Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Diabetes-Induced Neuropathic Pain.

Background: Diabetic neuropathic pain is a known complication of diabetes mellitus (DM) and results from the complex interaction of various factors affecting the nervous system. Yokuansan (YKS) is a versatile traditional Japanese herbal medicine with a wide range of applications, especially in pain management and neurological manifestations. YKS has analgesic properties for nerve damage and is a potential treatment for DM-induced neuropathic pain, especially in patients with diabetic neuropathy. Thus, we examined the anti-allodynic effect of YKS on DM-induced neuropathic pain. Methods: All experiments were performed on 6-week-old male Sprague-Dawley rats. DM and diabetic neuropathy were induced in rats with streptozotocin. Mechanical allodynia was assessed using dynamic plantar esthesiometry. Additionally, we conducted an immunological assessment of microglia cell changes in the spinal cord and an experiment to clarify the involvement of serotonin. Results: Diabetes significantly reduced withdrawal thresholds in rats during the initial two weeks of the experiment, which stabilized thereafter. However, this effect was not investigated in the control group. We assessed, using the dynamic plantar test, the anti-allodynic effects of orally administered YKS (1 g/kg). Daily YKS administration significantly increased the withdrawal threshold in DM animals. Additionally, oral YKS reduced the expression of Ibal-1-positive microglia. To elucidate the mechanism of action of YKS, we explored the involvement of serotonin (5-hydroxytryptamine [5-HT]) receptors in mediating its effects. Intrathecal administration of 5-HT receptor antagonists (WAY-100635, ketanserin, and ondansetron) inhibited the protective effects of YKS. Conclusions: YKS exhibited an anti-allodynic effect, suggesting that YKS may activate 5-HT receptors in the spinal cord, thereby alleviating diabetic neuropathic pain.

The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain.

Refractory peripheral neuropathy can occur as a side effect in 60-70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

Intravenous patient-controlled analgesia does not increase the risk of postoperative delirium compared to patient-controlled epidural analgesia: a propensity score-matched retrospective cohort study.

BACKGROUND: It is unclear whether the doses of opioids and the routes of administration used for postoperative analgesic management are associated with delirium. We aimed to compare the incidence of postoperative delirium (POD) between intravenous patient-controlled analgesia (IVPCA) and patient-controlled epidural analgesia (PCEA) in patients who underwent postoperative analgesic management using opioids. METHODS: We retrospectively investigated surgical patients (n=3,324) who received patient-controlled analgesia (PCA). Morphine was used for IVPCA, and fentanyl and ropivacaine were used for PCEA. The patients' background characteristics, perioperative management, presence of POD, and postoperative analgesia technique after IVPCA (n=1,184) or PCEA (n=2,140) were assessed. We divided the patients into IVPCA and PCEA groups and compared the incidence of POD by propensity score matching. We used the independent t-test for comparisons between the groups, and P<0.05 as considered as statistically significant. RESULTS: POD was noted in a total of 125 patients (3.8%); 55 patients (4.6%) with IVPCA and 70 patients (3.3%) with PCEA (P=0.046). There was no statistically significant difference in cumulative opioid usage up to postoperative day 2 (in mg) between patients with and without POD (POD 62.7±39.8 vs. non-POD 48.9±50.3, P=0.10). After propensity score matching, 1,156 patients with similar baseline characteristics were selected. POD was noted in 22 of 578 patients (3.8%) in the IVPCA group and 30 of 578 patients (5.2%) in the PCEA group, with no difference between the two groups (P=0.256). On the other hand, opioid usage was higher in the IVPCA group than in the PCEA group (P<0.001). CONCLUSIONS: There was no difference in the incidence of POD between morphine IVPCA and fentanyl PCEA when the patient characteristics were matched using propensity score matching. POD occurs regardless of the route and dose of opioid administration.