Optimal Post-Operative Nalbuphine Dose Regimen: A Randomized Controlled Trial in Patients with Laparoscopic Cholecystectomy.

Background and Objectives: Optimal opioid analgesia is an excellent analgesia that does not present unexpected adverse effects. Nalbuphine, acting on the opioid receptor as a partial mu antagonist and kappa agonist, is considered a suitable option for patients undergoing laparoscopic surgery. Therefore, we aim to investigate the appropriate dosage of nalbuphine for post-operative pain management in patients with laparoscopic cholecystectomy. Materials and Methods: Patients were randomly categorized into low, medium, and high nalbuphine groups. In each group, a patient control device for post-operative pain control was programed with a low (0.05 mg/kg), medium (0.10 mg/kg), or high (0.20 mg/kg) nalbuphine dose as a loading dose and each bolus dose with a lockout interval of 7 min and without background infusion. Primary and secondary outcomes included the post-operative pain scale and nalbuphine consumption, and episodes of post-operative opioid-related adverse events and satisfactory scores. Results: The low-dosage group presented a higher initial self-reported pain score in comparison to the other two groups for the two hours post-op (p = 0.039) but presented lower nalbuphine consumption than the other two groups for four hours post-op (p = 0.047). There was no significant difference in the analysis of the satisfactory score and adverse events. Conclusions: An appropriate administration of nalbuphine could be 0.1 to 0.2 mg/kg at the initial four hours; this formula could be modified to a lower dosage (0.05 mg/kg) in the post-operative management of laparoscopic cholecystectomy.

AAV-glycine receptor α3 alleviates CFA-induced inflammatory pain by downregulating ERK phosphorylation and proinflammatory cytokine expression in SD rats.

BACKGROUND: Glycine receptors (GlyRs) play key roles in the processing of inflammatory pain. The use of adeno-associated virus (AAV) vectors for gene therapy in human clinical trials has shown promise, as AAV generally causes a very mild immune response and long-term gene transfer, and there have been no reports of disease. Therefore, we used AAV for GlyRα1/3 gene transfer in F11 neuron cells and into Sprague-Dawley (SD) rats to investigate the effects and roles of AAV-GlyRα1/3 on cell cytotoxicity and inflammatory response. METHODS: In vitro experiments were performed using plasmid adeno-associated virus (pAAV)-GlyRα1/3-transfected F11 neurons to investigate the effects of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. In vivo experiment, the association between GlyRα3 and inflammatory pain was analyzed in normal rats after AAV-GlyRα3 intrathecal injection and after complete Freund's adjuvant (CFA) intraplantar administration. Intrathecal AAV-GlyRα3 delivery into SD rats was evaluated in terms of its potential for alleviating CFA-induced inflammatory pain. RESULTS: The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting and immunofluorescence; the level of cytokine expression was measured by ELISA. The results showed that pAAV/pAAV-GlyRα1/3 transfection into F11 cells did not significantly reduce cell viability or induce extracellular signal-regulated kinase (ERK) phosphorylation or ATF-3 activation. PGE2-induced ERK phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor, GlyRαs antagonist (strychnine), and a protein kinase C inhibitor. Additionally, intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not induce obvious histopathological injury but increased ATF-3 activation in dorsal root ganglion (DRGs). CONCLUSIONS: Antagonists of the prostaglandin EP2 receptor, PKC, and glycine receptor can inhibit PGE2-induced ERK phosphorylation. Intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not significantly induce gross histopathological injury but elicited ATF-3 activation. We suggest that PGE2-induced ERK phosphorylation can be modulated by GlyRα3, and AAV-GlyRα3 significantly downregulated CFA-induced cytokine activation.

Multimodal Analgesia With Extended-Release Dinalbuphine Sebacate for Perioperative Management: Expert Opinion and Consensus.

