Diosmetin alleviates neuropathic pain by regulating the Keap1/Nrf2/NF-κB signaling pathway.

BACKGROUND: Neuropathic pain, a chronic condition with a high incidence, imposes psychological burdens on both patients and society. It is urgent to improve pain management and develop new analgesic drugs. Traditional Chinese medicine has gained popularity as a method for pain relief. Diosmetin (Dio) is mainly found in Chinese herbal medicines with effective antioxidant, anti-cancer, and anti-inflammatory properties. There are few known mechanisms underlying the effectiveness of Dio in treating neuropathic pain. However, the complete understanding of its therapeutic effect is missing. PURPOSE: This study aimed to evaluate Dio's therapeutic effects on neuropathic pain models and determine its possible mechanism of action. We hypothesized that Dio may activate antioxidants and reduce inflammation, inhibit the activation of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and nuclear factor-k-gene binding (NF-κB), promote the metastasis of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of heme oxygenase 1 (HO-1), thus alleviating the neuropathic pain caused by spinal nerve ligation. METHODS: Chronic nociceptive pain mouse models were established in vivo by L4 spinal nerve ligation (SNL). Different dosages of Dio (10, 50, 100 mg/kg) were intragastrically administered daily from the third day after the establishment of the SNL model. Allodynia, caused by mechanical stimuli, and hyperalgesia, caused by heat, were assessed using the paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL), respectively. Cold allodynia were assessd by acetone test. RT-PCR was used to detect the content of interleukin-(IL)- 1ß, IL-6 and tumor necrosis factor (TNF)-a. Immunofluorescence and western blotting were employed to assess the expression levels of Glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), Keap1, Nrf2, HO-1, and NF-κB p-p65 protein. RESULTS: Dio administration relieved SNL-induced transient mechanical and thermal allodynia in mice. The protective effect of Dio in the SNL model was associated with its anti-inflammatory and anti-glial responses in the spinal cord. Dio inhibited both inflammatory factors and macrophage activation in the DRG. Furthermore, Dio regulated the Keap1/Nrf2/NF-κB signaling pathway. HO-1 and Nrf2 were upregulated following Dio administration, which also decreased the levels of Keap1 and NF-κB p65 protein. CONCLUSION: Mice with SNL-induced neuropathic pain were therapeutically treated with Dio. Dio may protect against pain by inhibiting inflammatory responses and improved Keap1/Nrf2/NF-κB pathway. These results highlight the potential therapeutic effect of Dio for the development of new analgesic drugs.

The negative impact of opioids on cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

PURPOSE: As one of the most effective analgesics, opioids are essential for patients with cancer-related pain, even in the context of the opioid abuse crisis. The current meta-analysis aimed to identify whether concomitant exposure to opioids can affect the efficacy of ICIs and lead to a worse prognosis. METHODS: PubMed, Embase, and the Cochrane Library were searched based on the PRISMA checklist, through April 2022, for the following terms: ("opioids" OR "concomitant medication") AND ("Neoplasm" OR "Carcinoma" OR "Cancer" OR "Tumor") AND ("Immunotherapy" OR "Immune Checkpoint Inhibitor" OR "PD-L1 Inhibitor" OR "PD-1 Inhibitor" OR "CTLA-4 Inhibitor"). The outcomes considered were overall survival (OS) and progression-free survival (PFS) calculated using the random-effects or fixed-effects model. RESULTS: After screening 531 studies, a total of 7 articles involving 2690 patients were eligible for quantitative analysis. The use of opioids was negatively correlated with OS (HR 1.75, 95%CI 1.32-2.31, P < 0.001; I2 = 81%, P < 0.001) and significantly reduced the PFS (HR 1.61, 95%CI 1.41-1.83, P < 0.001; I2 = 0%, P = 0.63) of patients treated with ICIs. Similar results were obtained in each subgroup analysis. While NSAIDs could lead to poor OS (HR 1.25, 95% CI 1.03-1.51, P = 0.02; I2 = 0%, P = 0.60) but not PFS (HR 1.11, 95% CI = 0.89-1.39, P = 0.36) for ICIs patients. And sensitivity analyses confirmed the reliability of the results. CONCLUSION: Opioids significantly reduced OS and PFS in patients receiving ICI therapy. Thus, the use of different types of opioids should be considered with caution, and it is necessary to actively develop alternative treatments.

Astaxanthin alleviates inflammatory pain by regulating the p38 mitogen-activated protein kinase and nuclear factor-erythroid factor 2-related factor/heme oxygenase-1 pathways in mice.

