Hydrogen sulfide attenuates diabetic neuropathic pain through NO/cGMP/PKG pathway and µ-opioid receptor.

IMPACT STATEMENT: There are currently approximately 425 million diabetic patients worldwide, of which approximately 90% of patients with diabetes suffer from neuropathy. Diabetic neuropathic pain (DNP) is a common complication of diabetic neuropathy. Nearly half of the patients hospitalized with diabetes have pain symptoms or symptoms related to neurological injury, and the incidence increases with age and diabetic duration. Anti-DNP analgesics have either limited therapeutic effects or serious side effects or lack of clinical trials, which has limited their application. Physiopathological mechanisms and treatment of DNP remain a significant challenge. The present confirmed that inhalation of H2S may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and µ-opioid receptor. It provides us the animal study foundation for the application of H2S on the treatment of DNP and clarifies some target molecules in the pain modulation of DNP.

Effect of morphine and a low dose of ketamine on the T cells of patients with refractory cancer pain in vitro.

The combination of morphine and ketamine is considered safe and efficacious in many patients. However, a considerable number of immunomodulatory effects have been reported to be produced by both morphine and ketamine. The aim of the present study was to assess the direct effect of morphine and a low dose of ketamine on the T cells of patients with refractory cancer pain in vitro. Venous blood was obtained from patients with refractory cancer pain and peripheral blood mononuclear cells were isolated using the Ficoll-Hypaque density gradient method. Anti-CD3 beads were used to isolate T cells by positive selection. Subsequently, the T cells were treated with vehicle, 200 ng/ml of morphine or 200 ng/ml of morphine + 100 ng/ml ketamine for 24 h, following which the cells were stimulated with anti-CD3 and anti-CD28. Flow cytometric analysis of CD3+ T cells, and interleukin (IL)-2 and interferon (IFN)-γ in the supernatant, reverse transcription-quantitative PCR analysis for the detection of IL-2 and IFN-γ and western blotting for the detection of p65 nuclear factor (NF)-κB were performed. In vitro, the CD4+ and CD8+ T cell counts, CD4+/CD8+ ratio, secretion of IL-2 and IFN-γ in the supernatant, mRNA expression levels of IL-2 and IFN-γ and expression of p65 NF-κB were significantly decreased following treatment with morphine and morphine + ketamine, compared with results in the control group (all P<0.05). However, there was no significant difference between treatment with morphine and that with morphine + ketamine. Treatment with morphine + ketamine in vitro decreased the immune functions of patients with refractory cancer pain, although the effect of treatment with morphine and a low dose of ketamine did not differ significantly from that with morphine treatment alone.

Morphine and ketamine treatment suppress the differentiation of T helper cells of patients with colorectal cancer in vitro.

There have been conflicting reports regarding the effects of anesthetic and analgesic drugs on immune function in patients with cancer. The aim of the present study was to investigate changes to T helper (Th) cell populations in patients with colorectal cancer (CRC) and to assess the effects of morphine and ketamine on the differentiation of Th cells harvested from patients with CRC in vitro. Peripheral blood samples were extracted from 20 patients with CRC and 20 healthy participants. Peripheral blood mononuclear cells were isolated and incubated in a solution containing phorbol-myristate-acetate (PMA) and ionomycin in the presence or absence of morphine or various ketamine concentrations (25, 50, and 100 µM). Samples were analyzed 4 h later. Th1 and Th2 cells were significantly increased by PMA and ionomycin stimulation; however, Th1 cells and the Th1/Th2 ratio in PMA and ionomycin treatments were significantly decreased in the CRC group compared with the control group. Following incubation with PMA and ionomycin, morphine significantly decreased Th1 cells and the Th1/Th2 ratio in the CRC group. Ketamine did not significantly affect levels of Th1 or Th2 cells or the Th1/Th2 ratio at a concentration of 25 µM; however, a significant increase in the Th1/Th2 ratio was observed at a concentration of 50 µM and, at 100 µM, a significant decrease in Th1 and Th2 cells and an increase in the Th1/Th2 ratio were observed. The present study suggests that CRC may shift the balance of Th1/Th2 towards Th2 by inducing an immunological response, morphine is able to suppress the differentiation of Th cells and decreases the Th1/Th2 ratio, and ketamine may affect the differentiation of Th cells in a dose-dependent manner.

Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice.

