Analgesic Effect Research Articles

Safety and efficacy of low-dose esketamine weakly opioidized anesthesia in elderly patients with lumbar spinal stenosis undergoing surgery: a prospective, double-blind randomized controlled trial

BackgroundThe perioperative use of esketamine may reduce opioid use and their adverse effects. We aimed to evaluate the intraoperative safety and efficacy of weak opioidized anesthesia with low-dose esketamine in the treatment of elderly patients with lumbar spinal stenosis undergoing total laminectomy with complete decompression and interbody implant fusion.MethodsIn total, 90 elderly patients were randomized into three groups: the esketamine HS group (0.2 mg/kg induction, 0.25 mg/(kg·h) infusion), the esketamine LS group (0.2 mg/kg induction, 0.125 mg/(kg·h) infusion), and the control group (group C receiving an equal volume of saline). The primary outcome was the cumulative dose of sufentanil administered during the perioperative period. Pain (VAS rest and movement scores) on preoperative day 1 (POD-1), postoperative day 1 (POD1), postoperative day 3 (POD3), and postoperative day 7 (POD7), and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) on POD-1, POD1, POD3, and POD7 were the secondary outcomes. We also measured mean arterial pressure and the heart rate of the three groups at each time point before anesthesia (T0), immediately after intubation (T1), 5 min after intubation (T2), at the time of surgical skin incision (T3), at the time of extubation (T4), and 30 min after surgery (T5), intraoperative propofol and remifentanil dosage, and the incidence of adverse reactions within 5 days postoperatively, etc.ResultsThe cumulative perioperative sufentanil dosage and the number of patients undergoing postoperative PACU remedial analgesia were significantly lower in the HS and LS groups compared to the C group (P < 0.05). Cumulative perioperative sufentanil use was lower in the HS group compared with the LS group (P < 0.01). The VAS dynamic and static pain scores were significantly lower in the HS group at POD1 compared to the C and LS groups. There was no significant difference in VAS dynamic and static pain scores among the three groups at POD3 and POD7 (P > 0.05). At POD1, the VAS dynamic and static pain scores were significantly lower in the HS group compared to the C and LS groups. VAS static pain scores were lower in the LS group at POD1 compared to group C (P < 0.05), whereas VAS dynamic pain scores did not differ compared to group C (P > 0.05). Compared with group C, the serum levels of TNF-α, IL-1β, and IL-6 were significantly lower in the HS and LS groups at POD1, POD3, and POD7. At POD1 and POD3, the serum levels of TNF-α, IL-1β, and IL-6 were lower in the HS group than in the LS group (P < 0.05). Serum IL-10 levels were significantly increased at POD1, POD3, and POD7 in the HS and LS groups compared with group C (P < 0.05). The incidence of intraoperative hypotension was significantly lower in the HS and LS groups compared with group C (P < 0.05). At T2 and T4, the HS and LS groups had significantly lower levels of MAP and HR decline than the C group. At T5, the MAP and HR of the C group were significantly higher than those of the HS and LS groups (P < 0.05). The HR at T3 was reduced in the LS group compared with the C and HS groups (P < 0.05). The incidence of postoperative respiratory depression was reduced in the HS and LS groups compared to the C group (P < 0.05). There was no significant difference between the three groups in terms of postoperative psychiatric adverse reactions, such as hallucinations, nightmares, diplopia, somnolence, and dizziness (P > 0.05).ConclusionLow-dose esketamine is used for its anti-inflammatory and analgesic effects in lumbar spine surgery of elderly patients. It is beneficial to hemodynamic stabilization and can reduce the incidence of postoperative respiratory depression in elderly patients. Among them, 0.2 mg/kg induction and 0.25 mg/(kg-h) infusion were more effective.Graphical