Inflammatory pain is a complex process that has a substantial negative impact on post-injury quality of life. Astaxanthin (AST), which is a lipid-soluble red-orange carotenoid that is found in lobsters, inhibits the development and maintenance of inflammation in mice via its antioxidant and anti-inflammatory activities. However, the specific mechanisms underlying these effects remain unclear. In this study, we aimed to elucidate the mechanism by which astaxanthin alleviated inflammation using a mouse model with Complete Freund's adjuvant (CFA)-induced inflammatory pain. Mechanical allodynia and thermal hyperalgesia were observed on days 1-14 post CFA injection. Expression of p38 mitogen-activated protein kinase (MAPK) in the left paw and L4-6 dorsal root ganglia (DRG) were upregulated in the CFA-induced mice. Expression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathways were also increased. Astaxanthin relieved mechanical allodynia and thermal hyperalgesia induced by CFA and inhibited the inflammatory response (e.g., infiltration of inflammatory cells and production of inflammatory factors) in the ipsilateral paw and DRG. Additionally, AST  inhibited p38 MAPK and enhanced Nrf2/HO-1 contents in the left paw and DRG, and reversed the pain induced by p38 MAPK agonist and Nrf2 inhibitors. These findings suggest that AST exerts anti-inflammatory effects and regulates p38 MAPK and Nrf2/HO-1 to alleviate inflammatory pain. AST may be a potential therapeutic agent for relieving inflammation.

Programmable Pump for Intrathecal Morphine Delivery to Cisterna Magna: Clinical Implications in Novel Management of Refractory Pain Above Middle Thoracic Vertebrae Level Utilizing a Prospective Trial Protocol and Review.

BACKGROUND: The cisterna Intrathecal Drug Delivery system (IDDS) with morphine has proven to be effective in treating refractory cancer pain above the middle thoracic vertebrae level in some countries. However, it has not been fully investigated in others. We designed the current project to investigate the efficacy and safety of cisterna IDDS for pain relief in refractory pain above the middle thoracic vertebrae level in advanced cancer patients. METHODS: This study protocol allows for eligible cancer patients to receive the cisterna IDDS operation. Pain intensity (Visual Analogue scale, VAS), quality of life (36-Item Short-Form Health Survey, SF-36), and depression (Self-Rating Depression scale, SDS) are assessed along with side effects in the postoperative follow-up visits. Recent literature suggests a potential role for cisterna IDDS morphine delivery for refractory pain states above the middle thoracic level. CONCLUSION: The results of this study may provide further evidence that cisterna IDDS of morphine can serve as an effective and safe pain relief strategy for refractory pain above the middle thoracic vertebrae level in advanced cancer patients.

Neurolytic Splanchnic Nerve Block and Pain Relief, Survival, and Quality of Life in Unresectable Pancreatic Cancer: A Randomized Controlled Trial.

BACKGROUND: Neurolytic splanchnic nerve block is used to manage pancreatic cancer pain. However, its impact on survival and quality of life remains controversial. The authors' primary hypothesis was that pain relief would be better with a nerve block. Secondarily, they hypothesized that analgesic use, survival, and quality of life might be affected. METHODS: This randomized, double-blind, parallel-armed trial was conducted in five Chinese centers. Eligible patients suffering from moderate to severe pain conditions were randomly assigned to receive splanchnic nerve block with either absolute alcohol (neurolysis) or normal saline (control). The primary outcome was pain relief measured on a visual analogue scale. Opioid consumption, survival, quality of life, and adverse effects were also documented. Analgesics were managed using a protocol common to all centers. Patients were followed up for 8 months or until death. RESULTS: Ninety-six patients (48 for each group) were included in the analysis. Pain relief with neurolysis was greater for the first 3 months (largest at the first month; mean difference, 0.7 [95% CI, 0.3 to 1.0]; adjusted P < 0.001) compared with placebo injection. Opioid consumption with neurolysis was lower for the first 5 months (largest at the first month; mean difference, 95.8 [95% CI, 67.4 to 124.1]; adjusted P < 0.001) compared with placebo injection. There was a significant difference in survival (hazard ratio, 1.56 [95% CI, 1.03 to 2.35]; P = 0.036) between groups. A significant reduction in survival in neurolysis was found for stage IV patients (hazard ratio, 1.94 [95% CI, 1.29 to 2.93]; P = 0.001), but not for stage III patients (hazard ratio, 1.08 [95% CI, 0.59 to 1.97]; P = 0.809). No differences in quality of life were observed. CONCLUSIONS: Neurolytic splanchnic nerve block appears to be an effective option for controlling pain and reducing opioid requirements in patients with unresectable pancreatic cancer.

