Prophylatic use of IV nalmefene to prevent epidural opioid-induced pruritus: A multicenter, randomized clinical trial.

STUDY OBJECTIVE: The incidence of pruritus from neuraxial opioids is about 60%. Pruritus causes discomfort and decreases the quality of recovery. This randomized double-blinded clinical trial was aimed to evaluate the prophylactic effects of a single dose IV nalmefene on the incidence and severity of epidural opioid-induced pruritus within 24 h after surgeries. DESIGN: A two-center, randomized, double blinded, controlled clinical trial. SETTING: The study was conducted from March 2022 to February 2023 at two tertiary care hospitals in China. PATIENTS: Patients aged between 18 and 80 years-old who underwent elective surgeries and received epidural analgesia intra- and post-operatively were screened for study enrollment. A total of 306 patients were enrolled, 302 patients underwent randomization and 296 patients were included in the final analysis. INTERVENTIONS: The nalmefene group was prophylactically given 0.5 µg/kg nalmefene intravenously while the control group was given the same volume of saline. MEASUREMENTS: The primary endpoint was the incidence of pruritus within 24 h after surgeries. The secondary endpoints included time of the first patient-reported pruritus, severity of pruritus after surgeries, severity of acute pain scores after surgeries and other anesthesia/analgesia related side effects. MAIN RESULTS: Pruritus occurred in 51 of the 147 (34.69%) patients in the control group and 35 of the 149 (23.49%) patients in the nalmefene group (odds ratio, 0.58; 95% CI, 0.35 to 0.96; P = 0.034) within 24 h postoperatively. Nalmefene group demonstrated delayed onset of pruritus, reduced severity of pruritus and decreased vomiting within 24 h after surgery. There were no significant differences in postoperative analgesia and the incidence of other anesthesia/analgesia associated side effects. CONCLUSIONS: A single dose of 0.5 µg/kg nalmefene intravenously significantly reduced the incidence and severity of epidural-opioid induced pruritus within 24 h after surgery without affecting the efficacy of epidural analgesia. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn) and the registration number is ChiCTR2100050463. Registered on August 27th, 2021.

Prevention of Pruritis following Spinal Morphine for Scheduled Cesarean Birth.

BACKGROUND: Intrathecal morphine provides effective analgesia after cesarean birth, yet up to 90% of women who receive it experience excessive itching, an undesirable dose-dependent effect. Pruritis may increase nursing workload, delay breastfeeding, and decrease patient satisfaction. When 0.1 mg spinal morphine is given, pruritis is markedly reduced while analgesia is preserved. PURPOSE: The purpose of this project was to determine possible causes and solutions for pruritus after cesarean birth. METHODS: Anesthesia providers were educated and encouraged to limit spinal morphine to 0.1 mg as a strategy to prevent pruritus. In a repeated measures design, the rate of treatment-required pruritus and opioid consumption were measured 24 hours after surgery. The project included an evaluation of 30 medical records before and 30 medical records after the project intervention. RESULTS: Preintervention rate of treatment-required pruritis was 37%, all received spinal morphine ≥ 1.5 mg. Postintervention rate of treatment-required pruritis was 13% and 57% after spinal morphine 0.1 mg and 0.2 mg, respectively. Opioid consumption was similar between groups. CLINICAL IMPLICATIONS: Mother-baby nurses can have an impact on the practice of anesthesia providers by advocating for evidence-based dosing of intrathecal morphine to reduce the incidence of pruritis while maintaining effective analgesia for women after cesarean birth.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

TRPA1 deficiency alleviates inflammation of atopic dermatitis by reducing macrophage infiltration.

AIMS: The aim of this study was to investigate the role of TRPA1 in the pathogenesis of AD. MAIN METHODS: The experimental atopic dermatitis (AD)-like skin lesions were established using 2,4-dinitrochlorobenzene (DNCB). Mice were divided into three groups: TRPA1-/- and WT groups were treated with DNCB dissolved in a 3:1 mixture of acetone and olive oil; the negative control group was treated with 3:1 mixture of acetone and olive oil without DNCB. The treatment lasted for 21 days, after which the animals were sacrificed and their blood, ears and dorsal skin tissue samples were collected for analysis. KEY FINDINGS: Lower dermatitis score, ear thickness, pruritus score, and epidermal hyperplasia were observed in mice in TRPA1-/- mice compared to the WT group. Besides, lower dermal mast cell infiltration, proinflammatory cytokines, Th2 cytokines and the infiltration of macrophages were observed in the TRPA1-/- mice compared to the WT group. Furthermore, we demonstrated that TRPA1 antagonist HC-030031 could alleviate AD-like symptoms and reduce the degree of epidermal hyperplasia in mice. SIGNIFICANCE: TRPA1 has a crucial role during the AD pathogenesis in mice, thus may be used as a potential new target for treating patients with chronic skin inflammatory disease.