The Pharmacology of Cannabinoids in Chronic Pain

Objective: Our objective is to provide an overview of the currently available scientific and clinical data supporting the use Cannabis and Cannabis-derived products for the treatment of chronic pain disorders. We also provide information for researchers, clinicians and patients to be better informed and understand the approach behind the recommendation of Cannabis as a potential adjuvant in the treatment/control of chronic pain. Background: Cannabis and its bioactive compounds have sparked interest in the field of pain treatment in spite of its controversial history and status as a controlled substance in many countries. With the increase in chronic pain, physicians and patients have started to look at alternative ways to treat pain aside from traditional treatments. One alternative is the use of cannabis to reduce/treat chronic pain disorders based on anecdotal accounts and the function of its phytocannabinoids. The two main cannabinoids in cannabis, THC and CBD, act on CB1 and CB2 receptors (in addition to several additional receptors). It is through these pleiotropic receptor interactions that these compounds elicit their biological function including the reduction of chronic pain. In this narrative review, we included the most recent evidence supporting the use of cannabis in the treatment of chronic pain disorders including chronic neuropathic pain, cancer-induced neuropathic pain, chronic musculoskeletal pain, and chronic headaches and migraines. Summary: Evidence suggests that cannabis and cannabinoids have an analgesic effect that arises from a combination of compounds and various receptor systems. These effects may be maximized with the use of a combination of cannabinoids. At the same time, the combination of cannabinoids helps to minimize the undesirable side effects of some cannabinoids such as the psychoactivity of THC. With these findings, further research is necessary to assess the analgesic properties of other cannabinoids like CBC and CBG, and their contributions to the reduction of pain.

Experimental and Computational Investigation of the Target and Mechanisms of Gelsemium Alkaloids in the Central Nervous System

Gelsemium has a long history of medicinal use but is also a poisonous plant. Some low-toxicity alkaloids in Gelsemium exhibit anxiolytic, anti-inflammatory, analgesic, and other pharmacological effects; however, certain alkaloids in Gelsemium are highly toxic. Nevertheless, the molecular targets underlying the biological effects of Gelsemium alkaloids remain poorly understood. We employed electrophysiological techniques and molecular modeling to examine the modulatory effects of Gelsemium alkaloids on inhibitory neurotransmitter receptors, as well as to elucidate the mechanisms underlying their molecular interactions. Our findings indicate that low-toxicity alkaloids primarily exert their pharmacological effects through actions on glycine receptors, with the binding site located at the orthosteric site between two α-subunits. Both highly toxic and low-toxicity alkaloids target GABAA receptors, using the β+/α− interface transmembrane structural domains as common binding sites. These results identify the targets through which Gelsemium alkaloids affect the central nervous system and predict the binding modes and key amino acids involved from a computational modeling perspective. However, further experimental validation through mutational studies is necessary to strengthen these findings.

Medicinal plants in the treatment and prevention of respiratory diseases (review)

Introduction. The aim of the review is to summaries information on medicinal plants used in the prevention of respiratory diseases.Text. According to Rosstat data, respiratory diseases occupy leading positions in the Russian Federation from year to year. For the treatment of acute respiratory diseases plant medicines are used, including Glycyrrhiza glabra L., Mentha spicata L., Eucalyptus globulus Labill., Citrus sinensis (L.) Pers., Cinnamomum camphora J. Presl.Conclusion. The given extracts of medicinal plants have a long experience of application in traditional and scientific medicine, contain a complex of biologically active substances such as essential oils, saponins, polyphenols and polysaccharides with antibacterial, anti-inflammatory, analgesic and other effects that will allow in the complex therapy of acute tonsillopharyngitis, relieve the symptoms of the disease.

Illusory finger stretching and somatosensory responses in participants with chronic hand-based pain.