Intrathecal Morphine Delivery at Cisterna Magna to Control Refractory Cancer-Related Pain: A Prospective Cohort Study.

Background: For patients suffering from primary or metastatic cancer above the middle thoracic vertebrae, refractory pain management still remains a great challenge. Theoretically, inserting a catheter tip into the cisterna magna may be a promising solution. However, at present, there have been no reliable data regarding this novel technique. We therefore investigated the efficacy and safety of an advanced approach for pain relief in a specific population. Methods: Thirty participants from two hospitals received the intrathecal deliveries of opioid to either one of two sites: cisterna magna (n = 15) or lower thoracic region (n = 15). Pain relief (visual analogue scale, VAS), quality of life (short form (36) health survey, SF-36) as well as depression (self-rating depression scale, SDS) were assessed in the follow-up visits and compared between the two groups. Results: Patients receiving intrathecal morphine delivery to cisterna magna achieved greater pain improvement indicated as significant decrease of VAS scores at day 1 and 7, and achieved better improvement in physical function (day 7 and 30), role physical (day 7 and 30), body pain (day 7, 30 and 90), general health (day 7, 30 and 90), vitality (day 7, 30 and 90), social function (day 90), role emotional (day 7 and 90), mental health (day 7, 30 and 90) and SDS (day 1 and 7). Conclusions: Intrathecal morphine delivery to cisterna magna might be an effective and safe technique for patients suffering from cancer at the middle thoracic vertebrae or above to control refractory pain. Trial registration: No. ChiCTR-ONN-17010681.

High-Voltage, Long-Duration Pulsed Radiofrequency on Gasserian Ganglion Improves Acute/Subacute Zoster-Related Trigeminal Neuralgia: A Randomized, Double-Blinded, Controlled Trial.

BACKGROUND: Trigeminal postherpetic neuralgia is a severe neuropathic pain and often refractory to existing treatment, it develops secondary to herpes zoster-infected Gasserian ganglion. Therefore, it is important to prevent the transition of acute/subacute zoster-related pain to trigeminal postherpetic neuralgia. Despite numerous studies, the optimal intervention that reduces trigeminal postherpetic neuralgia incidence is still unknown. OBJECTIVES: This study aimed to evaluate the efficacy and safety of high-voltage, long-duration pulsed radiofrequency (PRF) on the Gasserian ganglion in patients with acute/subacute zoster-related trigeminal neuralgia. STUDY DESIGN: Prospective, randomized, double-blinded study. SETTING: Department of Pain Medicine, the First Affiliated Hospital of China Medical University. METHODS: Ninety-six patients with acute/subacute zoster-related trigeminal neuralgia were equally randomly assigned into 2 groups. The electrode needle punctured the Gasserian ganglion guided by computed tomography in every patient. High-voltage, long-duration PRF at 42°C for 900 seconds was applied in the PRF group (n = 48). It was also applied in the sham group (n = 48) without radiofrequency energy output. The therapeutic effects were evaluated using a visual analog scale (VAS) and the 36-Item Short Form Health Survey (SF-36) at different time points. The average dosage of pregabalin (mg/d) administrated within the first month after treatment was also recorded. RESULTS: The postprocedure VAS scores in the PRF group were significantly lower than those in the sham group at different time points after treatment (P < 0.01). The SF-36 scores, which included physical functioning, physical role, bodily pain, general health perceptions, vitality, social function, emotional role, and the mental health index, were significantly improved at the sixth month after treatment in the PRF group compared with the sham group (P < 0.01). The average dosage of pregabalin administered (mg/d) within the first month after treatment was also significantly reduced in the PRF group compared with the sham group (P < 0.01). There were no bleeding, infection, or other severe side effects in both groups. LIMITATIONS: Single center study, relatively small number of patients. CONCLUSIONS: High-voltage, long-duration PRF on the Gasserian ganglion is an effective and safe therapeutic alternative for patients with acute/subacute zoster-related trigeminal neuralgia. KEY WORDS: Pulsed radiofrequency, zoster-related trigeminal neuralgia, visual analog scale, 36-Item Short Form Health Survey.

Impaired AMPK­CGRP signaling in the central nervous system contributes to enhanced neuropathic pain in high­fat diet­induced obese rats, with or without nerve injury.

Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP­activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene­related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague­Dawley rats consuming a high­fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)­AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low­fat (LF) diet. HF­fed rats that underwent spared nerve injury (SNI) also exhibited lower p­AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF­diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF­fed compared with LF­fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5­aminoimidazole­4­carboxamide riboside (AICAR) or the CGRP antagonist CGRP8­37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF­fed rats, but not LF­fed rats, with or without SNI. The results indicated that blocking the AMPK­CGRP pathway may enhance neuropathic pain in HF­induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity­associated neuropathic pain.

