Search Results (133)

Background: Application of the capsaicin 8% patch is commonly associated with treatment-related burning pain, which may necessitate rescue analgesia, compromise completion of the standardized 60 min application, and reduce acceptance of repeat treatment. Although capsaicin is an established therapy for painful diabetic peripheral neuropathy (PDPN), evidence supporting strategies to improve procedural tolerability remains limited. This study evaluated whether ultrasound-guided bilateral ankle nerve block (UGBANB) was associated with better procedural outcomes than topical eutectic mixture of lidocaine/prilocaine (EMLA) pretreatment or no pretreatment. Methods: This retrospective comparative cohort study included 90 adults with neurologist-confirmed PDPN who underwent capsaicin 8% patch therapy. Patients received no pretreatment (n = 30), topical EMLA pretreatment (n = 30), or UGBANB (n = 30). The primary outcome was cumulative procedural pain burden, quantified as the area under the Numeric Pain Rating Scale–time curve (AUC-NPRS) during the standardized 60 min application. Secondary outcomes included rescue tramadol requirements, treatment completion, early postprocedural pain intensity, procedural tolerability, willingness to undergo repeat treatment, and safety. Results: Cumulative procedural pain burden differed significantly among the three pretreatment strategies (one-way ANOVA: F = 289.8, p < 0.001; η² = 0.87). Mean AUC-NPRS was 481.5 ± 39.2 NPRS·min with no pretreatment, 429.2 ± 36.0 with topical EMLA, and 256.3 ± 38.4 with UGBANB, corresponding to approximately 47% and 40% lower cumulative pain burden with UGBANB than with no pretreatment and topical EMLA, respectively. No patient receiving UGBANB required intravenous rescue tramadol, compared with 60.0% receiving EMLA and 100.0% receiving no pretreatment (p < 0.001). Treatment completion was 100% with UGBANB, compared with 83.3% with EMLA and 73.3% with no pretreatment. UGBANB was also associated with lower early postprocedural pain, greater procedural tolerability, and greater willingness to undergo repeat treatment. No serious treatment- or block-related adverse events were observed during the available follow-up. Conclusions: UGBANB was associated with better procedural tolerability and treatment delivery during capsaicin 8% patch therapy than topical EMLA or no pretreatment in patients with PDPN. These findings relate specifically to procedural optimization and should not be interpreted as evidence that UGBANB enhances the intrinsic or long-term analgesic efficacy of capsaicin. Prospective multicenter randomized controlled trials are needed to confirm these associations and determine whether improved procedural tolerability translates into better long-term treatment adherence, clinical outcomes, health-related quality of life, safety, and cost-effectiveness. Full article

Primary sensory neurons of the dorsal root ganglion (DRG) express mu-type opioid receptors and undergo plasticity that can contribute to both analgesia and maladaptive outcomes such as opioid tolerance and opioid-induced hyperalgesia. Most mechanistic work has relied on rodent models, which may not fully capture the repertoire of opioid-responsive pathways present in humans. In this study, we tested whether morphine exposure reshapes gene expression programs in human nociceptors. Human induced pluripotent stem cell (hiPSC)-derived nociceptors were exposed to morphine (3.5 μM) acutely (1h, 16h) or repeatedly (2–3 days; daily 16h exposure separated by 8h washout) and profiled by time-series RNA sequencing. The transcriptional response to morphine included the induction of a small set of genes across exposure paradigms. P2RY11, encoding the purinergic G protein-coupled receptor P2Y11, was the most robustly induced transcript across the time course, and genes involved in purinergic signaling pathways exhibited coordinated expression dynamics. Since P2RY11 lacks a mouse/rat ortholog, its contribution to nociceptor biology and opioid responses has remained largely underexplored. Using human DRG tissue and primary human DRG cultures from organ donors, we detected P2RY11 mRNA and P2Y11 protein in neuronal populations. We observed increased P2Y11 expression in peripherin-positive neurons after morphine exposure in vitro, corroborating our sequencing results. These findings identify P2RY11/P2Y11 as a morphine-responsive purinergic receptor in DRG neurons and nominate purinergic signaling as a candidate pathway contributing to opioid-driven peripheral plasticity. Full article