Current pharmaceutical interventions for chronic pain are reported to be minimally effective, leading researchers to investigate non-pharmaceutical avenues for chronic pain treatment. One such avenue is resizing illusions delivered using augmented reality. These illusions resize the affected body part through stretching or shrinking manipulations and have been shown to give analgesic effects; however, the neural underpinnings of these illusions remain undefined. Steady-state evoked potentials (SSEPs) have been studied within populations without chronic pain undergoing hand-based resizing illusions, finding no convincing differences in SSEP amplitudes during illusory stretching. Here, we present comparable findings from a sample with chronic pain, who are thought to have blurred cortical representations of painful body parts, but again find no clear differences in SSEP amplitude during illusory stretching. However, no significant decreases in pain ratings were found following illusory resizing, and changes in SSEP amplitudes are thought to possibly reflect experiences of illusory analgesia. Despite a lack of illusory analgesia across the sample, several participants experienced clinically meaningful levels of pain reduction following illusory resizing, highlighting the potential of resizing illusions as an analgesia treatment avenue. Subjective illusory experience data showed significantly greater experiences of the illusion in the multisensory (visuotactile) condition compared to non-illusion conditions and a unimodal visual condition, replicating findings from participants without chronic hand-based pain. Exploratory analyses using subjective disownership data show that the multisensory condition did not elicit significant disownership experiences, demonstrating that the pain reductions seen in the multisensory condition do not arise from disownership of the limb, but more likely as a direct result of the illusory resizing manipulations.

General Anesthesia Combined with Quadratus Lumborum Block Reduces Emergence Delirium in Children after Laparoscopic Surgery: A Randomized Clinical Trial.

Emergency delirium (ED) is a common and serious postoperative complication especially after pediatric surgery. Quadratus lumborum block (QLB) are critical components of the multimodal, opioid-sparing analgesia regimens, which provide effective analgesia, reduce opioid consumption, and attenuate surgical stress response. Therefore, this trial was designed to validate the hypothesis that the adjunctive use of QLB reduces the incidence of ED after laparoscopic surgery in children. Children aged 1-6 years who underwent laparoscopic surgery under general anesthesia were randomly divided into general anesthesia combined with QLB group (Group G+Q) or general anesthesia group (Group G). The primary outcome was the incidence of ED in postanesthesia care unit (PACU), the incidence of delirium 24 hrs postoperatively, extubation time, length of stay in PACU, opioid consumption and pain score were recorded. From July 2020 to October 2022, 292 children were randomized and 287 completed the study. The incidence of delirium in Group G+Q were significantly lower than that in Group G in PACU (16.1% vs 47.9%, P<0.001) and 24 hrs postoperatively (3.4% vs 11.1%; P<0.05). The time of extubation time (21.2±11.4min vs 18.2±11.8min; P<0.05) and PACU stay in Group G were significantly longer than Group G+Q (57.2±20.3min vs 48.9±20.4min, P<0.01) compared with Group G. General anesthesia combined with QLB can significantly reduce the incidence of ED, shorten the extubation time and PACU residence time, and improve the quality of resuscitation.

Gallic acid protects intervertebral disc cells from ferroptosis and alleviates intervertebral disc degeneration by regulating key factors of oxidative stress

BackgroundIntervertebral disc degeneration (IDD) is a chronic degenerative disease and one of the main causes of low back pain (LBP). Currently, there is no effective treatment. Ferroptosis is a cell-regulated process that depends on iron deposition and lipid peroxidation. Inhibiting ferroptosis in nucleus pulposus cells is considered a potential strategy for the treatment of IDD. Gallic acid (GA) is naturally present in a variety of plants and has anti-inflammatory, antioxidant and analgesic effects. It has been shown to alleviate ferroptosis. However, the role of GA in IDD ferroptosis remains unclear.MethodsThis study explored the pathological mechanism of GA in IDD in relation to ferroptosis: (1) to identify ferroptosis-related targets for GA treatment of IDD using network pharmacology and molecular docking technology, (2) to evaluate the therapeutic effect of GA in an IDD rat model and changes in ferroptosis-related targets, (3) to investigate the changes of oxidative stress and lipid peroxidation products in NP cells after GA intervention, and (4) to study the changes of ferroptosis-related proteins and iron ions in cells and mitochondria after GA intervention.ResultsExperimental results confirmed that GA can treat IDD by reducing the degradation of extracellular matrix (ECM) and pathological changes in IDD. GA can also mitigate ferroptosis by reducing oxidative stress and lipid peroxidation in rat nucleus pulposus (NP) cells.ConclusionThe alleviation of disc degeneration ferroptosis by GA may be closely associated with the key ferroptosis proteins P53 and NRF2.

Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application.

Electroacupuncture induces analgesia by regulating spinal synaptic plasticity via the AMPA/NMDA receptor in a model of cervical spondylotic radiculopathy: secondary analysis of an experimental study in rats.