The Effect of Ultra-low-dose Intrathecal Naloxone on Pain Intensity After Lumbar Laminectomy With Spinal Fusion: A Randomized Controlled Trial.

BACKGROUND: Despite advances in pain management, several patients continue to experience severe acute pain after lumbar spine surgery. The aim of this study was to assess the safety and effectiveness of single ultra-low-dose intrathecal (IT) naloxone in combination with IT morphine for reducing pain intensity, pruritus, nausea, and vomiting in patients undergoing lumbar laminectomy with spinal fusion. MATERIALS AND METHODS: In this double-blind trial, patients scheduled for lumbar laminectomy with spinal fusion were randomly assigned to receive single ultra-low-dose IT naloxone (20 µg) and IT morphine (0.2 mg) (group M+N) or IT morphine (0.2 mg) alone (group M). The severity of postoperative pain, pruritus and nausea, and frequency of vomiting were assessed at recovery from anesthesia and, subsequently, at 1, 3, 6, 12, and 24 hours postoperatively using an 11-point (0-10) visual analogue scale. RESULTS: A total of 77 patients completed the study, and there were significant differences in postoperative pain, pruritus, and nausea visual analogue scale between the groups (P<0.05). After adjusting for body mass index and surgery duration, IT naloxone administration reduced the pain score (coefficient=1.84; 95% confidence interval [CI], 1.05-2.63; P<0.001), and the scores of pruritus and nausea (coefficient=0.9; 95% CI, 0.44-1.37; P<0.001 and coefficient=0.71; 95% CI, 0.12-1.31; P=0.02, respectively) compared with IT morphine alone. No serious adverse effects were observed. CONCLUSIONS: The addition of ultra-low-dose IT naloxone to IT morphine provides excellent postoperative pain management and effectively controls pruritus and nausea in patients undergoing laminectomy with spinal fusion.

Sub-hypnotic dose of propofol as antiemetic prophylaxis attenuates intrathecal morphine-induced postoperative nausea and vomiting, and pruritus in parturient undergoing cesarean section - a randomized control trial.

BACKGROUND: Postoperative Nausea and Vomiting (PONV) is a dreadful and uncomfortable experience that significantly detracts patients' quality of life after surgery. This study aimed to examine the antiemetic effect of a single sub-hypnotic dose of propofol as prophylaxis for PONV. METHOD: In this prospective, double-blind, randomized control trial, 345 parturients presented for elective cesarean section at the Obstetric unit of Tamale Teaching Hospital were recruited. Each recruited parturient was randomly assigned to one of three groups; Propofol group (n = 115) represented those who received propofol 0.5 mg/kg, Metoclopramide group (n = 115) represented those who received metoclopramide 10 mg and, Control group (n = 115) represented those who received 0.9% saline. Spinal anesthesia with 0.5% hyperbaric bupivacaine 7.5-10 mg, and intrathecal morphine 0.2 mg was employed for the anesthesia. RESULTS: The data indicate that 108 (93.9%) parturients from the control group, 10 (8.7%) from the propofol group and 8 (7.0%) from the metoclopramide group experienced some incidence of PONV. There was no significant difference in the incidence of PONV (nausea, vomiting, and none) between the propofol and the metoclopramide groups (P = 0.99; 0.31; and 0.35 respectively). Parturients who received antiemetic agents were 105 (97.2%), 1 (10.0%) and 3 (37.5%) from the control, propofol and metoclopramide groups respectively. The data indicated that 98 (85.2%) parturients from the control, 3 (2.6%) from propofol group, and 100 (87.0%) from the metoclopramide group experienced some levels of pruritus. There was a significant difference in the incidence of pruritus (mild, moderate, and no pruritus) between the metoclopramide and propofol groups (P <  0.01; P <  0.01; and P <  0.01 respectively). CONCLUSION: A sub-hypnotic dose of propofol is effective as metoclopramide in the prevention of PONV in parturient undergoing cesarean section under spinal anesthesia with intrathecal morphine. Sub-hypnotic dose of propofol significantly reduces the incidence of postoperative pruritus following intrathecal morphine use. TRIAL REGISTRATION: Current control trial, registered at ISRCTN trial registry: ISRCTN15475205 . Date registered: 03/04/2019. Retrospectively registered.