Tetrahydropalmatine exerts numerous pharmacological activities, including analgesic and narcotic effects; anti-arrhythmic, blood pressure lowering and cardioprotective effects; protective effects against cerebral ischemia-reperfusion injury; inhibition of platelet aggregation; prevention of ulcerative diseases and inhibition of gastric acid secretion; antitumor effects; and beneficial effects on the withdrawal symptoms associated with drug addiction. The present study aimed to investigate the protective effects of tetrahydropalmatine against ketamine­induced learning and memory impairment in mice. The Morris water maze test and open field test were used to analyzed learning and memory impairment in mice. ELISA kits and western blotting were used to analyze oxidative stress, inflammation factors, caspease­3 and caspase­9, iNOS, glial fibrillary acidic protein (GFAP), glial cell­derived neurotrophic factor (GDNF), cytochrome c and phospholipase C (PLC)­Î³1 protein expression. The results demonstrated that tetrahydropalmatine treatment significantly decreased escape latency in the learning phase and increased the number of platform site crossings in ketamine­induced mice. In addition, tetrahydropalmatine significantly inhibited oxidative stress, inflammation and acetylcholinesterase activity, and decreased acetylcholine levels in ketamine­induced mice. Tetrahydropalmatine also suppressed iNOS protein expression, weakened caspase­3 and caspase­9 activation, inhibited nuclear factor­κB, glial fibrillary acidic protein, cytochrome c and phospholipase C­Î³1 protein expression, and induced glial cell­derived neurotrophic factor protein expression in ketamine­induced mice. Taken together, these results indicated that tetrahydropalmatine may protect against ketamine­induced learning and memory impairment in mice via antioxidative, anti­inflammatory and anti­apoptotic mechanisms. The present study provided an experimental basis for the clinical application of tetrahydropalmatine to reduce the severe side effects associated with ketamine therapy in future studies.

Ketamine, as adjuvant analgesics for patients with refractory cancer pain, does affect IL-2/IFN-γ expression of T cells in vitro?: A prospective, randomized, double-blind study.

BACKGROUND: Ketamine has been used as an analgesic adjuvant with morphine in the treatment of refractory cancer pain recently. But both morphine and ketamine have been reported to produce a number of immunomodulatory effects. The current study was performed to assess whether the concentration of ketamine, as adjuvant analgesics for patient with refractory cancer pain, was related to its effect on T cells interleukin-2 (IL-2)/interferon-γ (IFN-γ) expression in vitro. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood of patients with refractory cancer pain over a Ficoll-Hypaque density gradient. T cells were isolated from by positive selection using anti-CD3 beads. T cells were then treated with vehicle (C group), morphine (200 ng/mL, M group), morphine (200 ng/mL), and different dose of ketamine (100, 200, 1000 ng/mL; MK1, MK5, MK10 group) for 24 hours before stimulation with anti-CD3 and anti-CD28. Then supernatant IL-2 and IFN-γ protein analysis, quantitative reverse transcription polymerase chain reaction (RT-PCR) for IL-2 and IFN-γ were done. RESULTS: There were no significant difference of supernatant IL-2 and IFN-γ among C group, M group, and MK1 group, but the mRNA of M group and MK1 group were decreased compared with C group (P < .05). Compared with C group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all significantly decreased (P < .01). Compared with M group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all decreased (P < .05), while supernatant IL-2 and the mRNA of MK10 group were significantly decreased (P < .01). CONCLUSION: In conclusion, we confirmed that just as morphine, ketamine dose-dependently suppressed IL-2 and IFN-γ of activated T lymphocyte of patients with refractory cancer pain in vitro, but the inhibitory action of low dose ketamine could be neglected.

Local anesthetic effects of bupivacaine loaded lipid-polymer hybrid nanoparticles: In vitro and in vivo evaluation.

PURPOSE: There is a compelling need for prolonged local anesthetic that would be used for analgesia with a single administration. However, due to the low molecular weight of local anesthetics (LA) (lidocaine, bupivacaine, procaine, dibucaine, etc), they present fast systemic absorption. METHODS: The aim of the present study was to develop and evaluate bupivacaine lipid-polymer hybrid nanoparticles (BVC LPNs), and compared with BVC loaded PLGA nanoparticles (BVC NPs). Their morphology, particle size, zeta potential and drug loading capacity were evaluated. In vitro release study, stability and cytotoxicity were studied. In vivo evaluation of anesthetic effects was performed on animal models. RESULTS: A facile nanoprecipitation and self-assembly method was optimized to obtain BVC LPNs, composed of PLGA, lecithin and DSPE-PEG2000, of ∼175nm particle size. Compared to BVC NPs, BVC LPNs exhibited prolonged in vitro release in phosphate-buffered saline (pH=7.4). Further, BVC LPNs displayed enhanced in vitro stability in 10% FBS and lower cytotoxicity (the concentration of BVC ranging from 1.0µM to 20µM). In addition, BVC LPNs exhibited significantly prolonged analgesic duration. CONCLUSION: These results demonstrate that the LPNs could function as promising drug delivery system for overcoming the drawbacks of poor stability and rapid drug leakage, and prolonging the anesthetic effect with slight toxicity.

