MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both Gq-mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse.

PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.

Atopic Dermatitis in Children.

Atopic dermatitis (AD) is extremely common in the pediatric population, and most children with AD will first present to their primary care provider (PCP). The PCP can recognize AD by its clinical features, including itch, a chronic relapsing course, and the characteristic eruption. The cornerstone of AD therapy is dry skin care, typically a short daily bath/shower followed by an emollient applied to all skin. Most children with AD will also require topical medications, such as topical corticosteroids and/or topical nonsteroidal therapies. For children with more severe disease, systemic agents, including several novel therapies, may be required. In managing AD, the clinician must monitor for side effects of medications as well as complications of the AD itself, the most common of which is secondary infection. An understanding of the pathogenesis, treatments, and complications of AD is essential for the PCP, as untreated (or undertreated) AD has a significant impact on the quality of life of affected children and their caregivers. [Pediatr Ann. 2024;53(4):e121-e128.].

Spinal Glycine Receptor Alpha 3 Cells Communicate Sensations of Chemical Itch in Hairy Skin.

Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, but the identity and role of the glycine-regulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 (Glra3) subunit-expressing neurons in Glra3-Cre female and male mice. Glra3-Cre(+) neurons express Glra3, are located mainly in laminae III-VI, and respond to glycine. Chemogenetic activation of spinal Glra3-Cre(+) neurons induced biting/licking, stomping, and guarding behaviors, indicative of both a nociceptive and pruriceptive role for this population. Chemogenetic inhibition did not affect mechanical or thermal responses but reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for these neurons. Spinal cells activated by compound 48/80 or chloroquine express Glra3, further supporting the phenotype. Retrograde tracing revealed that spinal Glra3-Cre(+) neurons receive input from afferents associated with pain and itch, and dorsal root stimulation validated the monosynaptic input. In conclusion, these results show that spinal Glra3(+) neurons contribute to acute communication of compound 48/80- and chloroquine-induced itch in hairy skin.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Neutrophil-derived oxidative stress contributes to skin inflammation and scratching in a mouse model of allergic contact dermatitis via triggering pro-inflammatory cytokine and pruritogen production in skin.

Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1ß and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.

An insular cortical circuit required for itch sensation and aversion.

Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC â†’ dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.

Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis.

Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study.

BACKGROUND: Itch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study. RESULTS: We successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4. CONCLUSIONS: Our findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.

Is epidural analgesia non-inferior to intrathecal fentanyl as initiation for neuraxial analgesia in early non-spontaneous labour?

BACKGROUND AND AIM: Intrathecal fentanyl, using the combined spinal-epidural (CSE) technique, provides rapid analgesia during early labour. Because of the technique's more complex and invasive nature, as its replacement we assessed the use of epidural analgesia in primiparous parturients with induced labour. The study was registered at www. CLINICALTRIALS: gov (NCT04645823). The aim was to compare the efficacy, duration of analgesia and maternal satisfaction. The primary outcome was the difference in pain visual analogue scale (VAS) between the interventions at 20 min after the analgesia administration. METHODS: Sixty volunteering parturients were randomly allocated in 1:1 ratio to receive either intrathecal fentanyl 20 µg or epidural analgesia (fentanyl 100 µg and lidocaine 80 mg). Contraction pain and maternal satisfaction were assessed by 0-100 mm VAS for 30 min, respectively. Foetal heart rate abnormalities, the time to first epidural dose and the incidence of pruritus were recorded. Non-inferiority margin for mean (95% CI) VAS after epidural analgesia was set at 20 mm above the VAS value for intrathecal fentanyl at 20 min. RESULTS: The contraction pain VAS fell from (median [interquartile range, IQR]) 82 (14) to 13 (20) mm and 76 (17) to 12 (27) mm in 20 min following the intrathecal fentanyl and epidural analgesia, respectively. The absolute mean difference (epidural-intrathecal fentanyl) in the VAS values was 3.3(-0.06 to 6.66) mm indicating non-inferiority. The median time to reach VAS <30 mm was 10 min in both groups. The duration until request for supplemental analgesia was 82(69-95) and 91(75-106) min after intrathecal fentanyl and epidural analgesia, respectively. The difference for the duration (epidural-intrathecal fentanyl) was 9 (6-12) min and for satisfaction-VAS 0.3 (-3.0 to 3.7) mm. There were no differences between the groups in the incidence of foetal heart rate abnormalities, while pruritus was more common after intrathecal fentanyl. CONCLUSION: After 20 min, epidural analgesia by lidocaine and fentanyl was within the non-inferior threshold compared with intrathecal fentanyl in efficacy. The duration of action was not shorter than that of intrathecal fentanyl and maternal satisfaction was also similar.

