will be made available through peer-reviewed scientific journals and presentations at relevant conferences, which will finally contribute to personalised postoperative pain management. TRIAL REGISTRATION NUMBER: NCT02383342.

[Evaluation of the association of polymorphisms of the CYP2C8 gene with the efficacy and safety of ketorolac in patients with postoperative pain syndrome].

AIM: To evaluate the possible association of CYP2C8 gene polymorphisms with the clinical efficacy and safety of ketorolac in relation to postoperative pain. MATERIALS AND METHODS: The study included 107 patients after video laparoscopic cholecystectomy, who received ketorolac (30 mg 2.0 w/m 3 r/d) as postoperative pain relief. All patients were genotyped for CYP2C8. The pain syndrome was assessed using the visual analog scale, the McGill pain questionnaire. The profile of adverse reactions was assessed by the dynamics of red blood counts, as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers (Global Trigger Tool GTT). RESULTS: According to visual analog scale data: in carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080) after 12, 24, 36, 48 hours the intensity of pain syndrome is lower than in carriers of the wild type (p0.05). According to the McGill pain questionnaire, there were no statistically significant differences in pain intensity between the two groups. CONCLUSION: In carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080), the effectiveness of anesthesia with ketorolac is higher than in carriers of the wild type. Carriage of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs10509681) does not affect the risk of developing adverse reactions after ketorolac anesthesia.