Lifestyle changes for treating psoriasis.

BACKGROUND: Psoriasis is an inflammatory skin disease that presents with itching, red, scaling plaques; its worsening has been associated with obesity, drinking, smoking, lack of sleep, and a sedentary lifestyle. Lifestyle changes may improve psoriasis. OBJECTIVES: To assess the effects of lifestyle changes for psoriasis, including weight reduction, alcohol abstinence, smoking cessation, dietary modification, exercise, and other lifestyle change interventions. SEARCH METHODS: We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched the China National Knowledge Infrastructure, the Airiti Library, and five trials registers up to July 2018. We checked the references of included trials for further relevant trials, and we asked the authors of the included trials if they were aware of any relevant unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of lifestyle changes (either alone or in combination) for treating psoriasis in people diagnosed by a healthcare professional. Treatment had to be given for at least 12 weeks. Eligible comparisons were no lifestyle changes or another active intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome measures were 'Severity of psoriasis' and 'Adherence to the intervention'. Secondary outcomes were 'Quality of life', 'Time to relapse', and 'Reduction in comorbidities'. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: We included 10 RCTs with 1163 participants (mean age: 43 to 61 years; 656 men and 478 women were reported). Six trials examined the effects of dietary intervention (low-calorie diet) in 499 obese participants (mean age: 44.3 to 61 years; where reported, 395 had moderate-to-severe psoriasis). One trial assessed a combined dietary intervention and exercise programme in 303 obese participants with moderate-to-severe psoriasis who had started a systemic therapy for psoriasis and had not achieved clearance after four weeks of continuous treatment (median age: 53 years). Another trial assessed a walking exercise and continuous health education in 200 participants (mean age: 43.1 years, severity not reported). Finally, two trials included education programmes promoting a healthy lifestyle in 161 participants (aged 18 to 78 years), with one trial on mild psoriasis and the other trial not reporting severity.Comparisons included information only; no intervention; medical therapy alone; and usual care (such as continuing healthy eating).All trials were conducted in hospitals and treated participants for between 12 weeks and three years. One trial did not report the treatment period. Seven trials measured the outcomes at the end of treatment and there was no additional follow-up. In two trials, there was follow-up after the treatment ended. Five trials had a high risk of performance bias, and four trials had a high risk of attrition bias.We found no trials assessing interventions for alcohol abstinence or smoking cessation. No trials assessed time to relapse. Only two trials assessed adverse events; in one trial these were caused by the add-on therapy ciclosporin (given in both groups). The trial comparing two dietary interventions to a no-treatment group observed no adverse events.The results presented in this abstract are based on trials of obese participants.Outcomes for dietary interventions versus usual care were measured 24 weeks to six months from baseline. Compared to usual care, dietary intervention (strict caloric restriction) may lead to 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.07 to 2.58; 2 trials, 323 participants; low-quality evidence). Adherence to the intervention may be greater with the dietary intervention than usual care, but the 95% CI indicates that the dietary intervention might also make little or no difference (RR 1.26, 95% CI 0.76 to 2.09; 2 trials, 105 participants; low-quality evidence). Dietary intervention probably achieves a greater improvement in dermatology quality-of-life index (DLQI) score compared to usual care (MD -12.20, 95% CI -13.92 to -10.48; 1 trial, 36 participants; moderate-quality evidence), and probably reduces the BMI compared to usual care (MD -4.65, 95% CI -5.93 to -3.36; 2 trials, 78 participants; moderate-quality evidence).Outcomes for dietary interventions plus exercise programme were measured 16 weeks from baseline and are based on one trial (303 participants). Compared to information only (on reducing weight to improve psoriasis), combined dietary intervention and exercise programme (dietetic plan and physical activities) probably improves psoriasis severity, but the 95% CI indicates that the intervention might make little or no difference (PASI 75: RR 1.28, 95% CI 0.83 to 1.98). This combined intervention probably results in a greater reduction in BMI (median change -1.10 kg/m², P = 0.002), but there is probably no difference in adherence (RR 0.95, 95% CI 0.89 to 1.01; 137/151 and 145/152 participants adhered in the treatment and control group, respectively). There were no data on quality of life. These outcomes are based on moderate-quality evidence. AUTHORS' CONCLUSIONS: Dietary intervention may reduce the severity of psoriasis (low-quality evidence) and probably improves quality of life and reduces BMI (moderate-quality evidence) in obese people when compared with usual care, while combined dietary intervention and exercise programme probably improves psoriasis severity and BMI when compared with information only (moderate-quality evidence). None of the trials measured quality of life.We did not detect a clear difference in treatment adherence between those in the combined dietary intervention and exercise programme group and those given information only (moderate-quality evidence). Adherence may be improved through dietary intervention compared with usual care (low-quality evidence). Participants generally adhered well to the lifestyle interventions assessed in the review.No trials assessed the time to relapse. Trial limitations included unblinded participants and high dropout rate.Future trials should reduce dropouts and include comprehensive outcome measures; they should examine whether dietary intervention with or without an exercise programme is effective in non-obese people with psoriasis, whether an additional exercise programme is more effective than dietary intervention alone, whether the time to relapse prolongs in people who receive dietary intervention with or without exercise programme, and whether smoking cessation and alcohol abstinence are effective in treating psoriasis.