Locoregional anaesthesia is vital in modern equine veterinary practice. It effectively manages acute pain and may reduce the anaesthetic requirements and adverse effects associated with general anaesthesia. This review summarises the currently described local anaesthetic techniques used in horses, with emphasis on epidural approaches, peripheral nerve blocks, and fascial plane techniques. The relevant literature was identified through searches of PubMed, Web of Science, and Scopus databases. The review discusses the pharmacological properties of commonly used local anaesthetics, differences between short- and long-acting agents, and the potential role of adjuvants in prolonging analgesia. In addition, the available evidence regarding ultrasound-guided and nerve stimulator-guided techniques is presented, including their applications in thoracic, abdominal, and reproductive procedures. Attention is given to recently described fascial plane blocks and to the growing use of ultrasound guidance for improving anatomical identification and needle placement. The available evidence suggests that locoregional anaesthesia can contribute to multimodal analgesia in horses while potentially reducing perioperative systemic analgesic requirements. However, the clinical evidence supporting several techniques remains limited, and further controlled studies are required to evaluate their efficacy, safety, and reproducibility under clinical conditions. Full article

Background and Objectives: Ultrasound-guided sciatic and saphenous nerve blocks are widely used as analgesic alternatives for multimodal analgesia. However, how to objectively quantify the opioid- and anaesthetic-sparing effects of an additional peripheral nerve block in patients undergoing ankle fracture surgery under general anaesthesia remains unclear. This study aimed to evaluate their efficacy in managing postoperative pain and opioid-sparing effects following ankle fracture surgery. Materials and Methods: Patients scheduled for ankle fracture surgery were randomly assigned to the nerve block (n = 30) or control group (n = 30). The primary outcome was the postoperative numeric rating scale (NRS) score. The secondary outcomes included the total doses of remifentanil and propofol, Quality of Recovery-40 Korean (QoR-40K) scores, and self-reported patient satisfaction. Results: The NRS score immediately after surgery was significantly lower in the nerve block group compared with that in the control group (2.6 ± 2.5 vs. 6.2 ± 2.6; p < 0.001). The total remifentanil dose required during surgery was also significantly lower in the nerve block group than in the control group (1148.1 ± 391.8 vs. 1487.4 ± 798.8; p = 0.041). However, the patient satisfaction scale (3 [IQR, 2–4] vs. 3 [IQR, 2–4]; p = 0.206) and QoR-40K score 24 h after surgery (169 [IQR, 155–184] vs. 175 [IQR, 154–165]; p = 0.324) did not differ significantly between the two groups. Conclusions: Ultrasound-guided sciatic and saphenous nerve blocks significantly reduced immediate postoperative pain and intraoperative remifentanil consumption under qNOX (quantitative nociception index)-guided general anaesthesia during ankle fracture surgery. Full article

Introduction: Pain is one of the most common reasons why patients seek medical care, and chronic pain is now recognized as a major health problem worldwide. Better understanding of pain mechanisms has shown the importance of distinguishing nociceptive, neuropathic, and nociplastic pain in order to choose the most effective treatment. In recent years, topical analgesics have gained increasing attention because they can provide pain relief directly at the site of application while reducing systemic exposure and the risk of adverse effects. This is especially important in older adults, patients with multiple diseases, and those exposed to polypharmacy. Methods: This narrative review presents the current knowledge on the pharmacology, efficacy, and safety of topical drugs used in pain treatment. Particular attention is given to topical non-steroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, menthol, and camphor. The review also discusses newer and less established therapies used mainly in neuropathic pain, including topical ketamine, amitriptyline, phenytoin, gabapentin, and clonidine. A structured, non-systematic literature search was conducted using the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases to identify studies evaluating the efficacy and safety of topical analgesic therapies. Results: Current evidence supports topical NSAIDs as first-line therapy for localized musculoskeletal pain and osteoarthritis, while lidocaine and high-concentration capsaicin patches are effective options in focal neuropathic pain. Although several newer topical therapies show promising results, more high-quality clinical studies are still needed. Overall, topical analgesia is an important part of multimodal pain management because it combines analgesic efficacy with a better safety profile compared with many systemic therapies. Conclusions: Taking the aspects discussed in this paper into account, it seems justified to search for new drug combinations that would contribute to effective pain therapy with topical agents. It is recognized that a multimodal approach to pain management, which utilizes drugs with different mechanisms of action, can increase efficacy and reduce the systemic adverse events of the drugs used. The effective and safe treatment of patients with pain, especially neuropathic pain, despite emerging new clinical trials, remains a challenge for clinicians. Full article

