Introduction: Rebound pain, transient and acute postoperative pain after the disappearance of regional block anesthesia, has been a concern in recent years. Insufficient preemptive analgesia and hyperalgesia induced by regional block are the main mechanisms. At present, the evidence for the treatment of rebound pain is limited. The esketamine, as an antagonist of the N-methyl-D-aspartate receptor, has been proven to prevent hyperalgesia. Therefore, this trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty.Methods/design: This study is a single-center, prospective, double-blind, randomized, placebo-controlled trial. Participants who plan to undergo total knee arthroplasty will be randomly assigned to the esketamine group (N = 178) and placebo group (N = 178) in a ratio of 1:1. This trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. The primary outcome of this trial is the incidence of rebound pain within 12 h after the operation in the esketamine group and the placebo group. The secondary outcome will be to compare (1) the incidence of rebound pain 24 h after the operation; (2) the time to enter the pain cycle for the first time within 24 h after the procedure; (3) the first time of rebound pain occurred within 24 h after surgery; (4) the modified rebound pain score; (5) NRS score under rest and exercise at different time points; (6) the cumulative opioid consumption at different time points; (7) patient’s prognosis and knee joint function evaluation; (8) blood glucose and cortisol concentration; (9) patient’s satisfaction score; (10) adverse reactions and adverse events.Discussion: The effect of ketamine on preventing postoperative rebound pain is contradictory and uncertain. The affinity of esketamine to the N-methyl-D-aspartate receptor is about four times higher than levo-ketamine, the analgesic effect is 3 times higher than levo-ketamine, and there are fewer adverse mental reactions. To our knowledge, there is no randomized controlled trial to verify the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. Therefore, this trial is expected to fill an important gap in relevant fields and provide novel evidence for individualized pain management.Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2300069044.

Background: General anesthesia may counteract the neuroprotective effects of S-ketamine, so previous trials may have underestimated the efficacy of S-ketamine to reduce postoperative delirium (POD). The authors hypothesized that administration of S-ketamine in a non–general anesthesia setting would reduce the risk of POD. Methods: This study was conducted at a high-volume arthroplasty referral center where standardized, evidence-based perioperative protocols are implemented with high fidelity. This study included 372 elderly patients undergoing total hip or knee arthroplasty under neuraxial anesthesia. Patients were enrolled from November 2023 to October 2024, and in-person follow-up assessments were conducted from admission to 3 days after surgery. Patients were randomized to receive either S-ketamine (n = 186) or normal saline placebo (n = 186). The primary outcome was risk of POD within 3 days after surgery. Secondary outcomes were number of POD episodes, POD onset time and duration, POD severity, POD subtype, pain score (numeric rating scale), opioid consumption, number of patients requiring rescue analgesia, sleep quality, clinical outcomes, and harms. Results: Within 3 days after surgery, 15 patients in the S-ketamine group (8.06%) developed POD, compared to 38 patients (20.43%) in the placebo group (adjusted odds ratio, 0.29; 95% CI, 0.14 to 0.63; P = 0.002). On postoperative day 1, patients in the S-ketamine group experienced significantly less pain during exercise and physical therapy and had a lower incidence of rescue analgesia use compared to the placebo group. The incidence of hallucinations, dizziness, and nightmares was higher in the S-ketamine group than in the placebo group. The incidence of other complications was low in both groups, with no statistically significant differences. Conclusions: S-ketamine can reduce risk of POD in elderly patients undergoing total hip or knee arthroplasty under neuraxial anesthesia. However, generalizability of these findings may be limited due to the study’s setting.