Prospective Evaluation of Nasopharyngeal Intubation During Radiofrequency Thermocoagulation of the Trigeminal Ganglion.

AIMS: To investigate whether nasopharyngeal airway (NPA) intubation could reduce the risk of complications caused by radiofrequency thermocoagulation (RFT) of the trigeminal ganglion. METHODS: From November 1, 2014 to May 1, 2015, 200 patients treated with sedation (combination of sufentanil and propofol) were randomly divided into two groups, one in which NPA intubation was used (intervention group) and one in which it was not used (control group). The primary outcome was the frequency of hypoxemia, and secondary outcomes were the frequency of hypotension, nasal mucosa damage, corneal numbness, masticatory weakness, palsies of other cranial nerves, and intracranial hemorrhage. Statistical analyses were performed by using the Statistical Package for Social Sciences version 19.0. A P value < .05 was considered to reflect statistical significance. Differences in the frequencies of adverse events between the two groups were assessed by using Fisher exact test. RESULTS: Five patients in the intervention group showed minor nasal mucosa injury (P = .027). Hypoxemia (19 vs 3, P < .001), corneal numbness (12 vs 4), and masticatory weakness (11 vs 3) occurred more frequently in the control group than in the intervention group (P < .05). No significant differences in the incidence of hypotension or palsies of other cranial nerves were observed between the two groups (P > .05). CONCLUSION: NPA intubation can reduce the frequency of hypoxemia and complications related to the thermocoagulation of the trigeminal ganglion with minor risks for nasopharyngeal injury.

Efficacy of Short-Term Spinal Cord Stimulation in Acute/Subacute Zoster-Related Pain: A Retrospective Study.

BACKGROUND: Postherpetic neuralgia (PHN) is a refractory condition that impairs the patient's quality of life (QoL), it develops secondary to herpes zoster infection. Therefore, it's important to prevent the transition of acute/subacute zoster-related pain to PHN. Despite of numerous studies, the optimal intervention that reduces PHN incidence is still unknown. OBJECTIVE: We evaluate the efficacy of short-term spinal cord stimulation (stSCS) in patients with refractory acute/subacute zoster-related pain. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center/teaching hospital. METHODS: A total of 46 patients who presented with acute/subacute zoster-related pain, and had previously failed conventional therapies, underwent stSCS treatment. Visual analog scale (VAS), Short Form Health Survey 12 items (SF-12), and analgesic consumptions were recorded before stSCS, post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stimulation. RESULTS: The VAS scores at post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stSCS treatment were significantly decreased compared with the baseline score (P < 0.001). Thirty-two patients (69.6%, 32/46) achieved the minimal clinically important difference (MCID), including 18 patients (39.1%, 18/46) who achieved complete pain relief (VASless than orequal to2). During the follow-up period, the efficacy of stSCS didn't decrease and VAS scores were declining. Similarly, SF-12 scores and analgesic consumptions improved after stSCS treatment. The efficacy of stSCS did not differ significantly among patients with different durations of acute/subacute zoster-related pain starting from the onset of rash. No serious adverse effects were observed in the entire follow-up period. LIMITATIONS: This study was not a randomized prospective controlled study. We did not compare the outcomes with patients presenting with mild or moderate pain, and did not compare the efficacy of stSCS treatment with conventional therapies. CONCLUSIONS: stSCS is a safe, effective, and less invasive analgesic method for patients with refractory acute/subacute zoster-related pain. KEY WORDS: Herpes zoster, zoster-related pain, postherpetic neuralgia, spinal cord stimulation, VAS.