BACKGROUND: The insufficient treatment of postoperative pain is considered a major barrier to enhanced patient recovery following surgery. Opioids remain the standard therapy for postoperative pain; however, the epidemic crisis of opioid abuse in the US has resulted in opioid-sparing multimodal analgesia (MMA) strategies in anesthesia practice. Complete perioperative pain management, particularly after discharge, may be undermined, resulting in chronic postsurgical pain. Thus, anesthesiologists and pain physicians should provide comprehensive MMA guidance for perioperative pain management. METHODS: The Taiwan Pain Society organized a working group, which included experts in the field of anesthesia, pain, and surgery. This group performed an extensive literature search, quality review, and drafted a consensus, which was discussed by experts and edited for feedback. Recommendations covered consent instruction, treatment interventions, intramuscular injection techniques, and prophylaxis for postoperative adverse events. RESULTS: This consensus included (1) a comparison of the pharmacology and pharmacokinetics between nalbuphine and dinalbuphine sebacate, (2) recommendations to help clinicians establish MMA with extended-release dinalbuphine sebacate injection, and (3) management of common adverse events during the perioperative pain period. CONCLUSION: Extended-release dinalbuphine sebacate combined with the MMA strategy can reduce the medical burden and improve the quality of recovery following surgery.

Trachway® flexible stylet facilitates the correct placement of double-lumen endobronchial tube: a prospective, randomized study.

BACKGROUND: The mainstream facilitation of one-lung ventilation is using double-lumen endobronchial tubes. However, it is more difficult to be positioned properly and more likely to cause airway injuries. How to place double-lumen endobronchial tubes rapidly and correctly is important for thoracic anesthesiologists. METHODS: One hundred eight patients with an American Society of Anesthesiologists physical status of I to III were 20 years of age or over, and required one-lung ventilation for thoracic surgery. They were randomly assigned to the conventional technique group (n = 36), the flexible fiberoptic bronchoscopy group (n = 36), or the Trachway® flexible stylet group (n = 36). The primary endpoint was the time needed for intubation. T1, the time from the tip of the blade passing between the patient's lips to identification of the vocal cords; and T2, the time from identification of the vocal cords to the bronchial lumen was in the correct position. RESULTS: T1 had no significant difference between groups, but T2 was significantly shorter in the Trachway® flexible stylet group (p < 0.0001) and longer in the conventional technique group (p < 0.0001). CONCLUSIONS: Using Trachway® flexible stylet for correct placement of double-lumen endobronchial tubes not only significantly shortened the intubation time, but also reduced incidence of carinal injuries. It is an alternative, and a choice with good safety. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02364622, 18/02/2015, Retrospectively registered.

Pancreatic Cancer and Microenvironments: Implications of Anesthesia.

Pancreatic malignancy is a lethal neoplasm, as well as one of the leading causes of cancer-associated mortality, having a 5-year overall survival rate of less than 10%. The average life expectancy of patients with advanced pancreatic cancer does not exceed six months. Although surgical excision is a favorable modality for long-term survival of pancreatic neoplasm, metastasis is initially identified in nearly 80% of the patients by the time of diagnosis, making the development of therapeutic policy for pancreatic cancer extremely daunting. Emerging evidence shows that pancreatic neoplastic cells interact intimately with a complicated microenvironment that can foster drug resistance, metastasis, or relapse in pancreatic cancer. As a result, the necessity of gaining further insight should be focused on the pancreatic microenvironment contributing to cancer progression. Numerous evidence reveals that perioperative factors, including surgical manipulation and anesthetics (e.g., propofol, volatile anesthetics, local anesthetics, epidural anesthesia/analgesia, midazolam), analgesics (e.g., opioids, non-steroidal anti-inflammatory drugs, tramadol), and anesthetic adjuvants (such as ketamine and dexmedetomidine), might alter the tumor microenvironment and cancer progression by affecting perioperative inflammatory or immune responses during cancer surgery. Therefore, the anesthesiologist plays an important role in perioperative management and may affect surgical outcomes. However, the literature on the impact of anesthesia on the pancreatic cancer microenvironment and progression is limited. This review summarizes the current knowledge of the implications of anesthesia in the pancreatic microenvironment and provides future anesthetic strategies for improving pancreatic cancer survival rates.

Cuff inflation technique is better than Magill forceps technique to facilitate nasotracheal intubation guiding by GlideScope® video laryngoscope.