Effect of S-adenosyl-L-methionine on liver biochemistry and quality of life in patients with primary biliary cholangitis treated with ursodeoxycholic acid. A prospective, open label pilot study.

BACKGROUND AND AIMS: Chronic liver disease induces an acquired deficiency of S-adenosyl-L-methionine (SAMe) leading to impairment of detoxifying processes in the liver. Ursodeoxycholic acid (UDCA) represents the standard treatment in primary biliary cholangitis (PBC). As both compounds exert their hepatoprotective effects by different mechanisms, it is conceivable that when used together their effect might be additive. The aim of this study was to analyse the effect of SAMe supplementation on liver biochemistry and health-related quality of life (HRQoL) in patients with PBC, treated with UDCA. METHODS: In this prospective pilot, proof of the principle, non-randomized and open label study we enrolled 24 patients with PBC treated with UDCA for at least 6 months. They had received both UDCA in a standard dose of 13-15 mg/kg b.w. and SAMe in the dose of 1200 mg daily over a period of 6 months. A group of 24 patients with PBC treated with UDCA served as control for liver biochemistry (Study registered on the platform ClinicalTrials.gov under ID: NCT02557360). RESULTS: We observed a significant decrease of ALP, GGT and total cholesterol in non-cirrhotic patients treated with SAMe. There was also a significant improvement of fatigue and pruritus in PBC-40 questionnaire and amelioration of anxiety in STAI 2 questionnaire in the SAMe group. Treatment with SAMe neither increased sulfation capacity of the liver nor had an effect on fibroblast growth factor-19 serum levels. CONCLUSIONS: Our pilot study demonstrates a positive effect of adding SAMe to UDCA in non-cirrhotic patients with PBC.

Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Epigallocatechin-3-gallate attenuates acute and chronic psoriatic itch in mice: Involvement of antioxidant, anti-inflammatory effects and suppression of ERK and Akt signaling pathways.