Bipolar High-Voltage, Long-Duration Pulsed Radiofrequency Improves Pain Relief in Postherpetic Neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is often refractory to existing treatments. Treatment of the dorsal root ganglion (DRG) using monopolar pulsed radiofrequency (PRF), which is a non- or minimally neurodestructive technique, is not efficacious in all patients. OBJECTIVES: This study aimed to determine the safety and clinical efficacy of bipolar high-voltage, long-duration PRF on the DRG in PHN patients. STUDY DESIGN: Self before-after controlled clinical trial. SETTING: Department of Pain Medicine, the First Affiliated Hospital of China Medical University. METHODS: Ninety patients diagnosed with PHN for > 3months were included. Bipolar high-voltage, long-duration PRF at 42°C for 900 seconds was applied after the induction of paresthesias covered the regions of hyperalgesic skin. The therapeutic effects were evaluated using a visual analog scale (VAS) and the 36-item Short Form health survey (SF-36) before treatment and one, 4, 8, and 12 weeks after PRF. RESULTS: The VAS scores at one, 4, 8, and 12 weeks after PRF treatment were significantly lower than before treatment (P < 0.001). The SF-36 scores, which included physical functioning, physical role, bodily pain, general health perceptions, vitality, social function, emotional role, and the mental health index, were significantly improved up to 12 weeks after PRF treatment (P < 0.001). No serious adverse effects were identified following treatment. The main adverse reactions included pain, tachycardia, and high blood pressure (especially when the field strength was enhanced). LIMITATIONS: Single center study, relatively small number of patients, lack of a control group. CONCLUSION: Bipolar high-voltage, long-duration PRF on the DRG is an effective and safe therapeutic alternative for PHN patients. This treatment could improve the quality of life of PHN patients. CLINICAL TRIAL REGISTRATION: NO ChiCTR-OCS-14005461.

Meta-analysis of black tea consumption and breast cancer risk: update 2013.

Black tea is a commonly consumed beverage in the world, comprising approximately 80% of all tea consumed. We sought to examine the association between black tea consumption and risk of breast cancer, using all available epidemiologic evidence to date. PubMed, EMBASE, ISI Web of Science, Chinese National Knowledge Infrastructure Database, and China Biological Medicine Database were used to search for citations using the MeSH terms as "breast neoplasm" AND "black tea." Then we performed a meta-analysis of studies of breast cancer risk published between 1985 and 2013 by using RevMan 5.0 software. The results showed that no association between black tea consumption and breast cancer risk in overall [odds ratio (OR) = 0.97; 95% confidence interval (CI) = 0.89-1.05]. We further performed a stratified analysis according to region (United States/Europe). Black tea consumption did not decrease breast cancer risk in the United States (OR = 0.91; 95% CI = 0.78-1.07) and in Europe (OR = 0.99; 95% CI = 0.93-1.06). In addition, the summary OR from all cohort studies (OR = 1.04, 95% CI = 0.91-1.18) or all case-control studies (OR = 0.95, 95% CI = 0.88-1.02) showed black tea intake has no effects on breast cancer risk. However, the association between black tea consumption and breast cancer incidence remains unclear based on the current evidence. Further well-designed large studies are needed to confirm our result.

Synergistic antitumor activity of resveratrol and miR-200c in human lung cancer.

MicroRNAs have emerged as promising molecular factors with potential for clinical applications in cancer diagnosis and therapy. In the present study, we demonstrated that the level of miR-200c in lung cancer tissues was lower than that in normal tissues using real-time PCR. To further investigate the effects of miR-200c expression in lung cancer cells, we upregulated miR-200c levels in H460 cells using transfection. We found that the percentage of apoptotic cells was higher in the cells expressing miR-200c than that in the untransfected cells. Furthermore, the antitumor activities of miR-200c were demonstrated in vivo. Notably, we confirmed that reservatol (RESV) showed stronger antitumor activities in miR-200c-positive cells than in miR-200c-negative cells. Finally, we demonstrated that expression of miR-200c in H460 cells suppressed cell growth by targeting RECK, followed by activation of the JNK signaling pathway and ER stress. Collectively, these data show that miR-200c expression sensitizes H460 cells to RESV and this is likely due to RECK expression.

Resveratrol mitigates isoflurane-induced neuroapoptosis by inhibiting the activation of the Akt-regulated mitochondrial apoptotic signaling pathway.

The inhalation anesthetic, isoflurane, induces learning and memory impairment. Mitochondrial dysfunction and oxidative stress are thought to play important roles in isoflurane-induced neuroapoptosis. In this study, we treated neuronal cells with isoflurane for 6 h. We found that isoflurane induced the opening of mitochondrial permeability transition pores, increased the levels of reactive oxygen species and the activation of caspase­3, and decreased the mitochondrial membrane potential and the intracellular calcium ion concentration. Resveratrol (RESV; trans-3,5,4'-trihydroxystilbene), a naturally occurring phytoalexin, is found at high concentrations in the skin of red grapes and red wine and has been demonstrated to have anti-infective, antioxidant and cardioprotective functions. Our findings demonstrated that the neuroprotective effects of RESV were independent on its direct radical scavenging properties. Following treatment of the cells with various concentrations of RESV, we found that RESV induced the expression of mitochondrial superoxide dismutase and catalase activity, and reduced mitochondrial oxidative stress and damage. The data from the present study demonstrate that RESV effectively protects neuronal cells from isoflurane-induced cytotoxicity by activating the Akt signaling pathway.