Comparison of the analgesic effect of dezocine and esketamine in combination with sufentanil respectively after laparoscopic cholecystectomy: a prospective randomized controlled study.

BACKGROUND: Sufentanil in combination with dezocine or esketamine is often used for postoperative analgesia. However, there is a lack of clinical evidence of efficacy. This study compares the analgesic effects of esketamine and dezocine combined with sufentanil for relieving pain after laparoscopic cholecystectomy(LC). METHODS: A total of 58 patients were randomly assigned to the esketamine group (ES group) and dezocine group (DE group). In the ES group, 1.5 mg/kg esketamine was used. In the DE group, 0.3 mg/kg dezocine was used. Primary outcome measures were Visual Analog Scale (VAS) score at 4 h, 8 h, 24 h and 48 h after surgery. The second outcome measures were Interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the serum 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery. RESULTS: The VAS scores at 4 h, 8 h, 24 h and 48 h after the surgery in the ES group vs DE group were 2.70 vs 3.50(P=0.013),2.35 vs 3.15(P=0.004),1.69 vs 2.58(P=0.002), and 1.50 vs 2.26(P=0.002), respectively. The serum IL-6 concentrations 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery in the ES group and DE group were 34.39 and 34.12(P=0.901),112.33 and 129.60(P=0.014), and 89.69 and 108.46(P<0.001), respectively. The CRP levels in serum 10 minutes before anesthesia induction, and at 24 h and 48 h after the surgery in the ES group and DE group were 5.99 and 5.86(P=0.639), 28.80 and 35.37(P<0.001), and 23.17 and 30.11(P<0.001), respectively. CONCLUSION: For postoperative pain after LC, 1.5mg/kg esketamine provided better analgesia and reduced inflammation levels than 0.3mg/kg dezocine. TRIAL REGISTRATION: This trial was registered in the China Clinical Research Information Center in 31/05/2023 : https://www.chictr.org.cn/bin/home (Registration number: ChiCTR2300072011).

Analgesic effect of the ultrasound-guided thoracolumbar paravertebral block in patients undergoing robot-assisted laparoscopic nephrectomy: a randomized controlled trial.

BACKGROUND: Paravertebral block has similar effect as epidural anesthesia, and has good somatic and visceral analgesic effect. Paravertebral block is widely used in thoracic surgery, but rarely used in abdominal surgery. AIMS: This study aimed to evaluate the analgesic effect of thoracolumbar paravertebral block in patients undergoing robot-assisted laparoscopic nephrectomy. METHODS: One hundred patients undergoing elective robot-assisted laparoscopic nephrectomy were included in this study. Based on whether the thoracolumbar paravertebral block was performed, the patients were randomly divided into the thoracolumbar paravertebral block combined with general anesthesia group (TL-PVB group) and simple general anesthesia group (NO-PVB group). Oxycodone was administered for patient-controlled intravenous analgesia (PCIA). The primary outcomes included the amount of remifentanil used during surgery, the amount of oxycodone used in 24 and 48 h after surgery. Secondary outcomes included the changes of heart rate (HR) and mean arterial pressure (MAP), time for the first analgesia administration, visual analog score (VAS) of pain during rest and movement, and time of postoperative recovery. RESULTS: Compared to the NO-PVB group, the amount of remifentanil used during surgery in patients with TL-PVB group was significantly reduced (1.78 ± 0.37 mg vs. 3.09 ± 0.48 mg, p < 0.001), the amount of oxycodone used 24 h after surgery was significantly reduced (8.70 ± 1.70 mg vs. 13.79 ± 2.74 mg, p < 0.001), and the amount of oxycodone used 48 h after surgery was remarkably reduced (21.83 ± 4.28 mg vs. 27.27 ± 4.76 mg, p < 0.001). There were significant differences in the changes of HR and MAP between the two groups (p < 0.001). The first analgesic requirement time of TL-PVB group was significantly longer than that of NO-PVB group (468.56 ± 169.60 min vs. 113.48 ± 37.26 min, p < 0.001). The postoperative VAS during rest and movement of TL-PVB group were significantly lower than that of NO-PVB group (p < 0.01). Compared with NO-PVB group, patients in TL-PVB group needed shorter time to awaken from anesthesia, leave the operating room, anal exhaust, get out of bed, and had shorter length of postoperative hospital stay (p < 0.001). The incidence of postoperative adverse reactions were lower in the TL-PVB group than that in the NO-PVB group (p < 0.05). CONCLUSIONS: Ultrasound-guided thoracolumbar paravertebral block significantly reduces intraoperative and postoperative opioid consumption, and provides better analgesia in patients undergoing robot-assisted laparoscopic nephrectomy, which is a recommendable combined anesthesia technique. TRIAL REGISTRATION: ChiCTR2200061326, 21/06/2022.