Chronic itch is a distressing symptom of many skin diseases and negatively impacts quality of life. However, there is no medication for most forms of chronic itch, although antihistamines are often used for anti-itch treatment. Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, exhibits anti-oxidative and anti-inflammatory properties. Our previous studies highlighted a key role of oxidative stress and proinflammatory cytokines in acute and chronic itch. Here, we evaluated the effects of green tea polyphenon 60 and EGCG on acute and chronic itch in mouse models and explored its potential mechanisms. The effects of EGCG were determined by behavioral tests in mouse models of acute and chronic itch, which were induced by compound 48/80, chloroquine (CQ), and 5% imiquimod cream treatment, respectively. We found that systemic or local administration of green tea polyphenon 60 or EGCG significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner in mice. Incubation of EGCG significantly decreased the accumulation of intracellular reactive oxygen species (ROS) directly induced by compound 48/80 and CQ in cultured ND7-23 cells, a dorsal root ganglia derived cell line. EGCG also attenuated imiquimod-induced chronic psoriatic itch behaviors and skin epidermal hyperplasia in mice. In addition, EGCG inhibited the expression of IL-23 mRNA in skin and TRPV1 mRNA in dorsal root ganglia (DRG). Finally, EGCG remarkably inhibited compound 48/80-induced phosphorylation of extracellular signal-regulated kinase (ERK) and imiquimod-induced p-AKT in the spinal cord of mice, respectively. Collectively, these results indicated EGCG could be a promising strategy for anti-itch therapy.

Efficacy of intravenous lidocaine on pain relief in patients undergoing laparoscopic cholecystectomy: A meta-analysis from randomized controlled trials.

OBJECTIVE: Whether intravenous lidocaine has a beneficial role in controlling acute pain after a laparoscopic cholecystectomy (LC) in currently unknown. We performed a meta-analysis from randomized controlled trials (RCTs) to determine the efficacy and safety of intravenous lidocaine for the treatment of acute postoperative pain after LC. METHODS: In November 2017, a systematic search was performed in PubMed, EMBASE, Web of Science, ScienceDirect, and the Cochrane Library. RCTs comparing lidocaine and placebo in patients undergoing LC were retrieved. The primary endpoint was the visual analogue scale (VAS) score and opioid requirements at 12 h, 24 h and 48 h. The secondary endpoint was the length of hospital stay and opioid-related adverse effect. Stata 12.0 was used for the data analysis. RESULTS: Finally, six RCTs were included in the meta-analysis. Results indicated that intravenous lidocaine was associated with reduced pain scores and cumulative opioid consumption at 12 h, 24 h, and 48 h following a LC. Similarly, lidocaine was associated with a reduction in the incidence of nausea and vomiting, ileus and pruritus. CONCLUSION: Intravenous use of lidocaine was able to reduce acute postoperative pain, total opioid requirements and opioid-related adverse effects following a LC. Further studies should determine whether lidocaine has a positive role in improving the postoperative function after a LC.

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7.

Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other NaV family members, including NaV1.4 expressed in muscle and NaV1.5 expressed in the heart, as well as TTX-resistant NaV channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple NaV1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective NaV1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.

Preliminary evaluation of cytosine-phosphate-guanine oligodeoxynucleotides bound to gelatine nanoparticles as immunotherapy for canine atopic dermatitis.

Cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN) are a promising new immunotherapeutic treatment option for canine atopic dermatitis (AD). The aim of this uncontrolled pilot study was to evaluate clinical and immunological effects of gelatine nanoparticle (GNP)-bound CpG ODN (CpG GNP) on atopic dogs. Eighteen dogs with AD were treated for 8 weeks (group 1, n=8) or 18 weeks (group 2, n=10). Before inclusion and after 2 weeks, 4 weeks, 6 weeks (group 1+2), 8 weeks, 12 weeks and 16 weeks (group 2) 75 µg CpG ODN/dog (bound to 1.5 mg GNP) were injected subcutaneously. Pruritus was evaluated daily by the owner. Lesions were evaluated and serum concentrations and mRNA expressions of interferon-γ, tumour necrosis factor-α, transforming growth factor-ß, interleukin (IL) 10 and IL-4 (only mRNA expression) were determined at inclusion and after 8 weeks (group 1+2) and 18 weeks (group 2). Lesions and pruritus improved significantly from baseline to week 8. Mean improvements from baseline to week 18 were 23 per cent and 44 per cent for lesions and pruritus, respectively, an improvement of ≥50 per cent was seen in six out of nine and three out of six dogs, respectively. IL-4 mRNA expression decreased significantly. The results of this study show a clinical improvement of canine AD with CpG GNP comparable to allergen immunotherapy. Controlled studies are needed to confirm these findings.

Randomized clinical trial of autologous skin cell suspension for accelerating re-epithelialization of split-thickness donor sites.