Efficacy and tolerability of oxycodone versus fentanyl for intravenous patient-controlled analgesia after gastrointestinal laparotomy: A prospective, randomized, double-blind study.

BACKGROUND: It has been suggested that oxycodone is effective in relieving acute postoperative pain. The aim of this study was to investigate the efficacy and tolerability of oxycodone (O) versus fentanyl (F), and the adequate potency ratio of oxycodone and fentanyl in patients with intravenous patient-controlled analgesia after gastric laparotomy. METHODS: In this double-blinded, randomized, controlled study, 60 patients undergoing elective gastric laparotomy were allocated to receive either oxycodone or fentanyl for postoperative intravenous patient-controlled analgesia (potency ratio 60:1). The patients received ketorolac 60 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 hours postsurgery. Pain severity, side effects and respiration rate were recorded 30 minutes, 3, 6, 12, 24, and 48 hours after the surgery. Cumulative opioid requirements and patient satisfaction were also measured. RESULTS: The median consumption more than 48 hours after operation of oxycodone was 50 mg (range: 40.0-62.4 mg) and fentanyl was 0.8 mg (range: 0.6-1.1 mg), and the percentage of patients requiring rescue medication was not statistically significant. Numeric rating scores at rest and upon movement were significantly lower in group O than in F (P < 0.05). Whereas the incidences of adverse events were similar between the groups (33.3% vs 27.6%, P = 0.64), a significant higher sedation scores were found in patients given fentanyl at 30 minutes after the surgery (P = 0.04). CONCLUSION: Oxycodone was comparable to fentanyl in the relief of postoperative pain following gastric laparotomy. Oxycodone not only provides better postoperative pain relief and less sedation, but also there was a tendency toward more side effects with oxycodone.

Effect of Oxycodone Combined With Dexmedetomidine for Intravenous Patient-Controlled Analgesia After Video-Assisted Thoracoscopic Lobectomy.

OBJECTIVE: To investigate the effect of the combination of oxycodone and dexmedetomidine for patient-controlled analgesia (PCA) after video-assisted thoracoscopic (VATS) lobectomy. DESIGN: A prospective, randomized, double-blind, controlled trial. SETTING: Shandong Cancer Hospital and Institute in Jinan, China. PARTICIPANTS: Eighty-four patients with lung cancer undergoing VATS lobectomies were recruited. INTERVENTIONS: Patients were randomly assigned to one of the following two groups: oxycodone and dexmedetomidine (group OD) or oxycodone alone (group O). Before induction of anesthesia, patients in group OD received 0.5 µg/kg, dexmedetomidine diluted to 20 mL with physiologic saline and infused for 10 minutes intravenously. The PCA protocol was 50 mg of oxycodone and 0.05 µg/kg/h dexmedetomidine diluted to 100 mL. Patients in group O received 20 mL of physiologic saline infused for 10 minutes. Their PCA protocol consisted of 50 mg of oxycodone diluted to 100 mL. Intravenous PCA was used for postoperative analgesia (lasting for 48 h). MEASUREMENTS AND MAIN RESULTS: Pain at rest and during movement was assessed by a blinded observer using the Visual Analog Scale pain score (VAS) at 4, 6, 24, and 48 hours after surgery, and the level of sedation simultaneously was assessed using the Ramsay Sedation Scale. Total oxycodone consumption, requirements for rescue analgesia, side effects, and satisfaction with pain management were recorded within 48 hours after surgery. Eighty patients' data were analyzed at the end of the study (40 in each group). Visual Analog Scale scores decreased at 4, 6, and 24 hours at rest and during movement in group OD compared with group O (p<0.05). The level of patient satisfaction in group OD was significantly higher than that in group O (p<0.05). Oxycodone consumption in group OD was significantly lower than that in group O (p<0.001). Group O experienced more nausea and vomiting 6 hours after surgery than did group OD (p< 0.05). CONCLUSION: The combination of oxycodone and dexmedetomidine for PCA after VATS lobectomy can reduce oxycodone consumption, improve patient satisfaction, and provide better analgesia with fewer side effects (nausea and vomiting) compared with PCA with oxycodone alone.

Morphine and ketamine inhibit immune function of gastric cancer patients by increasing percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells in vitro.