Video laryngoscopy is often selected to assist nasotracheal intubation in allowing better laryngeal visualization, although there is no comparative study evaluating the effectiveness between auxiliary techniques by using Magill forceps and inflated cuff in GlideScope video laryngoscopy for nasotracheal intubation. Fifty-one of 100 patients in a Magill forceps group and 47 of 100 patients in a cuff inflation group were included in the final analysis in this randomized, single-blind, parallel, clinical trial study. Induction agents were routinely administered according to body weight, while intubation time spent, attempts, and related side effects were recorded. Compared to the Magill forceps group, the cuff inflation technique shortened the total intubation time (70.0 ± 24.5 s vs. 87.0 ± 25.0 s, p = 0.001) and the time of advancing the nasotracheal tube from oropharyngeal space into the trachea (25.9 ± 16.4 s vs. 42.3 ± 21.2 s, p < 0.001). However, the number of intubation attempts was not significantly different between groups. During tube advancement, the tube was rotated to accommodate the glottis and trachea more frequently in the cuff inflation group (p = 0.009), but the blade of the laryngoscope shifted and was adjusted to the proper position more frequently in the Magill forceps group (p < 0.001). In the Magill forceps group, the tube cuff might be clipped incidentally and the intubator might shift their gaze away from the screen during intubation, although there was no significant difference in intubation-related side effects between groups. Unlike the conventional approach, nasotracheal intubation with the GlideScope® video laryngoscope using the auxiliary technique of cuff inflation could be more suited than using Magill forceps.

Persistent Postsurgical Pain in Oral Cancer Patients Reconstructed with Anterolateral Thigh Free Flap.

Background and Objectives: The anterolateral thigh (ALT) flap is widely used in head and neck reconstruction, but the postoperative thigh sensory function lacks sufficient evaluation. The present study reports the postsurgical pain and cancer-related quality of life (QoL) in different stages of oral cancer patients receiving anterolateral thigh (ALT) flap reconstruction. Materials and Methods: Patients were subgrouped into postoperative early-, mid-, and late-recovery stages (postoperative 0.5-1 years, 1-2 years, and above 2 years) according to the time point of assessment. The QoL was examined using the EORTC C-30. Postsurgical donor and receipt site pain was evaluated through subjective reports and sensory tests. Results: Ninety-four patients were included in the final analysis. The functional and global health-related QoL significantly improved with time after surgery. However, spontaneous pain was reported in 57.7%, 72.3%, and 42% of patients in early-, mid-, and late-recovery stages, mainly in donor sites rather than in receipt sites. The highest incidence of donor site pain after ALT flap reconstruction in oral cancer surgery was in the mid-recovery stage but remained high in the late-recovery stage (56.8% and 36.7%, respectively). Conclusions: The postsurgical pain in the donor site might persist to or exhibit delayed onset one to two years postoperatively but is much improved after postoperatively two years later. A longer postsurgical follow-up for over two years for pain and sensory dysfunction is indicated.

The Strategy to Use Sugammadex to Reduce Postoperative Pulmonary Complications after da Vinci Surgery: A Retrospective Study.

In 2000, the da Vinci Surgery System was approved by the United States Food and Drug Administration for general laparoscopic surgery and it became the first commercially available robotic surgery system. The aim of this study was to identify the incidence of postoperative pulmonary complications (PPCs) in patients undergoing da Vinci surgery and to observe whether the incidence of PPCs was affected by the usage of Sugammadex. Sugammadex is a gamma-cyclodextrin that encapsulates and subsequently inactivates steroidal neuromuscular blocking agents. A retrospective study was conducted on patients who had undergone da Vinci surgery in a single medical center in southern Taiwan during the period from January 2018 to December 2018. We extracted data on patient characteristics, usage of Sugammadex and PPCs for analysis. Three hundred and thirty-three patients were enrolled in the final analysis. While the overall incidence of PPCs was 30.3% (101/333 patients), the incidence of PCC in patients who received Sugammadex (24.2%) was significantly lower than those without (37.3%) (p = 0.001). Risk factors that appeared to be closely associated with PCC included age, malignancy, hypertension, chronic kidney disease, blood loss amount and anemia. The use of Sugammadex decreased the risk of PPC. In order to enhance early recovery after da Vinci surgery, the use of Sugammadex to rapidly reverse muscle relaxants may be an appropriate choice.

Safe Practice of Total Intravenous Anesthesia With Target-Controlled Infusion in Taiwan: A Recommendation.