Halobetasol Propionate 0.01% and Tazarotene 0.045% Lotion With a Ceramide-Containing Moisturizer in Adults With Psoriasis.

INTRODUCTION: Moisturizers are often used as adjuvant therapy for psoriasis to assist with rehydration and skin barrier restoration. Fixed-combination halobetasol propionate 0.01% and tazarotene 0.045% lotion (HP/TAZ) is indicated for the topical treatment of plaque psoriasis in adults, with a demonstrated clinical profile in two phase 3 trials. However, the effect of application order with HP/TAZ has yet to be explored. This study evaluated the clinical profile of HP/TAZ applied before versus after a ceramide-containing moisturizer in adults with mild-to-moderate plaque psoriasis. METHODS: Sixteen participants were randomized to apply HP/TAZ followed by moisturizer on one side and moisturizer followed by HP/TAZ on the other side once daily for 12 weeks. Tolerability, safety, efficacy, and quality of life endpoints were assessed.  Results: Significant Investigator's Global Assessment improvement was observed across all time points (P≤0.003) regardless of application order. Total Dermatology Life Quality Index scores significantly improved at all time points (P≤0.003), and visual analog scale for itch significantly improved at weeks 4, 8, and 12 (P<0.008). Four moderate adverse events were experienced by 3 participants. Two participants reported itching/irritation, which was worse when HP/TAZ was applied first. CONCLUSIONS: The application order of moisturizer did not decrease therapeutic efficacy of HP/TAZ. Moisturizer application before HP/TAZ may reduce incidence of application site adverse events, ultimately increasing tolerability and supporting the real-world recommendation that applying a ceramide-containing moisturizer before HP/TAZ, versus after, results in a safe and effective therapeutic option for plaque psoriasis. J Drugs Dermatol. 2024;23(2):50-53.     doi:10.36849/JDD.7928.

Different doses of nalmefene combined with hydromorphone hydrochloride for postoperative analgesia after colorectal surgery: a randomized controlled study.

BACKGROUND: Hydromorphone hydrochloride has a satisfactory postoperative analgesic effect for patients with colorectal cancer but is accompanied by a relatively high incidence of adverse events. Low-doses of naloxone combined with opioids for patient-controlled analgesia can reduce the incidence of drug-related adverse events. Nalmefene is a more selective opioid receptor antagonist than naloxone. The aim of this study was to determine the impact of low-doses of nalmefene on the analgesic effect and incidence of adverse events of patients with hydromorphone patient-controlled analgesia (PCA) undergoing colorectal radical surgery. METHODS: Ninety-nine patients undergoing elective laparoscopic or hand-assisted laparoscopic radical surgery under general anaesthesia were randomly divided into three groups. Group N1 received hydromorphone hydrochloride 0.15 mg/kg + nalmefene 2 µg/kg; Group N2 received hydromorphone hydrochloride 0.15 mg/kg + nalmefene 0.5 µg/kg; and the control group (Group C) received hydromorphone hydrochloride 0.15 mg/kg. All medications were diluted to 100 ml with normal saline. The primary outcome was pain intensity at 12 h after surgery; the secondary outcomes were the occurrence of nausea, vomiting and pruritus and the total analgesic consumption of the PCA pump at 1 h, 6 h, 12 h, 24 and 48 h after surgery. RESULTS: The NRS scores of Group N1 (2 µg/kg) were significantly lower than those of Group C (P = 0.025), and no difference was found between group N2 and group C (P > 0.05). Among the three groups, the NRS scores of Group N1 (2 µg/kg) were significantly lower than those of Group C at 12 h (P = 0.01) and 48 h (P = 0.01) postoperatively. Compared with 12 h postoperatively, the NRS scores were lower at 24 h postoperatively in Group N1 and Group C (P < 0.05) and significantly lower at 48 h postoperatively in all three groups (P < 0.001). There was a significant difference in the incidence of pruritus among the three groups (P = 0.036). CONCLUSIONS: Nalmefene at a dosage of 2 µg/kg enhances the postoperative analgesic effect of hydromorphone hydrochloride and reduces the occurrence of postoperative pruritus. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2000033520, date: 03/06/2020).