Analgesic Effect and Sleep Quality of Low-Dose Dexmedetomidine in Cardiac Surgical Patients After Ultrafast-Track Extubation: A Randomized Clinical Trial.

OBJECTIVE: To compare the analgesic and sleep quality effects of dexmedetomidine infusion versus placebo in patients undergoing cardiac surgery with ultra-fast track extubation. DESIGN: The randomized, double-blind clinical trial study. SETTING: At a single academic center hospital. PARTICIPANTS: We included patients aged 25 to 65 scheduled for elective cardiac surgery under general anesthesia with cardiopulmonary bypass from October 2021 to December 2022. INTERVENTION: After immediate extubation in the operating room, the patients who were allocated at first after providing their consent to either the dexmedetomidine group (Dex) or the placebo group (Placebo) received continuous infusion of dexmedetomidine (0.2 µg/kg/h) or saline for 12 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: The groups' demographic and perioperative variables were not statistically significant. Total morphine consumption in milligrams at 12 and 24 hours after administered study drug, total sleep time in hours by BIS value ≤85, and sleep quality with the Richard-Campbell Sleep Questionnaire were compared. The analysis included 22 Dex and 23 Placebo patients. The consumption of morphine was not statistically different between the Dex and Placebo groups at 12 and 24 hours (p = 0.707 and p = 0.502, respectively). The Dex group had significantly longer sleep time (8.7 h [7.8, 9.5]) than the Placebo group (5.8 h [2.9, 8.5]; p = 0.007). The Dex group also exhibited better sleep quality (7.9 [6.7, 8.7] vs 6.6 [5.2, 8.0]; p = 0.038). CONCLUSIONS: Sedation with low-dose dexmedetomidine infusion for ultra-fast track extubation following cardiac surgery enhances sleep duration and quality.

Clinical and preclinical evidence on the bioeffects and movement-related implications of photobiomodulation in the orthodontic tooth movement: A systematic review.

Photobiomodulation (PBM) has been demonstrated as a non-invasive and painless technique with great potential to accelerate orthodontic tooth movement (OTM). However, there is a great inconsistency among PBM protocols and reported outcomes, probably due to the poor translatability of preclinical knowledge into early clinical practice. Hence, this review aims to fill this gap by establishing the state-of-the-art on both preclinical and clinical applications of PBM, and by comprehensively discussing the most suitable stimulation protocols described in the literature. This review was conducted according to PRISMA guidelines. A bibliographic search was carried out in the PubMed, Scopus and Cochrane databases using a combination of keywords. Only studies written in English were eligible and no time limit was applied. A total of 69 studies were selected for this review. The revised literature describes that PBM can effectively reduce orthodontic treatment time and produce analgesic and anti-inflammatory effects. We found that PBM of 640 ± 25, 830 ± 20 and 960 ± 20 nm, delivered at a minimum energy density per irradiation point of 5 J/cm2 daily or every other day sessions is robustly associated with increased tooth movement rate. Pain relief seems to be achieved with lower irradiation doses compared to those required for OTM acceleration. For the first time, the bioeffects induced by PBM for the acceleration of OTM are comprehensively discussed from a translational point of view. Collectively, the evidence from preclinical and clinical trials supports the use of PBM as a coadjuvant in orthodontics for enhancing tooth movement and managing treatment-associated discomfort. Overall, the revised studies indicate that optimal PBM parameters to stimulate tissue remodelling are wavelengths of 830 ± 20 nm and energy densities of 5-70 J/cm2 applied daily or every other day can maximize the OTM rate, while lower doses (up to 16 J/cm2 per session) delivered in non-consecutive days seem to be optimal for inducing analgesic effects. Future research should focus on optimizing laser parameters and treatment protocols customized for tooth and movement type. By fine-tuning laser parameters, clinicians can potentially reduce treatment times, improve patient comfort and achieve more predictable outcomes, making orthodontic care more efficient and patient-friendly, thus consolidating PBM usage in orthodontics.