BACKGROUND: There is conflicting evidence regarding effects of anesthetic and analgesic drugs on immune function of cancer patients. This study was designed to observe changes of T cell subpopulations in the gastric cancer (GC) patients and to assess effects of morphine and ketamine on the CD4(+) T cells, CD8(+) T cells, and regulatory T cells (Tregs) populations obtained from the GC patients in vitro. METHODS: The peripheral blood samples from 20 GC patients and 20 healthy volunteers were obtained. The peripheral blood mononuclear cells were isolated and incubated in a solution containing phorbol-myristate-acetate and ionomycin (2 µL/mL) in the presence or absence of morphine (50 ng/mL) or different-concentration ketamine (25, 50, and 100 µM). The CD4(+) T cells, CD8(+) T cells, and Tregs were determined using the flow cytometric assay. RESULTS: The percentages of CD8(+) T cells were significantly decreased, but the ratio of CD4(+)/CD8(+) T cells and Tregs populations was significantly increased in the GC control group compared with the normal control group (P < 0.05). The ratio of CD4(+)/CD8(+) T cells was significantly increased in the groups M and K3 compared with the control group (P < 0.05) but was significantly decreased in the group K1 compared with the group K3. The percentage of Tregs was significantly increased in the groups M, K1, K2, and K3 compared with the control group. With the increased concentrations, ketamine increased the number of Tregs. CONCLUSIONS: GC shifts the balance of CD4(+)/CD8(+) T cells toward CD4(+) T cells and increases the Tregs populations by inducing immune responses. Morphine increases the ratio of CD4(+)/CD8(+) T cells and Tregs populations. Ketamine affects the ratio of CD4(+)/CD8(+) T cells and Tregs populations in a dose-dependent model.

Effect of Dexmedetomidine Alone for Intravenous Patient-Controlled Analgesia After Gynecological Laparoscopic Surgery: A Consort-Prospective, Randomized, Controlled Trial.

Gynecological laparoscopic surgery is minimally invasive compared with open surgical approaches, but postoperative pain is generally undermanaged. Pain management strategies related to the procedure-specific efficacy are needed. Many studies have shown that dexmedetomidine (DEX) has opioid-sparing properties. It is not clear whether DEX used alone for intravenous patient-controlled analgesia (PCA) could reduce postoperative pain after an invasive procedure. We hypothesized that DEX alone would reduce postoperative pain in women patients undergoing an elective gynecological laparoscopic procedure.This CONSORT-prospective randomized controlled clinical study aimed to investigate the effects of DEX alone for intravenous PCA after gynecological laparoscopic operation. Forty women patients scheduled for elective gynecological laparoscopy were enrolled into the study at Shandong Cancer Hospital and Institute and randomly allocated into two groups (n = 20 each). In the DEX group (group D), the intravenous PCA protocol was DEX 0.25 µg/kg/h diluted to 100 mL in 0.9% saline. In the fentanyl group (group F), the PCA protocol was fentanyl 20 µg/kg diluted to 100 mL in 0.9% saline. The primary outcome was the mean pain score on a visual analogue scale (VAS) at 6 hours after the operation. The secondary outcomes included the Ramsay sedation score, the incidence of postoperative nausea and vomiting (PONV), satisfaction with pain control, and time to recovery of gastrointestinal function.There were no significant differences in the patients' characteristics and intraoperative measurements (P > 0.05). No patients received rescue analgesic. The mean VAS scores at 6 hours post-operatively were not significantly different between the groups (P > 0.05). The incidence of PONV was less in group D than in group F (P < 0.05). The Ramsay sedation scores were not significantly between the groups (P > 0.05). Satisfaction with pain control was higher and time to recovery of gastrointestinal function was lower in group D (P < 0.05).DEX alone is effective for intravenous patient-controlled analgesia after gynecological laparoscopic surgery without a change in sedation and with fewer side effects, and this effect was associated with better satisfaction with postoperative pain control and earlier recovery of gastrointestinal function.

Effects of epidural analgesia with different concentrations of bupivacaine plus fentanyl on pain in patients undergoing thoracic surgery.

OBJECTIVE: To investigate and compared the efficacy and safety of epidural analgesia with different concentrations of bupivacaine plus fentanyl on pain in patients undergoing thoracic surgery. METHODS: 120 cases undergoing elective thoracic surgery were randomly divided into A, B, C and D four groups each with 30 cases, and they were treated with 0.25% (A group), 0.375% (B group), 0.50% (C group) and 0.75% (D group) bupivacaine plus fentanyl 0.4 mg. The pain conditions postoperative 4 h, 8 h, 12 h, 24 h and 48 h were evaluated by visual analogue scale (VAS). The PCA pressing numbers and incidence of adverse reactions were compared between the four groups. RESULTS: By postoperative 4 h, the VAS in D group were obviously lower than those in the other three groups (P all <0.05), and the other three groups showed no significances (P>0.05). However, the four groups showed no significant differences in VAS by postoperative 8 h, 12 h, 24 h and 48 h (P all >0.05). The incidences of respiratory depression in C and D groups were markedly higher than those in A and B groups (P all <0.05). CONCLUSIONS: 0.25%~0.375% bupivacaine plus fentanyl 0.4 mg using in epidural analgesia in patients undergoing thoracic surgery can lead to safe and effective analgesic effect.