Purpose: Neuropathic pain is a chronic intractable disease characterized by allodynia and hyperalgesia. Effective treatments are unavailable because of the complicated mechanisms of neuropathic pain. Transient receptor potential canonical 6 (TRPC6) is a nonselective calcium (Ca²⁺)-channel protein related to hyperalgesia. Dexmedetomidine (Dex) is an alpha-2 (α 2) adrenoreceptor agonist that mediates intracellular Ca²⁺ levels to alleviate pain. However, the relationship between TRPC6 and Dex is currently unclear. We speculated that the α 2 receptor agonist would be closely linked to the TRPC6 channel. We aimed to investigate whether Dex relieves neuropathic pain by the TRPC6 pathway in the dorsal root ganglia (DRG). Methods: The chronic constriction injury (CCI) model was established in male rats, and we evaluated the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). The expression of TRPC6 and Iba-1 in the DRG were analyzed using quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence assay. The levels of inflammatory cytokines were measured using an enzyme-linked immunosorbent assay. Results: Compared with the CCI normal saline group, both the MWT and TWL were significantly improved after 7 days of Dex administration. Results demonstrated that TRPC6 expression was increased in the DRG following CCI but was suppressed by Dex. In addition, multiple administrations of Dex inhibited the phosphorylation level of p38 mitogen-activated protein kinase and the upregulation of neuroinflammatory factors. Conclusion: The results of this study demonstrated that Dex exhibits anti-nociceptive and anti-inflammatory properties in a neuropathic pain model. Moreover, our findings of the CCI model suggested that Dex has an inhibitory effect on TRPC6 expression in the DRG by decreasing the phosphorylation level of p38 in the DRG.

Purpose: Investigating the effectiveness of S-ketamine in reducing rebound pain (RP) following total knee arthroplasty. Patients and Methods: This study was a randomized, double-blind, placebo-controlled trial involving 356 adult patients undergoing total knee arthroplasty. Patient enrollment occurred between April and October 2023, with in-person follow-up assessments conducted from admission to 3 days post-surgery. Participants were randomly assigned to the S-ketamine group (n = 178) and the placebo group (n = 178). In the S-ketamine group, participants received a continuous intraoperative infusion of S-ketamine at a dose of 0.30 mg/(kg·h) from the completion of spinal anesthesia until the beginning of joint cavity closure, whereas the placebo group received a continuous infusion of 0.9% saline at the same volume and duration. The primary outcome was the incidence of RP within 12 hours post-surgery. Secondary outcomes included the incidence of RP within 24 hours, time to RP onset, time to first rescue analgesia, pain scores, opioid consumption, clinical outcomes, and harms. Results: RP was observed in 21.3% of patients in the S-ketamine group compared with 34.8% in the placebo group within 12 hours post-surgery (adjusted RR, 0.62; 95% CI, 0.44 to 0.88; P = 0.008). The onset of RP was significantly delayed in the S-ketamine group compared with the placebo group (unadjusted HR, 0.60; 95% CI, 0.41 to 0.88; P = 0.009). The numerical rating scale during activity and physical therapy was lower in the S-ketamine group than in the placebo group (day 1 AM: unadjusted difference, − 1; 95% CI, − 1 to 0; P = 0.011; day 1 PM: unadjusted difference, − 1; 95% CI, − 1 to 0; P = 0.003; day 1 physical therapy: unadjusted difference, − 2; 95% CI, − 2 to − 1; P < 0.001). The quality of recovery score was higher in the S-ketamine group than in the placebo group (unadjusted difference, 5; 95% CI, 5 to 5; P < 0.001). Patient satisfaction was higher in the S-ketamine group than in the placebo group (unadjusted difference, 1; 95% CI, 1 to 1; P < 0.001). Conclusions: S-ketamine effectively reduces the risk of rebound pain and delays its onset in total knee arthroplasty. Additionally, S-ketamine can reduce early pain levels, enhance recovery quality, and improve patient satisfaction.