Preoperative versus postoperative nonsteroidal anti-inflammatory drugs in femoroacetabular impingement patients undergoing hip arthroscopy surgery: analgesic effect, joint function, patients' satisfaction, and quality of life.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic effects on femoroacetabular impingement (FAI) patients undergoing hip arthroscopy surgery (HAS). However, the influence of medication time on the analgesic effect of NSAIDs is uncertain. This study aimed to compare the analgesic effect, joint function, quality of life (QoL), and patients' satisfaction between preoperative and postoperative NSAIDs in these patients. METHODS: In this prospective, observational study, 165 FAI patients undergoing HAS with NSAIDs (celecoxib, meloxicam, and nimesulide) for analgesia were divided into preoperative (PRE-A) and postoperative analgesia (POST-A) groups according to their actual medication. RESULTS: The visual analog scale (VAS) pain scores on the 1st (P < 0.001) and 3rd (D3) (P = 0.015) days after the operation were lower in the PRE-A group versus the POST-A group but not preoperatively (P = 0.262) or on the 7th day after the operation (D7) (P = 0.302). The proportion of patients receiving rescue analgesia decreased in the PRE-A group versus POST-A group (P = 0.041). However, the modified Harris hip score (mHHS), proportion of patients with an mHHS ≥ 70, and EuroQol-5-dimensional score at preoperative, 1st month (M1), and 3rd month (M3) after the operation were similar between the groups (all P > 0.050). The VAS score on D7 was greater in the PRE-A group compared to the POST-A group (P = 0.014), but the scores at M1 and M3 and the satisfaction and very satisfaction rates at D7, M1, and M3 did not differ between the groups (all P > 0.050). Subgroup analysis revealed that the type of NSAID did not affect most outcomes. CONCLUSION: Preoperative NSAIDs elevate analgesic effect and patients' satisfaction, but not joint function or QoL compared to postoperative NSAIDs in FAI patients undergoing HAS.

Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Comparison of analgesic effects between erector spinae and transversus abdominis plane blocks in patients undergoing laparoscopic cholecystectomy.

Objective: To compare the analgesic effects and incidence of postoperative adverse events after the erector spine plane (ESP) and transversus abdominis plane (TAP) blocks in patients undergoing laparoscopic cholecystectomy (LC). Methods: In this retrospective observational study, clinical data of 103 patients undergoing LC in Changxing County People's Hospital from October 2020 to October 2022 were retrospectively reviewed, and the patients were divided into ESP-group (n=56) and TAP-group (n=57) based on the block method. The operation time, the change of visual analogue scale (VAS) score of static (sVAS) and dynamic (dVAS) pain after operation, the patient-controlled dose, and the remedial analgesic dose at 24 hours after the operation were compared between the two groups. The occurrence of postoperative adverse reactions in both groups was recorded. Results: The dVAS scores of the ESP-group at one hour, three hours, six hours, and 12 hours after the operation were lower than those of the TAP-group (P<0.05). The patient-controlled dose and remedial analgesia dose of the ESP-group were significantly lower than those of the TAP-group (P<0.05). There was no difference in the incidence of postoperative nausea and vomiting between the two groups (P>0.05). Conclusions: ESP block and TAP block in LC patients have similar operation time and incidence of postoperative adverse events such as nausea and vomiting. However, short-term postoperative analgesic effect of ESP block is superior to TAP and requires a lower dose of analgesia.

Opening the amino acid toolbox for peptide-based NTS2-selective ligands as promising lead compounds for pain management.

Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of µ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and nonselective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.

Analgesic effect of thoracic paravertebral block on patients undergoing thoracoscopic lobectomy under general anesthesia.

