Effect of A118G (rs1799971) single-nucleotide polymorphism of the µ-opioid receptor OPRM1 gene on intraoperative remifentanil requirements in Japanese women undergoing laparoscopic gynecological surgery.

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.

Persistent pneumothorax after laparoscopic appendectomy in a patient who had undergone radical esophagectomy 5 years before: possible relationship with vulnerability of the hiatus after esophagectomy: a case report.

Postoperative pneumothorax is a well-known but relatively rare complication after laparoscopic surgery. Herein, we report a case of persistent pneumothorax after laparoscopic appendectomy. A 57-year-old male, with a history of minimally invasive esophagectomy and intrathoracic gastric tube reconstruction 5 years before, underwent a laparoscopic appendectomy. A chest X-ray taken on postoperative Day 1 revealed the development of the right pneumothorax, which took more than 3 days to resolve spontaneously. Although the mechanism of postoperative pneumothorax was unclear, it seemed likely that the air that had replaced carbon dioxide in the peritoneal cavity migrated into the thoracic cavity through the esophageal hiatus, which was not covered by the peritoneum or pleura after surgical resection. The present case, together with our previous similar case, suggests that a history of esophageal cancer surgery per se increases the risk of pneumothorax after laparoscopic surgery, probably regardless of when this was performed.

Successful one-lung ventilation in a patient after laryngectomy by inserting a long spiral single-lumen tube into the left main bronchus: a case report.

Background: Patients who have had laryngectomy require a thorough preoperative assessment for potential stomal stenosis, and an action plan for possible inadvertent displacement of the voice prosthesis (VP) must be considered. We report the anesthetic management of a post-laryngectomy patient undergoing lung resection surgery. The patient had both a laryngectomy and a VP in situ. Case Description: A 66-year-old man with Parkinson's disease, who had previously undergone total laryngectomy for supraglottic laryngeal cancer, had a cuffed tracheostomy tube and a VP inserted into the tracheoesophageal fistula below it. He was scheduled for segmentectomy combined with lymph node dissection under combined epidural-general anesthesia due to lung cancer in the apical segment of the right lung. Following induction of general anesthesia, instead of using a double-lumen endotracheal tube, we inserted a long spiral single-lumen tube (SLT) (6 mm inner diameter, 8.7 mm outer diameter) through the tracheostoma under the guidance of a 4 mm bronchoscope because of concerns about airway injury due to the narrowed diameter of the stoma and potential dislodgement of the VP. The tube was carefully advanced and smoothly placed into the left main bronchus, and the surgery was completed using one-lung ventilation (OLV). Conclusions: For post-total laryngectomy patients, it is important to assess the size and condition of the tracheostoma and the usage of a VP, and choose an appropriate endotracheal tube. A long spiral SLT might be an option for OLV in patients after laryngectomy with a tracheoesophageal VP.

Prognosis for major abdominal surgeries based on intraoperative low-dose nutrition: A metabolic perspective.

BACKGROUND & AIMS: The optimal nutrition intake during surgery is unknown. This study aimed to investigate the prognosis of low-dose nutrition during laparoscopic colorectal cancer surgery. METHODS: In the glucose and amino acids (GA) group, 20 patients were infused with glucose (75 g/L) and amino acids (30 g/L) at 60 mL/h and bicarbonate Ringer's solution. However, 20 patients in the control (C) group were infused with bicarbonate Ringer's solution without GA. The length of hospital stay was determined, and measurements were taken before (TI) and after (T2) the surgery under general anesthesia. RESULTS: The lengths of hospital stay were comparable between the GA (13 days) and C (16 days) groups. Ketone body levels were 294 (C group) and 33 (GA group) µmol/L at T2. Nitrogen balance was 0.32 g (GA group) and -1.60 g (C group) at T2. CONCLUSIONS: Although the lengths of hospital stay were comparable, ketone body levels, and nitrogen balance were significantly different (P < 0.01) between the two groups after surgery.

Genome-Wide Association Study Identifies Novel Candidate Variants Associated with Postoperative Nausea and Vomiting.