BACKGROUND: Split-thickness skin graft (STSG) is used frequently, but may result in complications at the donor site. Rapid healing of donor-site wounds is critical to relieving morbidity. This study investigated whether autologous skin cell suspension could improve healing of STSG donor-site wounds. METHODS: Between September 2014 and February 2016, patients requiring STSGs were randomized to receive autologous skin cell suspension plus hydrocolloid dressings (experimental group) or hydrocolloid dressings alone (control group) for the donor site. The primary outcome was time to complete re-epithelialization. Secondary outcomes included pain and itching scores measured on a visual analogue scale, and adverse events. Patients were followed for 12 weeks to evaluate quality of healing. Analysis was by intention to treat. RESULTS: Some 106 patients were included, 53 in each group. Median time to complete re-epithelialization was 9·0 (95 per cent c.i. 8·3 to 9·7) days in the experimental group, compared with 13·0 (12·4 to 13·6) days in the control group (P < 0·001). Overall postoperative pain and itching scores were similar in both groups. No between-group differences in treatment-related complications were observed. Both patients and observers were more satisfied with healing quality after autologous skin cell suspension had been used. CONCLUSION: The use of autologous skin cell suspension with hydrocolloid dressings accelerated epithelialization and improved healing quality of the donor site compared with hydrocolloid dressings alone. Registration number: UMIN000015000 ( http://www.umin.ac.jp/ctr).

Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), and MEDLINE (OVID) up to 9 June 2016 and Embase (OVID) up to 7 June 2016. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 10 'Summary of findings' tables. MAIN RESULTS: In total, we included 50 studies and 1916 participants in the review. We added 10 studies with 627 participants for this update. Altogether, we included 39 different treatments for pruritus in four different patient groups.The overall risk of bias profile was heterogeneous and ranged from high to low risk. However, 48 studies (96%) had a high risk of bias due to low sample size (i.e. fewer than 50 participants per treatment arm). Using GRADE criteria, we downgraded our judgement on the quality of evidence to moderate in seven and to low in three comparisons for our primary outcome (pruritus), mainly due to imprecision and risk of bias.In palliative care participants with pruritus of different nature, the treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, reduced pruritus by 0.78 points (numerical analogue scale from 0 to 10; 95% confidence interval (CI) -1.19 to -0.37; one RCT, N = 48, quality of evidence: moderate) compared to placebo.For participants suffering from uraemic pruritus (UP), gabapentin was more effective than placebo (visual analogue scale (VAS): 0 to 10), mean difference (MD) -5.91, 95% CI -6.87 to -4.96; two RCTs, N = 118, quality of evidence: moderate). The κ-opioid receptor agonist nalfurafine showed amelioration of UP (VAS 0 to 10, MD -0.95, 95% CI -1.32 to -0.58; three RCTs, N = 422, quality of evidence: moderate) and only few adverse events. Moreover, cromolyn sodium relieved UP participants from pruritus by 2.94 points on the VAS (0 to 10) (95% CI -4.04 to -1.83; two RCTs, N = 100, quality of evidence: moderate) compared to placebo.In participants with cholestatic pruritus (CP), data favoured rifampin (VAS: 0 to 100, MD -24.64, 95% CI -31.08 to -18.21; two RCTs, N = 42, quality of evidence: low) and flumecinol (RR > 1 favours treatment group; RR 1.89, 95% CI 1.05 to 3.39; two RCTs, N = 69, quality of evidence: low) and showed a low incidence of adverse events in comparison with placebo. The opioid antagonist naltrexone reduced pruritus for participants with CP (VAS: 0 to 10, MD -2.26, 95% CI -3.19 to -1.33; two RCTs, N = 52, quality of evidence: moderate) compared to placebo. However, effects in participants with UP were inconclusive (percentage difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). Furthermore, large doses of opioid antagonists (e.g. naltrexone) could be inappropriate in palliative care patients because of the risk of reducing analgesia.For participants with HIV-associated pruritus, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the evidence was of very low quality (e.g. small sample size, lack of blinding). AUTHORS' CONCLUSIONS: Different interventions tended to be effective for CP and UP. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome.

BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.

Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders.