[Clinical and pathological analysis of 345 cases of vulvar lichen sclerosus and a preliminary study on the frequency of maintenance treatment].

Objective: To analyze and summarize the clinical and pathological characteristics, management, and efficacy of patients with vulvar lichen sclerosus (VLS) through a single center large sample study, and preliminarily to explore the frequency of maintenance treatment medication for VLS. Methods: The clinical data of VLS patients in Obstetrics and Gynecology Hospital of Fudan University from 2018 to 2021 were retrospectively collected. The clinicopathological characteristics (patients' age, course of disease, complicated disease history, family history, symptoms, signs and pathology), treatment and effects were retrospectively analyzed. The patients in the maintenance treatment stage were followed up regularly to explore the minimum frequency of individual medication to maintain the stability of the disease. Results: (1) General situation: a total of 345 patients with VLS were included in this study. The average age was (50.4±14.7) years (ranged from 8 to 84 years old), prevalence was highest in the 50-59 years group (30.1%, 104/345). Immune diseases occurred in 18.6% (33/177) of patients, 24.3% (43/177) of patients had allergic skin diseases, and 5.6% (10/177) of the patients' immediate family members had chronic vulvar pruritus or vulvar hypopigmentation. (2) Clinical features: the most common symptom was vulvar pruritus (96.1%, 196/204) among 204 patients with recorded symptoms. The most common sign was hypopigmentation of the vulva (96.3%, 206/214). The most common involved sites were labia minora (70.3%, 142/202), labia majora (67.8%, 137/202), and labial sulcus (59.4%, 120/202). The cumulative number of sites involved in 62 vulvar atrophy patients (2.7±1.1) was significantly higher than that in 152 non-atrophy patients (2.2±1.0; t=3.48, P=0.001). The course of vulvar atrophy was (9.3±8.5) years, which was significantly longer than that of non-atrophy patients [(6.6±5.6) years; t=2.04, P=0.046]. (3) Pathological features: among the 286 patients with electronic pathological sections, the most common pathological feature in the epidermis was epithelial nail process passivation (71.3%, 204/286). The common pathological features in the dermis were interstitial collagenization (84.6%, 242/286), and inflammatory cell infiltration (73.8%, 211/286). (4) Treatment: 177 patients received standardized treatment after diagnosis and were followed up regularly in our hospital. In the initial treatment stage, 26.0% (46/177) of the patients were treated with 0.05% clobetasol propionate cream, and 74.0% (131/177) of the patients were treated with 0.1% mometasone furoate ointment. The complete remission rates of the two methods were respectively 80.4% (37/46) and 74.0% (97/131), and there was no statistically significant difference (χ²=0.76, P=0.385). During maintenance treatment, 27.1% (48/177) of the patients took the medication twice a week, 35.0% (62/177) took the medication once a week, and 37.9% (67/177) took the medication once every 10 days. During follow-up after 6 months of maintenance treatment, there were no patients with recurrence of pruritus or progression of vulvar signs. Conclusions: The majority of VLS patients have itching, hypopigmentation, involvement of labia minora and labia majora, progressive atrophy, and inflammatory infiltration of dermis. Local treatments of mometasone furoate and clobetasol propionate have good initial therapeutic effects. The frequency exploration of individualized maintenance treatment could minimize the occurrence of adverse reactions when ensuring the stability of the patients' condition.