Cervical spondylotic radiculopathy (CSR) is characterized by neuropathic pain (NP). Although the analgesic effect of electroacupuncture (EA) has been widely recognized in clinical practice, the mechanism of EA in the treatment of CSR remains unknown. We previously reported that 7 days of EA improved behavioral markers of NP, attenuated increases in α-synuclein, synapsin 1 and 2, postsynaptic density (PSD)-95 and growth-associated protein (GAP)-43, and improved ultrastructural changes within synapses in a rat model of CSR. Herein, we present supplemental data from the same cohort of animals examining the timing of behavioral improvement within the first week (through additional measurements at 3 and 5 days into the EA treatment) and new data on the effects of EA on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-d-aspartic acid receptor (NMDAR) levels. As previously reported, the rats were divided into four groups at random: normal, sham, CSR and CSR + EA. EA at bilateral LI4 and LR3 was administered once a day for 7 days (20 min each) in the CSR + EA group after the CSR model was established by inserting a fishing line under the laminae. Behavioral assessments were carried out prior to initiation of EA and at 3, 5 and 7 days into the 7-day treatment course. Concentrations ofγ-aminobutyric acid (GABA) and glutamate (Glu) were determined using enzyme-linked immunosorbent assay and ultraviolet colorimetry, respectively, and AMPAR (glutamate receptor (GluR)1 and GluR2 membrane protein) expression was determined using Western blotting. Immunohistochemistry was used to detect the protein expression and average optical density (AOD) of NMDAR1 (NR1), NMDAR2A (NR2A) and NMDAR2B (NR2B). Quantitative reverse transcription-polymerase chain reaction was used to detect the mRNA expression of NR1, NR2A and NR2B. Transmission electron microscopy was used to observe changes in synaptic ultrastructure. EA significantly improved the pressure pain threshold (PPT) and mechanical withdrawal threshold (MWT) 5 days into the intervention, although effects were less pronounced than at 7 days (at completion of treatment). However, significant effects on gait scores were not seen prior to 7 days. As previously reported, EA also improved markers of synaptic ultrastructure. In the spinal cord, GluR1 membrane protein expression was decreased, GluR2 membrane protein expression was increased, and the GluR1/GluR2 ratio was decreased. Protein and mRNA expression of NR1, NR2A and NR2B was significantly decreased. GABA concentration was markedly increased, while Glu concentration was markedly decreased. Evidence of EA analgesia (higher PPT and MWT scores) was seen after 5 days of EA, while positive effects on motor function required 7 days of treatment. The underlying mechanism may be related to inhibition of AMPAR and NMDAR expression, regulation of the concentration of related neurotransmitters and improvement of spinal cord synaptic plasticity. This study establishes a preliminary theoretical foundation for the use of EA in the clinical treatment of CSR.

Pharmacodynamic characteristics of curcumin

Curcumin, an active ingredient derived from turmeric root (Curcuma longa), has significant pharmacological properties including anti-inflammatory, antioxidant, antimicrobial, anticancer and analgesic activities. Studies show that curcumin affects the expression of various microRNAs and long non-coding RNAs to regulate cell proliferation and apoptosis in various types of malignant tumours. In addition, curcumin modulates signalling pathways such as PI3K/Akt/mTOR, MAPK/ERK and AMPK, activating autophagy and inhibiting tumour angiogenesis. It also inhibits metastasis and invasion of tumour cells by affecting epithelial-mesenchymal transition and expression of matrix metalloproteinases. Curcumin exhibits antibacterial and antiviral activity by disrupting bacterial cell membranes and inhibiting viral replication. The antioxidant properties of curcumin are due to its ability to neutralise reactive oxygen species and stimulate antioxidant enzymes. Curcumin also promotes wound healing by modulating inflammatory processes and stimulating angiogenesis. The analgesic effect of curcumin is due to its ability to stimulate the release of endogenous opioid peptides and modulate the activity of GABA receptors and ASIC and TRPV ion channels. Curcumin has an effect on lipid and carbohydrate metabolism, which makes it a promising agent for the treatment of dyslipidaemia and insulin resistance. The effect of curcumin on haemostasis is manifested in its ability to inhibit platelet aggregation and blood clotting, which may be useful for the prevention of cardiovascular diseases.