There have been immense advances in the safety and variety of intravenous anesthetic delivery systems including drug cost reduction, development of more effective opioids, and improvement in depth of anesthesia monitoring in the last 20 years. Propofol-based total intravenous anesthesia (TIVA) with target-controlled infusion (TCI) is relatively easy to practice. While this technique promotes a higher overall anesthesia quality and patient survival, especially for cancer patients, there are deficiencies in training and education of the technique. Therefore, the Society for Intravenous Anesthesia and the Association of Anesthetists (United Kingdom) have laid out guidelines in an attempt to highlight multiple important TIVA-related safety issues to help clinicians feel more confident. In the present article, we discuss five recommendations and four special clinical situations. Preparation, equipment familiarity, and safe delivery techniques are extremely important for the proper employment of this method. Herein, we emphasize the importance of proper education, and the clinical practice experience of the TIVA technique. Additionally, we suggest a modified connection method to set up a safely administered line. We highlight the advantages of using processed electroencephalogram monitoring (such as bispectral index or Entropy) to prevent awareness during TIVA administration in difficult clinical situations. These situations may include triple low patients (e.g., low blood pressure, low maintained effect-site concentration of propofol, and low body weight ≤ 18), obese patients, and patients with difficult infusion site monitoring or use of neuromuscular blocking agents. Due to a limited consensus among Taiwanese medical professionals, this document is intended to act as a safe practice reference for the use of TIVA with TCI. Additionally, two pithy formula codes, 4321 for propofol with fentanyl/alfentanil and 42222111 for propofol with remifentanil, are provided for the general population and one pithy formula code, 4321 for propofol with fentanyl, is provided for pediatric patients.

Loganin prevents CXCL12/CXCR4-regulated neuropathic pain via the NLRP3 inflammasome axis in nerve-injured rats.

BACKGROUND: Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown. PURPOSE: This study investigated the underlying mechanisms of loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies. RESULTS: Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1ß, and IL-18 were enhanced on day 7 after CCI, and all were reduced after loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in loganin-treated rats. Moreover, loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome. CONCLUSION: Our findings suggest that loganin might be a suitable candidate for managing CCI-provoked neuropathic pain.

Propofol-based total intravenous anesthesia is associated with better survival than desflurane anesthesia in glioblastoma surgery.

BACKGROUND: Previous research has shown that anesthetic techniques can influence patient outcomes following cancer surgery. However, the effects of anesthesia in patients undergoing glioblastoma surgery are still not known. We studied the relationship between the type of anesthesia and patient outcomes following elective glioblastoma surgery. METHODS: This was a retrospective cohort study of patients who underwent elective glioblastoma surgery between January 2008 and December 2018. Patients were grouped according to the anesthesia they received, desflurane or propofol. A Kaplan-Meier analysis was conducted, and survival curves were presented from the date of surgery to death. Univariable and multivariable Cox regression models were used to compare hazard ratios for death after propensity matching. RESULTS: A total of 50 patients (45 deaths, 90.0%) under desflurane anesthesia and 53 patients (38 deaths, 72.0%) under propofol anesthesia were included. Thirty-eight patients remained in each group after propensity matching. Propofol anesthesia was associated with improved survival (hazard ratio, 0.51; 95% confidence interval, 0.30-0.85; P = 0.011) in a matched analysis. Furthermore, patients under propofol anesthesia exhibited less postoperative recurrence than those under desflurane anesthesia (hazard ratio, 0.60; 95% confidence interval, 0.37-0.98; P = 0.040) in a matched analysis. CONCLUSIONS: In this limited sample size, we observed that propofol anesthesia was associated with improved survival and less postoperative recurrence in glioblastoma surgery than desflurane anesthesia. Further investigations are needed to examine the influence of propofol anesthesia on patient outcomes following glioblastoma surgery.

Comparison of laryngeal mask airway and endotracheal tube in preterm neonates receiving general anesthesia for inguinal hernia surgery: a retrospective study.