OBJECTIVE: Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching. METHODS: A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3ß-hydroxy-C27-steroid-oxidoreductase [n = 7] and Δ-3-oxosteroid-5ß-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle. RESULTS: Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean ±â€Šstandard deviation: 16.1 ±â€Š4.3 nmol ·â€ŠmL ·â€Šmin) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 ±â€Š4.7 nmol ·â€ŠmL ·â€Šmin; P < 0.01) and healthy controls (7.6 ±â€Š2.3 nmol ·â€ŠmL ·â€Šmin; P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P < 0.001 and r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X-receptor ligands. CONCLUSIONS: Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders.

Prophylactic Ondansetron for the Prevention of Intrathecal Fentanyl- or Sufentanil-Mediated Pruritus: A Meta-Analysis of Randomized Trials.

BACKGROUND: Pruritus is a common side effect of intrathecal fentanyl or sufentanil that decreases patient satisfaction and may delay hospital discharge. There are conflicting reports about the efficacy of prophylactic ondansetron in reducing the incidence of pruritus. This meta-analysis aimed to assess the effect of prophylactic ondansetron on the incidence of intrathecal fentanyl- or sufentanil-mediated pruritus and the need for rescue treatment. METHODS: A systematic search on PubMed, Medline, and the Cochrane Central Register of Controlled Trials from January 1, 1994, to January 1, 2014, was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Randomized controlled trials evaluating the efficacy of prophylactic ondansetron on pruritus associated with intrathecal fentanyl or sufentanil were included. The primary outcome was the incidence of pruritus, and the secondary outcome was patients' need for rescue therapy. Sensitivity analyses were conducted to assess the outcomes in obstetric and nonobstetric patients and in patients who received ondansetron before or after intrathecal opioid injection. Analyses used random-effect models. RESULTS: Six randomized controlled trials involving 555 patients were included. In the overall analysis, prophylactic ondansetron did not significantly decrease the incidence of pruritus, but there was a trend toward reduced rescue medication use (risk ratio [RR], 0.57; 95% confidence interval [CI], 0.35-0.91; I = 0%; P = 0.02). Exploratory subgroups, including nonobstetric surgery patients and patients who received ondansetron before spinal opioid administration, also suggest a trend toward less rescue medication use (RR, 0.47; 95% CI, 0.26-0.85; P = 0.01; and RR, 0.62; 95% CI, 0.38-1.00; P = 0.05). CONCLUSIONS: IV 8 mg prophylactic ondansetron does not decrease the incidence of fentanyl- or sufentanil-mediated pruritus but may decrease the need for pruritus rescue medication, particularly in specific subgroups. Randomized trials are needed to confirm these results.

A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain.

We searched MEDLINE, Embase, CINAHL, AMED and CENTRAL databases until December 2014 and included 133 randomised controlled trials of peri-operative gabapentin vs placebo. Gabapentin reduced mean (95% CI) 24-h morphine-equivalent consumption by 8.44 (7.26-9.62) mg, p < 0.001, whereas more specific reductions in morphine equivalents were predicted (R(2)  = 90%, p < 0.001) by the meta-regression equation: 3.73 + (-0.378 × control morphine consumption (mg)) + (-0.0023 × gabapentin dose (mg)) + (-1.917 × anaesthetic type), where 'anaesthetic type' is '1' for general anaesthesia and '0' for spinal anaesthesia. The type of surgery was not independently associated with gabapentin effect. Gabapentin reduced postoperative pain scores on a 10-point scale at 1 h, 2 h, 6 h, 12 h and 24 h by a mean (95% CI) of: 1.68 (1.35-2.01); 1.21 (0.88-1.55); 1.28 (0.98-1.57); 1.12 (0.91-1.33); and 0.71 (0.56-0.87), respectively, p < 0.001 for all. The risk ratios (95% CI) for postoperative nausea, vomiting, pruritus and sedation with gabapentin were: 0.78 (0.69-0.87), 0.67 (0.59-0.76), 0.64 (0.51-0.80) and 1.18 (1.09-1.28), respectively, p < 0.001 for all. Gabapentin reduced pre-operative anxiety and increased patient satisfaction on a 10-point scale by a mean (95% CI) of 1.52 (0.78-2.26) points and 0.89 (0.22-1.57) points, p < 0.001 and p = 0.01, respectively. All the effects of gabapentin may have been overestimated by statistically significant small study effects.