Fibromyalgia: do I tackle you with pharmacological treatments?

Pharmacological approaches are frequently proposed in fibromyalgia, based on different rationale. Some treatments are proposed to alleviate symptoms, mainly pain, fatigue, and sleep disorder. Other treatments are proposed according to pathophysiological mechanisms, especially central sensitization and abnormal pain modulation. Globally, pharmacological approaches are weakly effective but market authorization differs between Europe and United States. Food and Drug Administration-approved medications for fibromyalgia treatment include serotonin and noradrenaline reuptake inhibitors, such as duloxetine, and pregabalin (an anticonvulsant), which target neurotransmitter modulation and central sensitization. Effect of analgesics, especially tramadol, on pain is weak, mainly on short term. Low-dose naltrexone and ketamine are gaining attention due their action on neuroinflammation and depression modulation, but treatment protocols have not been validated. Moreover, some treatments should be avoided due to the high risk of abuse and severe side effects, especially opioids, steroids, and hormonal replacement.

Repetitive transcranial magnetic stimulation for fibromyalgia: are we there yet?

Repetitive transcranial magnetic stimulation (rTMS) has increasingly been used to modify cortical maladaptive plastic changes shown to occur in fibromyalgia (FM) and to correlate with symptoms. Evidence for its efficacy is currently inconclusive, mainly due to heterogeneity of stimulation parameters used in trials available to date. Here, we reviewed the current evidence on the use of rTMS for FM control in the format of a narrative review, in which a systematic dissection of the different stimulation parameters would be possible. We conducted a search in Medline and Embase for controlled trials on rTMS in people with FM with at least 10 participants in each treatment arm, and treatment/follow-up of at least 3 weeks. The search identified 482 abstracts, of which 45 were screened to full review, and 11 met inclusion criteria. Six out of 11 trials were positive. The dorsolateral prefrontal cortex was the target in 218 patients (49.2%), and the primary motor cortex (M1) in 225 (50.8%). Studies targeting M1 at 10 Hz, with stimulation current delivered in the posterior-anterior, were systematically positive, frequently showing that maintenance sessions delivered weekly, and biweekly were able to maintain the analgesic effects seen after daily induction sessions. Studies assessing the effects of rTMS for FM are still marked by heterogeneity in stimulation petameters, choice of primary outcomes, and inclusion criteria. The selection of the stimulation parameters associated with significant analgesic effects is likely to benefit following larger multicenter trials and improve the overall management of pain and associated symptoms in people with FM.

A comparative study of analgesic effect between ultrasound-guided posterior vis-a-vis lateral transversus abdominis plane block in patients undergoing total abdominal hysterectomy with bilateral salpingo-oophorectomy under spinal anesthesia

Background: Transversus abdominis plane (TAP) block is used to reduce pain after total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH+BSO). Two important approaches are ultrasound-guided lateral and posterior approaches. Ultrasound-guided blocks help in the correct localization of the plane and proper deposition of drugs. Aims and Objectives: This study was done to compare the analgesic effect of posterior TAP block and lateral TAP block in TAH+BSO.Materials and Methods: A double-arm observational study was conducted on eighty patients (ASA 1 and 2) posted for TAH+BSO under spinal anesthesia. They were randomly divided into two equal groups, 40 each (Groups L and P). Ultrasound-guided lateral TAP block and posterior TAP block were administered bilaterally with 20 mL 0.25% bupivacaine in the L group and P group, respectively, on each side of the abdomen after skin closure at the end of the operation. The intensity of post-operative pain was evaluated by a 10 cm Visual Analog Scale (VAS) Score at 1, 3, 6, 9, 12, and 24 h. If VAS was more than 4, 1 g paracetamol infusion was given. Duration of analgesia, total rescue analgesic requirement, and hemodynamic changes by measuring mean arterial pressure and pulse rate were also observed. Results: VAS score was significantly less in Group P than in Group L (P&lt;0.05). The time of first rescue analgesia requirement was longer in Group P compared to Group L. Total analgesic requirement in 24 h was less in Group P compared to Group L. Hemodynamic changes were comparable in both groups. Conclusion: Posterior TAP block provides better post-operative analgesia than lateral TAP block with stable hemodynamics in patients undergoing TAH BSO operation under spinal anesthesia.