Efficacy and Safety of Tralokinumab in Real Life: Possible Predictive Rapid Response Factors.

Background: Tralokinumab has been recently approved for the management of moderate-to-severe atopic dermatitis (AD). Despite its effectiveness and safety have been widely reported, there are no studies investigating factors that may affect clinical outcomes. Objective: To evaluate the effectiveness and safety of tralokinumab, also to investigate possible predictive response factors that may affect the time of onset of treatment response. Methods: A monocentric retrospective real-life study was performed enrolling AD patients undergoing treatment with tralokinumab for at least 24 weeks. AD severity was assessed at baseline and at week (W)16, and W24. Similarly, treatment-related adverse events (AEs) were evaluated at each follow-up visit. Results: A total of 57 patients were enrolled. AD severity started to improve at W4, continued to improve at W16 and W24. In our cohort, we found out that gender, age, atopic comorbidities, and previous treatments did not affect treatment outcomes. However, we observed that patients with higher Pruritus-Numerical Rating Scale (≥8), relapsing form of AD, Eczema Area and Severity Index (EASI) ≤24, and Investigator Global Assessment (IGA) ≤3 achieved more frequently EASI75 response at W16. No significant AEs were collected. Conclusions: Our study confirmed the effectiveness and safety of tralokinumab. In particular, a higher pruritus, a relapsing course of the disease, a reduced EASI, a reduced IGA, and a brief duration of the disease seem to be associated with the fastest onset of treatment effectiveness.

Real-world experience of baricitinib in atopic dermatitis: including add-on therapy for patients using dupilumab.

BACKGROUND: Little real-world experience regarding the use of baricitinib, an oral selective JAK1/JAK2 inhibitor, for treating moderate to severe atopic dermatitis (AD) has been reported. METHODS: This study aimed to assess the overall outcomes in Korean patients with AD treated with baricitinib. All patients with moderate to severe AD treated with baricitinib between June 2021 and June 2022 were included, and their cases were retrospectively analyzed using medical records. Patients with moderate to severe AD, aged ≥18 years who had failed previous therapies, including those who demonstrated unsatisfactory improvement with dupilumab, were prescribed baricitinib. Patients whose follow-up period was <8 weeks were excluded. The dermatologist evaluated the AD status, including eczema area and severity index (EASI), itch Numeric Rating Scale, and improvement of remaining lesions despite dupilumab therapy. RESULTS: We analyzed 34 AD patients who received baricitinib. Twelve patients treated with dupilumab were additionally prescribed baricitinib due to unsatisfactory treatment effects and demonstrated improvement in the remaining lesions despite dupilumab treatment. Their itching improved after 1.4 weeks. Among them, eight patients (66.7%) had head and neck dermatitis, and seven of them demonstrated improvement after the coadministration of baricitinib. Among the other 22 patients who were prescribed baricitinib only, 10 patients (45.5%) achieved EASI 75 at 8 weeks, with five (22.7%) revealing EASI 90. CONCLUSIONS: Overall, baricitinib was well tolerated and resulted in clinical improvement in AD patients in a real-world clinical setting. Additionally, baricitinib may be beneficial in treating lesions refractory to dupilumab therapy.

Ondansetron for the Prevention of Pruritus in Women Undergoing Cesarean Delivery With Intrathecal Opioid: A Systematic Review and Meta-Analysis.