Objective: To investigate the analgesic effect of thoracic paravertebral block (TPVB) in patients undergoing thoracoscopic lobectomy under general anesthesia (GA). Methods: Clinical records of 82 patients who underwent thoracoscopic lobectomy under GA from October 2021 to October 2022 in the General Hospital of Southern Theater Command were retrospectively analyzed. The patients were divided into two groups according to the method of anesthesia used: general anesthesia group (Group-G, n=37), and TPVB plus GA group (Group-T, n=45). The analgesic effect, mean arterial pressure (MAP), heart rate (HR) and the rate of adverse events in both groups were compared. Results: Visual analogue scale (VAS) scores of patients in Group-T at 12h, 24h and 48h after the operation were significantly lower compared to Group-G (P<0.05). MAP and HR the time of tracheal intubation induction (T1), single lung ventilation (T2), skin incision (T3), operation completion (T4), and 20 minutes after the extubation (T5) were lower in both groups compared to T0, and were significantly higher in Group-T compared to Group-G (P<0.05). The rate of adverse events in Group-T was 6.67%, significantly lower compared to Group-G (24.32%) (P<0.05). Conclusions: TPVB combined with GA can improve the analgesic effect, improve MAP and HR during the operation, and reduce the incidence of adverse events in patients undergoing thoracoscopic lobectomy.

Icetexane diterpenoids as Cav3.2 T-type calcium channel inhibitors from Salvia prattii and analgesic effect of their Semi-synthesized derivatives.

Ten new icetexane diterpenoids, salpratins E-N (1-10) and a known analogue (11) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 â†’ 3)-abeo-icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Cav3.2 T-type Ca2+ channel (TTCC) inhibitors with IC50 values of 2.9, 5.1, 2.3, and 3.2 µM, respectively. Five icetexane related derivatives (13-17) were synthesized from an abietane type precursor, (+)-carnosic acid (12), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Cav3.2, having IC50 values of 6.7 and 2.4 µM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Cav3.2 analgesics.

Analgesic effect of perioperative duloxetine in patients after total knee arthroplasty: a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: To investigate the analgesic effect of perioperative use of duloxetine in patients received total knee arthroplasty (TKA). METHOD: This prospective randomized, double-blind, placebo-controlled trial study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). 100 patients were finally enrolled. The hospital pharmacy prepared small capsules containing either duloxetine or starch (placebo) which were all identical in appearance and weight (50:50). The 100 enrolled patients were given a capsule (containing either 60 mg duloxetine or 60 mg placebo) every night before sleep since preoperative day 2 till postoperative day 14 (17 days in all) by a nurse who were not involved in this trial. Other perioperative managements were the same in the two groups. The primary outcome was the VAS score, including rVAS (visual analogue scale at rest) and aVAS (visual analogue scale upon ambulation) throughout the perioperative period. The secondary outcomes included opioid consumption, range of motion, including both active range of motion (aROM) and passive range of motion (pROM) and adverse events. The patients were followed up everyday until 7 days after TKA, afterwards, they were followed up at the time of 3 weeks and 3 months after TKA. RESULT: rVAS in duloxetine group were significantly less than placebo group throughout the postoperative period: 4.7 ± 2.3 vs 5.9 ± 2.6 (P = 0.016) at 24 h postoperative; 2.1 ± 1.6 vs 2.8 ± 1.7 (P = 0.037) at 7 days postoperative. In terms of aVAS, similarly, duloxetine group had less aVAS than placebo group throughout the postoperative period: 6.2 ± 2.1 vs 7.1 ± 2.2 (P = 0.039) at 24 h postoperative; 3.3 ± 1.7 vs 4.1 ± 2.0 (P = 0.034) at 7 days postoperative. Patients in duloxetine group consumed significantly less opioids per day than the placebo group: 24.2 ± 10.1 g vs 28.5 ± 8.3 g (P = 0.022) at 24 h postoperative; 2.7 ± 2.5 g vs 4.1 ± 2.6 g (P = 0.007) at 7 days postoperative. aROM in duloxetine group were significantly better than placebo group until postoperative day 6, the aROM became comparable between the two groups: 110.2 ± 9.9° in duloxetine group vs 107.5 ± 11.5° in control group (P = 0.211). In terms of pROM, duloxetine group had significantly better pROM until postoperative day 5, the pROM became comparable between the two groups: 103.8 ± 12.1° in duloxetine group vs 99.5 ± 10.8° in control group (P = 0.064). No significant difference was found between the two groups in the rates of dizziness, bleeding, sweating, fatigue and dryness of mouth. In the placebo group, more patients got nausea/vomiting and constipation (P < 0.05). However, in terms of drowsiness, duloxetine group was reported higher rate (P < 0.05). CONCLUSION: Several other RCTs have already mentioned the analgesic effect of duloxetine, but not in the immediate postoperative period. In this study, we found duloxetine could reduce acute postoperative pain in the immediate postoperative period and decrease the opioids consumption as well as accelerating postoperative recovery, without increasing the risk of adverse medication effects in patients undergoing TKA. Duloxetine could act as a good supplement in multimodal pain management protocol for patients undergoing TKA. TRIAL REGISTRATION STATEMENT: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). The date of registration was 06/16/2020.