A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor.

β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET2-based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that dependent on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP's inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect in vivo, as intrathecal injection of ARIP potentiated morphine's analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes.

Role of bilevel erector spinae with high thoracic block vs conventional unilevel block in analgesia and reduction of pain in axilla in breast cancer surgeries: a randomized controlled trial.

Management of pain associated with breast cancer surgeries is crucial in reducing incidence of postmastectomy pain syndrome. The pain distribution involves the anterior chest wall, axillary area and ipsilateral upper limb. This study was designed to investigate the effect of bilevel erector spinae plane block (ESPB) with high thoracic block vs the conventional unilevel ESPB vs opioids in patients with cancer undergoing modified radical mastectomy regarding pain control and reducing pain in axilla. One hundred twenty-six female patients with cancer and American Society of Anesthesiology II, III were randomized into 3 groups: bilevel ESPB, unilevel ESPB, and control group. The primary outcome was total postoperative morphine consumption. Total postoperative morphine consumption was higher for the control group compared with the bilevel and unilevel groups (5.5 ± 1.8 vs 3.0 ± 0.0 and 4.3 ± 1.6 mg, P = 0.038). First time to receive morphine was longer for bilevel and unilevel groups compared with the control group (20.7 ± 3.1 and 17.7 ± 4.1 vs 8.2 ± 5 hours, P < 0.001). There was 96.1% and 90.3% reduction in morphine intake with odds ratio 25.6 (95% confidence interval [CI]: 6.6-100) and 10.3 (95% CI: 3.7-28.6) for the bilevel and unilevel groups compared with the control group. There was 98.5% and 65.4% reduction in the incidence of pain in axilla with odds ratio 66.6 (95% CI: 16.9-250) and 21.7 (95% CI: 6.75-66.6) for the bilevel and unilevel groups compared with the control group. Postoperative visual analog scale was lower for the bilevel group after 2, 4, and 24 hours compared with both the control group and the unilevel groups, P < 0.005. Both conventional unilevel and high thoracic bilevel ESPB had better analgesic profile when compared with opioids. Although the bilevel ESPB had additional merits to the unilevel ESPB in analgesic effects, both can be used effectively.

Upskilling pain relief after surgery: a scoping review of perioperative behavioral intervention efficacy and practical considerations for implementation.

Perioperative skills-based interventions may support non-pharmacological management of pain and opioid reduction after surgery. Such interventions may target and enhance predictors for surgical recovery and possibly reduce chronic postsurgical pain. Existing meta-analyses are limited by inclusion of studies that are either non-surgical or with outcomes occurring only in the hours after surgery. Lacking is a scoping review of studies testing perioperative skills-based interventions for postsurgical pain relief and opioid reduction in the days and months after surgery. We reviewed the efficacy of perioperative behavioral interventions; over what time frame and in which surgical populations efficacy evidence exists; and whether such interventions can prevent chronic postsurgical pain. 20 randomized trials were included, with the following intervention types: hypnosis, relaxation therapy, stress management training, mindfulness, mixed-type skills interventions (mind-body skills, preoperative pain self-management, empowered relief for surgery); cognitive behavioral-therapy (CBT); and mindfulness-based CBT. We summarize study methods, treatment specifics, and analgesic effects. No studies were designed to test intervention efficacy for preventing chronic postsurgical pain. Only two studies used active controls as the study comparator. Two studies showed positive effects on postsurgical opioid use. No studies tested whether the interventions enhanced time to pain cessation after surgery. Four studies demonstrated durable analgesic effects at 3-12 months after surgery. We describe the real-world practicality of intervention integration into the perioperative pathway and provide dissemination and implementation methodologies that may increase intervention uptake and therefore fulfill calls from national agencies to better integrate behavioral pain treatments into perioperative care.