BACKGROUND: Pruritus is a frequently reported and unpleasant side effect following intrathecal opioid use with frequency further increased among parturients. We have performed a systematic review to assess the overall efficacy of ondansetron for the prevention of pruritus in patients receiving intrathecal opioid as part of spinal anesthesia for cesarean delivery. METHODS: A literature search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted from date of inception to September 2022. Studies that included patients undergoing cesarean delivery with spinal anesthesia using intrathecal opioid were included. The primary outcome was the presence of pruritus, and the secondary outcome was time to onset of pruritus. Data from included studies were pooled for analysis using an appropriately determined random-effects model. Outcomes were presented using forest plots and 95% confidence intervals. Additional sensitivity and subgroup analysis were performed. Trial sequential analysis was conducted for the primary outcome. RESULTS: Twenty-three randomized controlled trials with a total of 2586 patients were included: 1219 received ondansetron, 1030 received a placebo, and a further 337 received a different study drug and were excluded from analysis. Opioids used in the included studies were morphine, fentanyl, and sufentanil. Patients who received ondansetron showed a significant reduction in the incidence of pruritus compared to the control group (RR, 0.81; 95% confidence interval [CI], 0.71-0.92; I 2 = 64%). There was no significant difference in pruritus onset between the groups (mean difference [MD], 17.54 minutes; 95% CI, -2.18 to 37.26; I 2 = 83%). The overall Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment of quality of evidence was low. CONCLUSIONS: This systematic review has demonstrated a significant reduction in the incidence of pruritus following the use of ondansetron. This is in contrast to previously published meta-analyses. Studies included were of varying quality and some at high risk of bias with a high degree of statistical heterogeneity. Furthermore, high-quality and well-powered studies are required to confirm these findings.

Comparison of dexmedetomidine and opioids as local anesthetic adjuvants in patient controlled epidural analgesia: a meta-analysis.

BACKGROUND: Data on the efficacy and incidence of adverse effects associated with dexmedetomidine (DEX) as a local anesthetic adjuvant for patient-controlled epidural analgesia (PCEA) are inconclusive. This meta-analysis assessed the efficacy and risks of DEX for PCEA using opioids as a reference. METHODS: Two researchers independently searched PubMed, Embase, Cochrane Library, and China Biology Medicine for randomized controlled trials comparing DEX and opioids as local anesthetic adjuvants in PCEA. RESULTS: In total, 636 patients from seven studies were included in this meta-analysis. Postoperative patients who received DEX had lower visual analog scale (VAS) scores than those who received opioids at 4-8 h (mean difference [MD]: 0.61, 95% CI [0.45, 0.76], P < 0.001, I2 = 0%), 12 h (MD: 0.85, 95% CI [0.61, 1.09], P < 0.001, I2 = 0%), 24 h (MD: 0.59, 95% CI [0.06, 1.12], P = 0.030, I2 = 82%), and 48 h (MD: 0.54, 95% CI [0.05, 1.02], P = 0.030, I2 = 91%). Additionally, patients who received DEX had a lower incidence of itching (odds ratio [OR]: 2.86, 95% CI [1.18, 6.95], P = 0.020, I2 = 0%) and nausea and vomiting (OR: 6.83, 95% CI [3.63, 12.84], P < 0.001, I2 = 24%). In labor analgesia, no significant differences in neonatal (pH and PaO2 of cord blood, fetal heart rate) or maternal outcomes (duration of labor stage, mode of delivery) were found between the DEX and opioid groups. CONCLUSIONS: Compared with opioids, using DEX as a local anesthetic adjuvant in PCEA improved postoperative analgesia and reduced the incidence of itching and nausea and vomiting without increasing the incidence of adverse events.

The Influence of Dexmedetomidine as an Adjuvant in Intrathecal Labor Analgesia: A Multicenter Study on Efficacy and Maternal Satisfaction.