Introduction: Postoperative delirium (POD) is an acute, transient brain disorder associated with decreased postoperative quality of life, dementia, neurocognitive changes, and mortality. A small number of trials have explored the role of S-ketamine in the treatment of POD due to its neuroprotective effects. Surprisingly, these trials have failed to yield supportive results. However, heterogeneity in delirium assessment methodologies, sample sizes, and outcome settings as well as deficiencies in S-ketamine use methods make the evidence provided by these studies less persuasive. Given the severe impact of POD on the health of elderly patients and the potential for S-ketamine to prevent it, we believe that designing a large sample size, and rigorous randomized controlled trial for further evaluation is necessary.Methods: This is a single-center, randomized, double-blind, placebo-controlled, pragmatic study. Subjects undergoing total hip or knee arthroplasty will be randomized in a 1:1 ratio to intervention (n = 186) and placebo (n = 186) groups. This trial aims to explore the potential role of S-ketamine in the prevention of POD. Its primary outcome is the incidence of POD within 3 postoperative days. Secondary outcomes include the number of POD episodes, the onset and duration of POD, the severity and subtype of POD, pain scores and opioid consumption, sleep quality, clinical outcomes, and safety outcomes.Discussion: To our knowledge, this is the first pragmatic study that proposes to use S-ketamine to prevent POD. We reviewed a large body of literature to identify potential preoperative confounding variables that may bias associations between the intervention and primary outcome. We will use advanced statistical methods to correct potential confounding variables, improving the test’s power and external validity of test results. Of note, the patient population included in this trial will undergo intraspinal anesthesia. Although large, multicenter, randomized controlled studies have found no considerable difference in the effects of regional and general anesthesia on POD, patients receiving intraspinal anesthesia have less exposure to at-risk drugs, such as sevoflurane, propofol, and benzodiazepines, than patients receiving general anesthesia. At-risk drugs have been shown to negatively interfere with the neuroprotective effects of S-ketamine, which may be the reason for the failure of a large number of previous studies. There is currently a lack of randomized controlled studies evaluating S-ketamine for POD prevention, and our trial helps to fill a gap in this area.Trial registration: http://www.chictr.org.cn, identifier ChiCTR2300075796.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which systemic inflammation may put individuals at increased risk of developing frailty and metabolic syndrome (MetS). However, the relationship between MetS severity and frailty remains poorly understood in individuals with RA. Further, traditional MetS diagnostic methods do not assess severity and thus may lack sensitivity in capturing subtle metabolic abnormalities. In this cross-sectional study, data from the National Health and Nutrition Examination Survey (2003–2018) were used to construct weighted multivariable logistic regression models to explore the risk association between MetS severity and frailty in RA patients. Restricted cubic spline analysis was used to examine non-linear correlation between MetS severity and frailty. We also conducted subgroup analyses and interactions as well as sensitivity analysis to evaluate the robustness of results. A total of 802 RA patients were included in this study, among whom 442 were identified as frail (52.05%). RA patients with higher MetS severity had significantly increased frailty risk [adjusted odds ratio (aOR): 1.26; 95% CI: 1.09–1.46; p = 0.003]. There was a non-linear relationship between MetS severity and frailty (p for overall < 0.001; p for non-linear < 0.001), with an inflection point at 0.089. When MetS z-score was < 0.089, there was no significant association between MetS z-score and frailty (p > 0.05), whereas the association was positive for scores ≥ 0.089 (aOR: 1.68; 95% CI: 1.30–2.17; p < 0.001). The risk of frailty increased significantly with increasing MetS severity among alcohol drinkers (aOR: 1.43; 95% CI: 1.19–1.71; p < 0.001) compared with non-drinkers (aOR: 0.97; 95% CI: 0.73–1.29; p = 0.085). Sensitivity analysis confirmed robustness of the association between MetS severity and risk of frailty. We identified a significant association between MetS severity and frailty risk in patients with RA. As MetS severity increased, the risk of frailty was higher among alcohol drinkers compared to non-drinkers. Clinicians should enhance frailty screening and management in patients with RA by incorporating assessments of MetS severity into routine practice.