Intrathecal Clonidine versus Dexmedetomidine as Adjuvants to Hyperbaric Ropivacaine in Lower Limb Orthopaedic Surgeries: A Randomised Clinical Study

Introduction: Subarachnoid block is the most chosen mode for orthopaedic surgeries in lower limb. Adjuvants such as opioids and α2 agonists are often added intrathecally to improve or prolong the anaesthetic and analgesic effects. Ropivacaine, a novel local anaesthetic agent, is widely accepted as it has better safety profile as compared to bupivacaine and lignocaine. Aim: To compare clonidine and dexmedetomidine as adjuvants to hyperbaric ropivacaine given intrathecally in lower limb orthopaedic surgeries, focusing on haemodynamic changes, sedation, duration of analgesia, and sensory and motor blockades. Materials and Methods: This randomised clinical study was conducted in a teritary care facility at the Operation Theatre (OT) complex in the Department of Anaesthesiology at Dhiraj Hospital, Smt. Bhikhiben Kanjibhai Shah Medical Institute and Research Centre (SBKS and MIRC), Piparia, Waghodia, Vadodara, Gujarat, India. The study duration was 18 months, with a total sample size of 60 patients, comprising of 30 patients in each group. Group RC30 (Ropivacaine+Clonidine) was given 3.5 mL of 0.75% hyperbaric ropivacaine with 30 μg of clonidine, while Group RD5 (Ropivacaine + Dexmedetomidine) was given 3.5 mL of 0.75% hyperbaric ropivacaine along with 5 μg of dexmedetomidine, intrathecally. Results were assessed by comparing the onset and duration of sensory and motor blockade. The absolute and effective analgesia durations were also compared and side-effects and complications along with haemodynamic changes were analysed. Data was analysed using Statistical Package of Social Sciences (SPSS) Software version 26.0. Mean and Standard Deviation (SD) were derived for continuous variables and t-test or Analysis of Variance (ANOVA) was used to evaluate relationship between them, proportions for categorical variables and the Chi-square test was used for categorical variables. Results: The mean for age in Group RD5 was 39.43±10.6 years and Group RC30 was 41.43±13.65 years. The time to S2 regression was longer in Group RD5 (136.10±8.10 min) compared to Group RC30 (102.67±7.69 min) (p&lt;0.0001). Longer duration of sensory and motor blockade was seen in Group RD5 (312.53±23.22 min, 381.40±30.01 min) as compared to Group RC30 (279.90±29.64 min, 321.63±38.82 min) (p&lt;0.0001, respectively). Group RD5 also required fewer analgesic interventions in the first 24 hours. Absolute and effective analgesia was found longer in Group RD5 as compared to Group RC30 (p=0.0006, p=0.0022, respectively). Conclusion: Dexmedetomidine offers superior postoperative analgesia compared to clonidine but is associated with a higher incidence of bradycardia and hypotension, both of which are manageable with standard interventions.

Motor-sparing regional anaesthesia for total knee arthroplasty: a narrative and systematic literature review.

Total knee arthroplasty is a life-changing surgical procedure that is associated with a high incidence of severe postoperative pain. Key to enhancing recovery after surgery is effective analgesia and early mobilisation. Innovations in motor-sparing regional anaesthesia techniques that have improved recovery include targeted surgical local infiltration analgesia, adductor canal blockade, genicular nerve blocks, and the infiltration between the popliteal artery and posterior capsule of the knee (iPACK) block. This narrative review discusses the current available motor-sparing regional anaesthetic techniques and assesses the evidence supporting each.