Tracing analgesic constituents from crude and vinegar-processed resin of Boswellia carterii by integrating ultra-performance liquid chromatography tandem mass spectrometry-based determination, analgesic evaluation in mice, and gray relationship analysis.

The analgesic effect of the resin of Boswellia carterii (BC) is well known; however, the constituents that contribute to the analgesic effect remain elusive. The current study integrates ultrasonic-assisted extraction, quantitative determination, analgesic evaluation in rats, and gray relationship analysis for tracing analgesic constituents from the resin of BC. First, a robust and precise ultra-performance liquid chromatography tandem mass spectrometry approach with multiple reaction monitoring mode was developed for the simultaneous quantification of seven major constituents in crude and vinegar-processed resin of BC. Glycyrrhetinic acid was chosen as the internal standard. The approach showed good linearity. The intra- and inter-day precisions of each constituent were within 3.0%. The recoveries of each constituent were in the range of 96.4-102.7%. The approach was then applied to determine the seven constituents in 10 batches of crude and vinegar-processed resin of BC. Second, the analgesic effects of crude and vinegar-processed resin of BC were assessed in mice. Third, chemometrics methods, gray relationship analysis, and partial least squares regression were employed for determining the relationship between the contents of seven constituents and their analgesic effects. 11-Keto-ß-boswellic acid, 3-acetyl-ß-boswellic acid, 3-acetyl-α-boswellic acid, 3-acetyl-11-keto-ß-boswellic acid, and ß-sitosterol were identified as the key analgesic constituents of BC.

Berberine attenuates hyperalgesia in mice with adenomyosis.

PURPOSE: Adenomyosis is a common gynecological disease, but its pathogenesis and treatment options are not yet completely clear. This study aimed to investigate the analgesic effect of berberine on tamoxifen-induced neonatal mouse adenomyosis and its curative effects on the disease. METHODS: The mouse adenomyosis model was established in neonatal female mice via oral administration of tamoxifen suspended solution. Adenomyosis mice were given berberine by intraperitoneal injection with the dosage of 5, 10, and 20 mg/kg body weight, respectively, at 17 weeks after birth. The pain sensation of the mice was evaluated by hotplate and tail-flick tests. The mRNA levels of gene expression were detected by RT-qPCR. The protein expression was analyzed by ELISA and Western blot. RESULTS: Berberine reduced the uterine weight, suppressed the myometrial infiltration of ectopic endometrium, improved the hotplate and tail-flick latency of the adenomyosis mice. Mechanistically, berberine downregulated the expression of genes related to pain and inflammation, such as TRPV1, COX-2, VEGF and OTR, impaired the inflammatory response at the DRG site, and inhibited the expression of TLR4 in DRG and uterine tissues. CONCLUSIONS: Berberine attenuates hyperalgesia and exhibits analgesic and therapeutic effects on adenomyosis mice.

Flavonoid-Rich Fraction from Croton blanchetianus (Euphorbiaceae) Leaves Exerts Peripheral and Central Analgesic Effects by Acting via the Opioid and Cholinergic Systems.