Considerable individual differences are widely observed in the incidence of postoperative nausea and vomiting (PONV). We conducted a genome-wide association study (GWAS) to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to PONV by utilizing whole-genome genotyping arrays with more than 950,000 markers. The subjects were 806 patients who provided written informed consent and underwent elective surgery under general anesthesia with propofol or desflurane. The GWAS showed that two SNPs, rs2776262 and rs140703637, in the LOC100506403 and CNTN5 gene regions, respectively, were significantly associated with the frequency of nausea. In another GWAS conducted only on patients who received propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with the frequency of nausea as well as the rs2776262 SNP, and the rs45574836 and rs1752136 SNPs in the ATP8B3 and LOC105370198 gene regions, respectively, were significantly associated with vomiting. Among these SNPs, clinical and SNP data were available for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. These results indicate that these SNPs could serve as markers that predict the vulnerability to PONV. Our findings may provide valuable information for achieving satisfactory prophylactic treatment for PONV.

Persistent bilateral pneumothorax after robotic-assisted inguinal hernia repair: possible relevance to recent esophageal cancer surgery - a case report.

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.

Negative pressure pulmonary edema due to upper airway obstruction after general anesthesia in a patient with Parkinson's disease: A case report.

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.

Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses.

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching protocol remain unclear. Opioid anesthetic efficacy is decided in part by MOR desensitization; thus, in this study, we investigated the desensitization profiles of REM and FEN to MOR. The efficacy and potency during the 1st administration of REM or FEN in activating the MOR were almost equal. Similarly, in ß arrestin recruitment, which determines desensitization processes, they showed no significant differences. In contrast, the 2nd administration of FEN resulted in a stronger MOR desensitization potency than that of REM, whereas REM showed a higher internalization potency than FEN. These results suggest that different ß arrestin-mediated signaling caused by FEN or REM led to their distinct desensitization and internalization processes. Our three-dimensional analysis, with in silico binding of REM and FEN to MOR models, highlighted that REM and FEN bound to similar but distinct sites of MOR and led to distinct ß arrestin-mediated profiles, suggesting that distinct binding profiles to MOR may alter ß arrestin activity, which accounts for MOR desensitization and internalization.

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.

Postoperative analgesia following robot-assisted thoracic surgery for mediastinal disease: retrospective comparative study of general anesthesia alone, combined with epidural analgesia, and with ultrasound-guided thoracic paraspinal block.

Background: Recently, robot-assisted thoracic surgery has been increasingly performed for mediastinal disease. However, appropriate postoperative analgesic methods have not been evaluated. Methods: We retrospectively studied patients who underwent robot-assisted thoracic surgery for mediastinal disease at a single university hospital between January 2019 and December 2021. Patients were performed either general anesthesia alone, general anesthesia combined with thoracic epidural anesthesia, or general anesthesia combined with ultrasound-guided thoracic block. Patients were divided into three groups [non-block (NB), thoracic epidural analgesia (TEA), and thoracic paraspinal block (TB)] according to postoperative analgesic methods, and they compared with terms of postoperative pain scores by using numerical rating scale (NRS) at 0, 3, 6, 12, 18, 24, and 48 h. Additionally, rescue supplemental analgesic within 24 h, side effects of anesthesia such as respiratory depression, hypotension, postoperative nausea and vomiting, pruritus and urinary retention, time to ambulation after surgery, and hospital stay after surgery were also compared among the three groups. Results: Data from 169 patients (Group NB: 25, Group TEA: 102, and Group TB: 42) were progressed to the analysis. Postoperative pain scale at 6 and 12 h was significantly lower in Group TEA than NB (1.2±1.6 vs. 2.4±1.8, P<0.01; and 1.2±1.5 vs. 2.2±1.7, P=0.018, respectively). There were no differences in pain scores between Groups TB and TEA at any point. The incidence of patients using rescue analgesics within 24 h was significantly different between groups [Group NB: 15/25 (60%), Group TEA: 30/102 (29.4%), Group TB: 25/42 (59.5%), P=0.01]. For postoperative side effects, only the number of patients complaining of postoperative nausea and vomiting for 24 h after surgery differed significantly between groups [Group NB: 7/25 (28%), Group TEA: 19/102 (18.6%), Group TB: 1/42 (2.4%), P=0.01]. Conclusions: TEA provided better analgesia after robot-assisted thoracic surgery for mediastinal disease than NB as indicated by lower pain scores and fewer rescue analgesic requirements. However, the frequency of postoperative nausea and vomiting was lowest in Group TB of all the groups. Thus, TBs might also provide adequate postoperative analgesia following robot-assisted thoracic surgery for mediastinal disease.