In silico Evaluation of Anacyclus pyrethrum Composition for Inhibition of Spike RBD-ACE-2 Interaction to Treat COVID-19

Background: The spike glycoprotein of SARS-CoV-2, via its S1-subunit, binds with host angiotensin-converting enzyme 2 (ACE-2) receptors, and its S2-subunit mediates the fusion of the virus to the host cell. The entry of SARS-CoV-2 inside the host cell can be prevented by inhibition of the receptor binding domain (RBD) of S1-subunit of the spike. Anacyclus pyrethrum, a native herb of Algeria, Spain and Morocco has antidepressant, analgesic, antimicrobial, anesthetic, antioxidant, anti-inflammatory, aphrodisiac, antidiabetic and immunostimulant effects. Still, its antiviral effect has not been established yet. Methodology: The present study deals with ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity), molecular docking and molecular dynamic simulation based investigation to evaluate the potential of Anacyclus pyrethrum constituents for effective spike RBD inhibition. Results: ADMET analysis revealed that 10 out of 12 significant constituents belongs to toxicity class 4 to 6 proving least toxicity of the plant extract with high LD50 values. Molecular docking analysis of 10 considered compounds revealed that morphinan-6-one, 4,5.alpha.-epoxy-3-hydroxy-17-methyl, a derivative of morphine (well-known analgesic and anti-inflammatory compound) gave the maximum negative binding energy of -6.9Kcal/mol in best-docked conformation with spike RBD having 2 hydrogen bonds. Molecular dynamic simulation disclosed effective RMSD, RMSF, and Rg values over the simulation trajectory with significant hydrogen bonding proving stable interaction of the compound with that of the spike RBD. Conclusion: Hence, all these outcomes revealed the outstanding potential of the Anacyclus pyrethrum extract to inhibit the spike RBD of SARS-CoV-2. Therefore, further in-vitro investigation can develop natural and effective treatments against COVID-19 disease.

Tetrahydropalmatine ameliorates peripheral nerve regeneration by enhancing macrophage anti-inflammatory response.

Peripheral nerve injury (PNI) is a common clinical problem that can result in partial or complete loss of sensory, motor, and autonomic functions. Tetrahydropalmatine (THP), a Corydalis yanhusuo-derived phytochemical alkaloid, possesses hypnotic, soothing, analgesic, and other effects, but little is known about the effect of THP on moderating peripheral nerve regeneration and its possible underlying mechanism of action. In this study, we aim to elucidate the protective function of THP on PNI and further reveal the underlying pharmacological mechanisms. PNI rats were in suit injection of THP solution at doses of 40mg/kg for consecutive 3, 7, or 28days, followed by harvesting the sciatic nerve tissues. The protective effect of THP on PNI was evaluated by electrophysiological test, transmission electron microscopy, immunofluorescence (IF), and western blotting (WB). Macrophage polarization, the expression of inflammatory-related genes and cytokines, and its upstream signaling pathways were detected by IF, WB, enzyme-linked immunosorbent assay (ELISA), mRNA-seq, and WB. In vitro, the Raw 264.7 cells were treated with lipopolysaccharide containing with/without THP. The degree of inflammatory activation and its potential pharmacological mechanism were measured by ELISA, qRT-PCR, IF staining, flow cytometry, and WB. Additionally, a pharmacological agonist or inhibitor was added to the cell medium to further identify the role of THP's potential pharmacological mechanism in regulating inflammatory response via IF and ELISA technology. Using the sciatic nerve crush model, we found that THP significantly enhanced the rate of axonal growth and functional recovery, and altered macrophage subtype transformation from the M1/M0 phenotype into the M2 phenotype, inducing the secretion of large amounts of anti-inflammatory factors. Moreover, THP significantly increased the phosphorylation level of PI3K, AKT, GSK3β, and IκBa, and decreased the expression of TLR4 protein and NF-κB phosphorylation. Similarly, in vitro, THP also facilitated Raw 264.7 cell polarization to the M2 subtype under the condition of LPS stimulation. Meanwhile, the change of PI3K/AKT/GSK3β and TLR4/NF-κB signaling-related proteins in vitro was consistent with the results in vivo. Additionally, the THP-medicated anti-inflammatory effect on Raw 264.7 cells was partly eliminated when pharmacological intervention of these two signaling pathways. THP has anti-inflammatory effects on facilitating M2-subtype macrophage polarization, which produces abundant anti-inflammatory cytokines to ameliorate peripheral nerve regeneration. Moreover, the potential mechanism of THP action may be intimately associated with activating the PI3K/AKT/GSK3β axis and inhibiting the TLR4/NF-κB pathway.