The ethanolic extract from Croton blanchetianus leaves has been shown to have antinociceptive activity in mice. Here, we investigated the antinociceptive activity of an ethyl acetate fraction (EAF) from this extract in mice and the possible pathways involved in the analgesic effect. Adverse effects on behavior and motor coordination were also evaluated. The EAF was characterized by liquid chromatography coupled with mass spectrometry and evaluated (12.5, 25, and 50 mg/kg per os) in the acetic acid-induced abdominal writhing, formalin, hot plate, and tail immersion assays. Naloxone, atropine, glibenclamide, prazosin, or yohimbine was pre-administered to mice to investigate the involved pathways in the formalin test. The open-field, rotarod, and elevated plus-maze tests were used to assess behavior and locomotion. The main components of the EAF were quercetin-3-O-(2-rhamnosyl) rutinoside, hyperoside, quercetin rutinoside pentoside, and quercetin hexoside deoxyhexoside. EAF showed antinociceptive effects in all models and was effective against both neurogenic and inflammatory pain. The reversion of the effects in the formalin test by naloxone and atropine revealed that the EAF acted via the opioid and cholinergic systems. In the open-field test, the behavior of the animals treated with the EAF was like that of control, except at the highest dose, when hypnosis, eyelid ptosis, decreased walking, hygiene, and rearing behaviors were observed. No muscle relaxant effect was observed, but an anxiogenic effect was observed at all doses. This study provides new scientific evidence on the pharmacological properties of C. blanchetianus leaves and their potential for the development of phytomedicines with analgesic properties.

Janus Kinase Inhibitors Improve Disease Activity and Patient-Reported Outcomes in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 24,135 Patients.

Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.

The analgesic effect and safety of preoperative versus postoperative administration of celecoxib in patients who underwent arthroscopic rotator cuff repair: a randomized, controlled study.

AIMS: Celecoxib presents a good analgesic effect in patients who undergo arthroscopic rotator cuff repair (ARCR) surgery, while few studies investigate the optimal timing of celecoxib administration. This study aimed to explore the analgesic effect of preoperative versus postoperative administration of celecoxib in ARCR-treated patients. METHODS: A total of 106 ARCR-treated patients were enrolled and randomized at a 1:1 ratio into preoperative analgesia group (N = 53) and postoperative analgesia group (N = 53). The pain visual analog scale (VAS) score at rest or flexion, salvage consumption of pethidine, patient's satisfaction score, modified University of California at Los Angeles (UCLA) score and adverse events were evaluated. RESULTS: Pain VAS scores at rest at 12 h and D1 (but not D2, D3 or D7) and pain VAS scores at flexion at 12 h, D1 and D2 (but not D3 or D7) were decreased in preoperative analgesia group compared to postoperative analgesia group. Meanwhile, rescue analgesia rate and 7-day pethidine consumption in preoperative analgesia group were lower than that in postoperative analgesia group. Besides, the overall satisfaction scores at D1 and D3 (but not at D7 or M3) were elevated in preoperative analgesia group compared to postoperative analgesia group. However, no difference of modified UCLA scores at D7 or M3, or the occurrences of adverse events were found between the two groups. CONCLUSIONS: Celecoxib preoperative administration remits acute pain and facilitates satisfaction but does not improve long-term shoulder joint function recovery compared to its postoperative administration in patients who undergo ARCR surgery.

Analgesic Effects of Sokeikakketsuto on Chemotherapy-Induced Mechanical Allodynia and Cold Hyperalgesia in Rats.

The anticancer agents including oxaliplatin, paclitaxel, and bortezomib cause severe peripheral neuropathy. The Kampo medicine Sokeikakketsuto (SOKT) has been widely used to treat several types of pain. In this study, the analgesic effects of SOKT on oxaliplatin-, paclitaxel-, and bortezomib-induced peripheral neuropathy were investigated in rat models. Rats were treated with oxaliplatin (4 mg/kg, intraperitoneally (i.p.), twice a week for four weeks), paclitaxel (4 mg/kg, i.p., twice a week for two weeks), or bortezomib (0.2 mg/kg, i.p., twice a week for two weeks). SOKT (0.3 or 1.0 g/kg) or duloxetine hydrochloride (30 mg/kg, as a positive control) was administered orally after neuropathy developed. Mechanical allodynia and cold hyperalgesia were assessed using the von Frey test and the acetone test, respectively. These tests were performed immediately before and 30, 60, 90, and 120 min after the administration of the drugs. Repeated treatment of oxaliplatin induced mechanical allodynia and cold hyperalgesia. A single administration of SOKT (1 g/kg, per os (p.o.)), as well as duloxetine, temporarily reversed both the mechanical allodynia and the cold hyperalgesia. Repeated administration of paclitaxel and bortezomib also induced the mechanical allodynia. SOKT and duloxetine reversed the mechanical allodynia caused by bortezomib, but not by paclitaxel. SOKT might have the potential to become a new drug to relieve the symptom of oxaliplatin- or bortezomib-induced peripheral neuropathy.