BACKGROUND: Preterm neonates are at higher risk of developing inguinal hernia, and have an increased risk of perioperative adverse events. Laryngeal mask airway (LMA) is claimed to be associated to decreasing perioperative respiratory complications compared to endotracheal tube (ETT) in infants under one year of age receiving minor surgery; thus, we conducted a retrospective survey in former preterm neonates below 5000 g to compare the respiratory complications between LMA and ETT in general anesthesia for inguinal hernia surgeries. METHODS: The inclusion criteria were: gestational age at birth under 37 weeks, body weight at surgery below 5000 g, and receiving scheduled inguinal hernia repair under general anesthesia with LMA or ETT. Infants who were dependent on mechanical ventilation preoperatively were excluded. The postoperative respiratory complications including delayed extubation, re-intubation, and apnea within postoperative 24 h were compared between groups. RESULTS: From July 2014 to December 2017, 72 neonates were enrolled into final analysis. There were 57 neonates managed with LMA, and only 15 neonates intubated with ETT during the study period. The gestational age at birth and post-menstrual age at surgery showed no significant difference between groups, although in the ETT group, the body weight at birth and at surgery were lower, and more infants had history of severe respiratory distress syndrome and had received oxygen therapy within two weeks prior to surgery. Surprisingly, none one of the infants developed delayed extubation, re-intubation, or postoperative apnea in the LMA group. In the ETT group, 40 percent of the neonates could not be successfully extubated in the operation theater. CONCLUSION: In preterm neonates, even in those younger than 52 weeks post-menstrual age who undergoing inguinal hernia repair in their early infancy, LMA appears feasible and safe as the airway device during general anesthesia in specific patient group. However, anesthesiologist might prefer ETT rather than LMA in some complex situation. In neonates with lower body weight at birth and at surgery, and with a history of severe RDS and oxygen-dependence, further prospective study is required.

BKCa Channel Inhibition by Peripheral Nerve Injury Is Restored by the Xanthine Derivative KMUP-1 in Dorsal Root Ganglia.

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BKCa current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4-L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BKCa currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BKCa. Real-time PCR was used to measure BKCa mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BKCa currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BKCa channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BKCa-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BKCa mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BKCa current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain.

Extended-Release Dinalbuphine Sebacate Versus Intravenous Patient-Controlled Analgesia with Fentanyl for Postoperative Moderate-to-Severe Pain: A Randomized Controlled Trial.

INTRODUCTION: Post-operative pain control remains unsatisfactory in patients after laparotomy. This study aimed to evaluate the efficacy, safety, and quality of life with a single dose of extended-release dinalbuphine sebacate (ERDS) pre-operatively to intravenous patient-controlled analgesia (PCA) with fentanyl in patients undergoing laparotomy. METHODS: This was a prospective, open-label, randomized controlled study. Of 110 randomized patients, 107 completed all assessments. The area under the curve (AUC) of visual analogue scale (VAS) from baseline to 48 h after surgery, VAS throughout 7 days after surgery, post-operative analgesics use, quality of life, satisfaction, and safety were evaluated. RESULTS: The AUC of VAS from baseline to 48 h after surgery were 118.6 [97.5% confidence interval (CI) 95.6-141.6] in ERDS group and 176.13 (97.5% CI 150.8-201.4) in PCA group, which showed the non-inferiority because the upper limit of the 97.5% CIs of ERDS group was lower than the lower limit of PCA group (P < 0.001), but also had superiority in favor of ERDS group (P < 0.001). ERDS group reported a significant reduction in VAS pain intensity at 4, 24, 32, 72, 120, and 144 h after surgery, and better quality of life (P < 0.05). The safety profile was comparable between ERDS and PCA groups. CONCLUSIONS: In patients undergoing laparotomy, a single dose of dinalbuphine sebacate was superior to intravenous PCA with fentanyl on lower pain intensity and better quality of life. TRIAL REGISTRATION: NCT03296488.

Upregulation of miR-133a-3p in the Sciatic Nerve Contributes to Neuropathic Pain Development.

The micro (mi)RNAs expressed in the sciatic nerve of streptozotocin (STZ)-induced diabetic rats were evaluated in terms of their therapeutic potential in patients with diabetic neuropathic pain (DNP). Relative miRNA expression in sciatic nerve with DNP was analyzed using next-generation sequencing and quantitative PCR. Potential downstream targets of miRNAs were predicted using Ingenuity Pathway Analysis and the TargetScan database. In vitro experiments were performed using miR-133a-3p-transfected RSC96 Schwann cells. We performed micro-Western and Western blotting and immunofluorescence analyses to verify the role of miR-133a-3p. In vivo, the association between miR-133a-3p with DNP was analyzed via AAV-miR-133a-3p intraneural (intra-epineural but extrafascicular) injection into the sciatic nerve of normal rats or injection of an miR-133a-3p antagomir into the sciatic nerve of diabetes mellitus (DM) rats. miR-133a-3p mimics transfected into RSC96 Schwann cells increased VEGFR-2, p38α MAPK, TRAF-6, and PIAS3 expression and reduced NFκB p50 and MKP3 expression. In normal rats, AAV-miR-133a-3p delivery via intraneural injection into the sciatic nerve induced mechanical allodynia and p-p38 MAPK activation. In DM rats, miR-133a-3p antagomir administration alleviated DNP and downregulated p-p38 phosphorylation. Overexpression of miR-133a-3p in the sciatic nerve induced such pain. We suggest that miR-133a-3p is a potential therapeutic target for DNP.

Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-α/IL-1ß-mediated NF-κB activation and Schwann cell demyelination.

BACKGROUND: Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. PURPOSE: This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. RESULTS: Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1ß), inflammatory proteins (TNF-α, IL-1ß, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. CONCLUSION: Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1ß-dependent NF-κB activation.

Pretreatment of ankle nerve block provides better postoperative analgesia than peri-incisional local anesthetic infiltration in hallux valgus correction surgery.

Adequate postoperative analgesia after hallux valgus (HV) correction surgery improves early mobilization and decreases hospital stay. Peripheral nerve block and peri-incisional local anesthetic (LA) infiltration are both widely used for pain management in orthopedic surgeries. The aim of this study was to compare the analgesic effects between the ankle block and peri-incisional infiltration technique in patients undergoing HV correction surgery. Ninety patients scheduled for hallux valgus correction surgery were randomly allocated into three groups. In group N, patients were pretreated with tibial and peroneal nerve blocks with 8-10 mL of 0.25% bupivacaine before surgery. In group P, patients received the same LA for peri-incisional infiltration preoperatively. In group C, patients underwent surgery without regional analgesic pretreatment. All patients had intravenous fentanyl patient control analgesia as part of multimodal postoperative pain management. Fentanyl consumption, rest and moving pain scale, and adverse effects were evaluated at postoperative 6 h (Poh6), Poh12, Poh 24, and Poh36, respectively. Patients receiving bilateral feet surgeries were excluded in this study. Seventy-five patients were enrolled into final analysis. The patients in group N expressed lower resting and moving pain scores at Poh6, but the pain scores turned similarly among the three groups following Poh12 and then. The total fentanyl consumption was significantly less in group N than in group P. The postoperative activities and mood disturbance were not significantly different between groups after Poh12 and then. We conclude that ankle block is better than peri-incisional LA infiltration in HV correction surgery in pain relief and fentanyl consumption.

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model.

Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFκB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3ß/GSK-3ß), proinflammatory cytokines (TNF-α and IL-1ß) and nuclear pNFκB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti-neuroinflammation action involving reduction of pNFκB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3ß-mediated neuronal death from injury to peripheral nerves.

Advances in Experimental Medicine and Biology: Intrafascicular Local Anesthetic Injection Damages Peripheral Nerve-Induced Neuropathic Pain.

Peripheral nerve blockade (PNB) is advantageous for patients undergoing surgery to decrease the perioperative opioid consumptions and enhance recovery after surgery.Inadvertent local anesthetic (LA) administration into nerve fiber intrafascicularly easily results in unrecognized nerve injury. Using nerve block guidance either by ultrasound, electrical nerve stimulator, or using pressure devices does not prevent nerve damage, even though most of the nerve injury is transiently. The incidence of neurologic symptoms or neuropathy is in the range of 0.02-2.2%, and no significant difference of postoperative neurologic symptoms is found as compared with using ultrasound or guided nerve stimulator technique. However, intrafascicular lidocaine brought about macrophage migration into the damaged fascicle, Schwann cell proliferation, increased intensity of myelin basic protein, and shorten withdrawal time to mechanical stimuli. In dorsal root ganglion (DRG), intrafascicular LA injection increased the activated transcriptional factor 3 (ATF-3) and downregulated Nav1.8 (Nav1.8). In spinal dorsal horn (SDH), the microglia and astrocytes located in SDH were activated and proliferated after intrafascicular LA injection and returned to baseline gradually at the end of the month. This is a kind of neuropathic pain, so low injection pressure should be maintained, the correct needle bevel used, nerve stimulator or ultrasound guidance applied, and careful and deliberately slow injection employed as important parts of the injection technique to prevent intrafascicular LA administration-induced neuropathic pain.