In this study, we examined the impact of dexmedetomidine (DEX) on the effectiveness of epidural analgesia and labor outcomes. We administered different doses of DEX combined with 0.1% ropivacaine for epidural analgesia to evaluate the clinical effects and safety. To assess the effects of different concentrations of DEX in parturient women receiving epidural analgesia, we conducted a randomized double-blind trial. We selected 400 parturient women and randomly assigned them to 4 groups, with 100 parturient women in each group: S0.1 (0.1 µg/mL DEX), S0.2 (0.2 µg/mL DEX), S0.3 (0.3 µg/mL DEX), and a control group (0.3 µg/mL sufentanil). Post-analgesia, we recorded the Bromage score, duration of labor, method of delivery, bleeding, neonatal Apgar score, adverse reactions, and maternal satisfaction. The number of patients with a Bromage score of ≥2 and the incidence of bradycardia were higher in the S0.3 group compared with the other 3 groups (P < .05), whereas the high satisfaction rate was lower in the S0.3 group (P < .05). Moreover, we found that the number of times that additional patient-controlled analgesia was administered was higher in the S0.1 group compared with the remaining 3 groups (P < .05). The control group exhibited a higher incidence of pruritus than the other 3 groups (P < .05). In conclusion, when administering spinal anesthesia for the relief of labor pain, epidural analgesia with 0.1% ropivacaine combined with 0.2 µg/mL DEX provides relatively ideal analgesic effects, higher maternal satisfaction, and reduces the incidence of pruritus, compared with the combination of 0.1% ropivacaine and 0.3 µg/mL sufentanil.

Electrical matrix stimulation suppresses acute itch independently of activation of sleeping nociceptors.

INTRODUCTION: Itch can be reduced by pain. Activation of sleeping nociceptors (CMi) is a crucial mechanism for the peripheral component of intense and long-lasting pain. Thus, activation of CMi might be especially effective in itch reduction. Electrical stimulation using sinusoidal pulses activates CMi with tolerable pain intensity, whereas short rectangular pulses with low intensity do not. In humans, histaminergic itch is mediated by histamine-sensitive CMi, whereas other pruritogens activate polymodal nociceptors (CM). METHODS: In a psychophysical approach in a balanced crossover repeated-measures design in healthy volunteers, we activated nociceptors by two different electrical stimulation paradigms via a matrix electrode: 4 Hz sinusoidal pulses that activate C-nociceptors including CMi or 4 Hz rectangular stimuli to activate nociceptors excluding CMi. After 5-min stimulation, itch was induced by either histamine iontophoresis or application of cowhage spicules. Itch ratings were assessed via a numerical rating scale (NRS). RESULTS: Electrical 4 Hz sine wave stimulation (0.1 mA) with low pain ratings of 1.5 (NRS; 0-10) induced an axon reflex erythema (3 cm2 ), indicating activation of CMi, whereas rectangular 0.2 ms pulses (average 0.91 mA) with the same pain rating did not. Both electrical stimulation paradigms reduced itch magnitude over time evoked by either histamine or cowhage to a similar extent. Peak maximum itch evoked by histamine was reduced by both stimulation paradigms, but not cowhage maximum itch. DISCUSSION: Since electrical stimulation with the rectangular pulse paradigm reduces itch to a similar extent as the sine wave stimulation paradigm, the input of CMi is not necessarily required for itch suppression. The input of A-fibres and polymodal nociceptors, similarly, as also achieved by scratching, seems to be sufficient for both forms of chemically evoked itch. SIGNIFICANCE: Since activation of CMi does not provide additional benefit for itch suppression, spinal pain pathways transmitted via CM versus CMi have differential effects on itch-processing circuits. This is important knowledge for using electrical matrix stimulation as itch suppressor since activation of sleeping nociceptors either requires significantly painful stimulation paradigms or specialized stimulation paradigms as sinusoidal pulses. An alternative approach using half-sine wave pulses with low pain intensity activating specifically polymodal nociceptors to suppress itch via matrix electrode stimulation may be considered.