The efficacy of ultrasound-guided stellate ganglion block in alleviating postoperative pain and ventricular arrhythmias and its application prospects.

Stellate ganglion block (SGB) has been applied in clinic for almost a century as a therapeutic procedure to alleviate pain-related syndromes and vascular deficits in the upper extremities. A great number of causative side effects and complications due to technological insufficiency and anatomical variations called for the popularity of ultrasound-guided SGB which has made tremendous contribution for clinical diagnosis and therapy, primarily in postoperative pain and cardiac and vascular disorders. This work was aimed at systematically summarizing the current clinical application of ultrasound-guided SGB and putting forward the potential prospective application in future. By searching ultrasound-guided SGB-related works on PubMed database, we mainly elucidated the analgesic effect of preoperative SGB in patients undergoing surgical procedures and substantial reduction in patients with ventricular arrhythmias. The volume of local anesthetics used in ultrasound-guided SGB has been diminished in the recent few years' investigations and successful operation of ultrasound-guided SGB could be achieved with minimal safe volume of local anesthetics. This invasive and safe procedure shows vast potential for future development in clinical treatment for autonomic nervous system and autoimmune disorders. We also put forward hypothesis that ultrasound-guided SGB could be applied combined with controlled hypotension to reduce the intraoperative complications in orthopedic surgery such as insufficiency of cerebral blood flow and reflexive tachycardia. Thus, it is of vital essence to improve the professional skills of physicians for the high rate of success and explore more effective measures which could enhance therapeutic effects when combined with ultrasound-guided SGB in alleviating misery of patients.

Lyophilization Serves as an Effective Strategy for Drug Development of the α9α10 Nicotinic Acetylcholine Receptor Antagonist α-Conotoxin GeXIVA[1,2].

α-Conotoxin GeXIVA[1,2] is a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype. It has the advantages of strong efficacy, no tolerance, and no effect on motor function, which has been expected help patients with neuropathic pain. However, drug development for clinical use is severely limited owing to its instability. Lyophilization is applied as the most preferred method to solve this problem. The prepared lyophilized powder is characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR). Molecular simulation is also used to explore the internal distribution and forces formed in the system. The analgesic effect on paclitaxel-induced neuropathic pain following single and 14-day repeated administrations are evaluated by the von Frey test and the tail-flick test. Trehalose combined with mannitol in a ratio of 1:1 is employed as the excipients in the determined formulation, where trehalose acts as the stabilizer and mannitol acts as the bulking agent, according to the results of DSC, PXRD, and FTIR. Both GeXIVA[1,2] (API) and GeXIVA[1,2] lyophilized powder (formulation) could produce stable analgesic effect. These results indicated that GeXIVA[1,2] lyophilized powder could improve the stability and provide an effective strategy to push it into clinical use as a new analgesic drug.

Carvacrol inhibits the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.3, Nav1.7, and Nav1.8 expressed in Xenopus oocytes with different potencies.

Carvacrol is the predominant monoterpene in essential oils from many aromatic plants. Several animal studies showing analgesic effects of carvacrol indicate potential of carvacrol as a new medication for patients with refractory pain. Voltage-gated sodium channels (Nav) are thought to have crucial roles in the development of inflammatory and neuropathic pain, but there is limited information about whether the analgesic mechanism of carvacrol involves Nav. We used whole-cell, two-electrode, voltage-clamp techniques to examine the effects of carvacrol on sodium currents in Xenopus oocytes expressing α subunits of Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8. Carvacrol dose-dependently suppressed sodium currents at a holding potential that induced half-maximal current. The half-maximal inhibitory concentration values for Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 were 233, 526, 215, 367, and 824 µmol/L, respectively, indicating that carvacrol had more potent inhibitory effects towards Nav1.2 and Nav1.6 than Nav1.3, Nav1.7, and Nav1.8. Gating analysis showed a depolarizing shift of the activation curve and a hyperpolarizing shift of the inactivation curve in all five α subunits following carvacrol treatment. Furthermore, carvacrol exhibits a use-dependent block for all five α Nav subunits. These findings provide a better understanding of the mechanisms associated with the analgesic effect of carvacrol.