Incidences of and risk factors for clinical and subclinical contrast-associated acute kidney injury in patients who underwent neuroendovascular surgery.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) can develop after intravascular administration of iodinated contrast media. Neutrophil gelatinase-associated lipocalin (NGAL) is an early marker for AKI that helps to detect subclinical CA-AKI. We investigated the incidence of and risk factors for clinical and subclinical CA-AKI in patients who underwent neuroendovascular surgery. METHODS: We retrospectively investigated 228 patients who underwent neuroendovascular surgery in 2020. Changes in serum creatinine and urine output were used to detect clinical CA-AKI. Urine NGAL concentration was used to detect subclinical CA-AKI in 67 out of 228 patients. RESULTS: In 228 patients, serum creatinine, hemoglobin, hematocrit, total protein, and blood urea nitrogen (BUN) decreased significantly (p < 0.001) after surgery. However, serum creatinine decreased less significantly (p < 0.05) than hemoglobin, hematocrit, total protein, and BUN on postoperative Day 3. Two patients out of 228 developed clinical CA-AKI, and seven patients out of 67 with urine NGAL measurements developed subclinical CA-AKI. Multivariate regression analysis revealed that diabetes mellitus and carotid artery stenosis were significantly (p < 0.05) associated with the development of clinical and/or subclinical CA-AKI. CONCLUSION: There was a large difference between the incidences of clinical CA-AKI (0.88%) and subclinical CA-AKI (10.4%). The difference might have primarily resulted from the different sensitivities between serum creatinine and urine NGAL and possibly from underestimation of the incidence of clinical AKI due to a postoperative decrease in serum creatinine caused by hemodilution. In addition to diabetes mellitus, carotid artery stenosis could also be a risk factor for CA-AKI.

Associations among preoperative transthoracic echocardiography variables and cerebral near-infrared spectroscopy values at baseline before anesthesia in patients undergoing cardiac surgery: a retrospective observational study.

Cerebral tissue oximetry with near-infrared spectroscopy (NIRS) is used to monitor cerebral oxygenation during cardiac surgery. To date, reduced baseline cerebral NIRS values have been attributed to reduced cerebral blood flow primarily based on a significant positive correlation between left ventricular ejection fraction (LVEF) and baseline rSO2 measured with the INVOS 5100C oximeter. Reportedly, however, rSO2, but not StO2 measured with the FORESIGHT Elite oximeter, correlated with LVEF. We, thus, investigated associations among baseline NIRS values measured with three different oximeters before anesthesia for cardiac surgery and preoperative transthoracic echocardiography (TTE) variables, including LVEF, to examine whether there are inter-device differences in associations among baseline NIRS values and TTE variables. Using Spearman's correlation coefficient, we retrospectively investigated associations among 15 preoperative TTE variables, including LVEF, and baseline NIRS values, including rSO2, StO2, and TOI with the NIRO-200NX oximeter in 1346, 515, and 301 patients, respectively. Only rSO2 (p < 0.00001), but not TOI or StO2 (p > 0.05), positively correlated with LVEF. On the other hand, baseline rSO2, TOI, and StO2 consistently, negatively correlated with the left atrial diameter index (LADI), early diastolic transmitral flow velocity (E), E-to-early diastolic mitral annular velocity ratio (E/e'), estimated right ventricular systolic pressure (eRVP), and inferior vena cava diameter index (IVCDI) (p < 0.0005 to p < 0.00001). Because all of these five TTE variables could be positively associated with right as well as left ventricular filling pressure, our results indicated that reduced baseline NIRS values were consistently associated not with reduced LVEF but with TTE findings indicative of elevated biventricular filling pressure. Our data suggest that regional venous congestion greatly contributes to reduced baseline NIRS values in patients undergoing cardiac surgery.

Introduction of a Multidisciplinary Preoperative Clinic at Juntendo University Hospital - A Retrospective Observational Study Focusing on Effects of Preoperative Interventions on Clinical Outcomes.

Objectives: To investigate the effects of interventions provided by a multidisciplinary team consisting of anesthesiologists, dentists, pharmacists, and nurses at a Preoperative Clinic (POC) on postoperative outcomes. Methods: We retrospectively investigated patients who underwent preoperative evaluation at the POC at Juntendo University Hospital between May and July, 2019. Patients were divided into intervention and non-intervention groups according to whether they received intervention(s) at the POC or not. Postoperative outcomes were compared between the groups, before and after propensity score (PS) matching. Results: We investigated 909 patients who completed POC evaluation and underwent surgery. Patients in the intervention group (n = 455 [50.1%]) received at least one intervention delivered, in the order of higher delivery frequencies, by dentists, pharmacists, nurses, and anesthesiologists. Before PS matching, the intervention group was associated with older age, more frequent cardiovascular comorbidities, and higher ASA-PS grades than the non-intervention group, while neither frequencies nor severities of postoperative complications differed between the groups. These outcomes did not differ between 382 PS-matched pairs with comparable risk factors either. Conclusions: Before PS matching, postoperative outcomes did not differ between the groups, although the intervention group was associated with higher risks. These suggested that POC interventions could have improved postoperative outcomes in the higher-risk intervention group to the same level as in the non-intervention group. However, such potential beneficial effects of interventions could not be proven after PS matching. Further studies are required to elucidate effects of POC interventions on postoperative outcomes.

Effects of the Multidisciplinary Preoperative Clinic on the Incidence of Elective Surgery Cancellation.

To evaluate effects of the multidisciplinary preoperative clinic (POC) consisting of anesthesiologists, dentists, pharmacists, and nurses on elective surgery cancellation, we retrospectively investigated patients who underwent elective non-cardiac, non-obstetric surgeries between October, 2018 and March, 2019 (before the POC establishment: Group 1) and between October, 2019 and March, 2020 (after the POC establishment: Group 2). Among reasons for surgery cancellation allocated into eight categories, three reasons for cancellation (related to consent authorization, medication, and significant comorbidities) were considered preventable. We compared incidences of overall and preventable cancellations of surgeries between 4,198 patients in Group 1 and 4,664 patients in Group 2, who had significantly different clinical backgrounds, including the ASA-PS class. There was no significant difference in the incidence of overall cancellation between Group 1 and Group 2 (4.1% vs. 4.1%, p = 0.96). However, the incidence of preventable cancellation was significantly lower in Group 2 than in Group 1 (0.4% vs. 0.7%, p = 0.045). In addition, the incidence of overall cancellation was significantly lower in 3,741 Group 2 patients visiting the POC than in 5,121 patients not visiting the POC in both Groups (3.2% vs. 4.7%, p < 0.001). Further, in 3,423 pairs of patients with comparable clinical backgrounds created from both Groups using propensity score matching, incidences of overall cancellation (2.2% vs. 3.1%) and preventable cancellation (0.1% vs. 0.6%) were significantly lower in Group 2 than in Group 1 (p = 0.036 and 0.008, respectively). In conclusion, the multidisciplinary POC was effective in reducing elective surgery cancellation.

Anti-Inflammatory Action of Dexmedetomidine on Human Microglial Cells.

Neuroinflammation, where inflammatory cytokines are produced in excess, contributes to the pathogenesis of delirium. Microglial cells play a central role in neuroinflammation by producing and releasing inflammatory cytokines in response to infection, tissue damage and neurodegeneration. Dexmedetomidine (DEX) is a sedative, which reduces the incidence of delirium. Thus, we hypothesized that DEX may alleviate delirium by exhibiting anti-inflammatory action on microglia. In the present study, we investigated the anti-inflammatory action of DEX on human microglial HMC3 cells. The results indicated that DEX partially suppressed the IL-6 and IL-8 production by lipopolysaccharide (LPS)-stimulated HMC3 cells as well as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. Furthermore, DEX substantially suppressed IL-6 and IL-8 production by unstimulated HMC3 cells as wells as the phosphorylation of p38 MAPK and IκB and the translocation of NF-κB. These observations suggest that DEX exhibits anti-inflammatory action on not only LPS-stimulated but also unstimulated microglial cells via the suppression of inflammatory signaling and cytokine production.

Retroperitoneoscopic Surgery in Children Does Not Cause Pathological Desaturation in Cerebral/Renal Oxygenation on Near-Infrared Spectroscopy Compared with Laparoscopic and Thoracoscopic Surgery.

Introduction: Cerebral and renal regional oxygen saturation (C-rSO2 and R-rSO2, respectively) were monitored using near-infrared spectroscopy in pediatric patients (range: 0.3-14.3 years) during minimally invasive surgery (MIS) taking at least 3 hours performed by laparoscopy (Lap), thoracoscopy (Tho), or retroperitoneoscopy (Ret) from January 2019 to December 2021. Materials and Methods: Criteria compared were operative time, preoperative/intraoperative hemoglobin, blood loss, mean arterial pressure, arterial partial pressure of carbon dioxide (PaCO2), peripheral oxygen saturation (SpO2), C-rSO2, and R-rSO2. Pathological desaturation (PD) was defined as >20% decrease from baseline, and statistical significance as P < .05. Results: Subjects (n = 79) were similar for gender, age, and body mass index. MIS procedures were: Lap = 45, Tho = 20, Ret = 14; one Lap case required conversion for severe adhesions, not PD. Intraoperative PaCO2 (mmHg) was significantly higher in Tho (maximum: 59.5 ± 17.0, minimum: 39.9 ± 7.5) versus Lap (maximum: 39.9 ± 5.1, minimum: 34.6 ± 3.9) and Ret (maximum: 37.8 ± 4.2, minimum: 35.0 ± 3.3); P < .0001 (maximum), P = .0013 (minimum). Minimum intraoperative SpO2 was significantly lower in Tho (P < .0001). Mean operative times were significantly shorter in Tho (259 ± 114 minutes) versus Lap (433 ± 154 minutes) and Ret (342 ± 100 minutes); P < .0001, respectively. PD was absent during Ret (C-rSO2: 0/14 = 0% and R-rSO2: 0/14 = 0%). Differences in PD for Lap (C-rSO2: 7/45 = 15.6% and R-rSO2: 10/45 = 22.2%) and Tho (C-rSO2: 9/20 = 45.0%, and R-rSO2: 7/20 = 35.0%) were significant; P = .0028 for C-rSO2 and P = .0497 for R-rSO2. Hemoglobin and blood loss were similar. Conclusions: PD was absent during Ret, despite longer operative times. If Ret is indicated for a procedure, neurodevelopmental sequelae of MIS could be minimized.

Comparison of desflurane and propofol in the speed and the quality of emergence from anesthesia in patients undergoing lung cancer surgery-a prospective, randomized study.

Background: Anesthesia with desflurane or propofol enables rapid emergence. In patients undergoing lung cancer surgery, however, the speed of emergence from desflurane, but not from propofol, may be affected by the deteriorated postoperative respiratory function. We prospectively compared the speed and quality of emergence between desflurane and propofol. Methods: We conducted a parallel study. Eighty patients scheduled for lung cancer surgery were randomly allocated to Desflurane group (Group D) and Propofol group (Group P). Combined general and epidural anesthesia was performed in the identical way except for the anesthetic. Results: There was no significant difference between the groups in the time to awakening, extubation, or orientation. However, emergence agitation (EA) occurred more frequently in Group D than in Group P (20/40 vs. 4/40, P<0.001). Numbers of patients not achieving full scores in respiration and circulation components of the modified Aldrete score 5 min after extubation were more in Group D (4/40 vs. 0/40, P=0.040; and 8/40 vs. 2/40, P=0.043, respectively). More patients required antiemetics during postoperative 24 hours in Group D (15/40 vs. 7/40, P=0.045). Conclusions: Desflurane was not inferior to propofol in the speed of emergence from anesthesia after lung cancer surgery, but it was slightly inferior to propofol in the quality of emergence. Trial Registration: UMIN-CTR identifier: UMIN000009221.

Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.

BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.

Short Tandem Repeat Variation in the CNR1 Gene Associated With Analgesic Requirements of Opioids in Postoperative Pain Management.

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.

Associations between the C3orf20 rs12496846 Polymorphism and Both Postoperative Analgesia after Orthognathic and Abdominal Surgeries and C3orf20 Gene Expression in the Brain.

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.