Adductor canal block (ACB) is widely used for perioperative analgesia in knee surgery because it provides effective pain control while preserving quadriceps muscle strength. With the increasing use of ultrasound-guided regional anesthesia, interest has expanded beyond conventional morphologic imaging toward quantitative assessment of peripheral nerve function and biomechanics. Shear wave elastography (SWE) is an emerging ultrasound-based technique that enables real-time quantification of tissue stiffness and has recently gained attention in peripheral nerve evaluation. Previous SWE studies have primarily focused on chronic neuropathic conditions, including entrapment neuropathy and diabetic neuropathy, in which increased nerve stiffness is commonly observed. However, emerging observations suggest that peripheral nerve stiffness may dynamically decrease following regional anesthesia procedures such as ACB. This finding raises the possibility that nerve stiffness reflects not only chronic structural pathology but also transient physiologic and biomechanical modulation. Potential mechanisms underlying reduced stiffness after ACB include perineural hydrodissection, decreased fascial compression, sympathetic blockade-induced vasodilation, altered intraneural pressure, and changes in surrounding muscle tension. Because the saphenous nerve within the adductor canal is superficial and consistently visualized under ultrasound guidance, ACB represents an attractive model for investigating dynamic changes in peripheral nerve biomechanics. This narrative review summarizes current evidence regarding SWE assessment of peripheral nerves and discusses the potential implications of dynamic stiffness changes after regional anesthesia. We review the biomechanical principles of SWE, factors affecting nerve stiffness, current evidence in neuropathic and perioperative settings, technical limitations, and future clinical applications. Understanding the dynamic behavior of peripheral nerve stiffness may expand the role of SWE from a diagnostic tool for neuropathy to a quantitative biomarker for regional anesthesia and perioperative nerve physiology. Full article

Introduction: Labor pain is among the most intense forms of acute pain, mediated in part by excitatory glutamatergic neurotransmission within central nociceptive pathways. Glutamate plays a key role in spinal dorsal horn signaling and central sensitization, yet its peripheral dynamics during labor and in response to different analgesic modalities remain unclear. This exploratory study aimed to evaluate whether maternal salivary glutamate levels differ between epidural labor analgesia and systemic morphine analgesia during normal vaginal delivery. Method: In this observational comparative study, 36 women were selected to either epidural analgesia (n = 16) or systemic morphine analgesia (n = 20). Salivary samples were collected during active labor and analyzed for glutamate concentration using a validated enzymatic colorimetric assay. Clinical and demographic data were recorded. Non-parametric tests were applied due to non-normal distribution of glutamate levels. Results: Baseline maternal and perinatal characteristics were comparable between groups. Median salivary glutamate levels were higher in the epidural group than in the morphine group (5.32 nmol/µL [IQR 2.83–8.00] vs. 3.99 nmol/µL [IQR 2.26–8.03]), but the difference was not statistically significant (p = 0.599). Glutamate concentrations showed marked inter-individual variability (0.14–29.89 nmol/µL) and a right-skewed distribution. No significant associations were observed between glutamate levels and maternal age, Body Mass Index, gestational age, birth weight, or obstetric comorbidities. Conclusion: In this exploratory cohort, maternal salivary glutamate concentrations did not differ significantly between epidural labor analgesia and systemic morphine analgesia during labor. The variability observed suggests complex and heterogeneous regulation of peripheral glutamatergic activity in parturition. Further larger-scale studies integrating central and peripheral measurements are warranted. Full article

Background: Cancer pain affects approximately 44.5% of all patients with malignancy and up to 55–65% of those with advanced or metastatic disease; a substantial proportion remain inadequately controlled with conventional pharmacological approaches alone. Peripheral nerve stimulation (PNS), a minimally invasive neuromodulatory strategy, has emerged as a potential opioid-sparing analgesic option for the perioperative management of oncologic surgical patients. Objectives: This narrative review synthesizes current evidence on the application, mechanisms, clinical efficacy, safety, and integration of temporary and permanent PNS systems in cancer patients, with specific focus on cancer-specific pain syndromes, key clinical studies, opioid-sparing immunological implications, evidence quality, and directions for future research. Methods: As a narrative review, this work was structured in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) to ensure methodological transparency. A focused, non-systematic literature search of PubMed/MEDLINE, Embase, and the Cochrane Library was performed from database inception through March 2026, supplemented by hand-searching of reference lists and targeted retrieval of clinical practice guidelines. Sources were selected on the basis of relevance to PNS or closely analogous peripheral neurostimulation modalities in oncologic, perioperative, or chronic pain contexts. Evidence was synthesized narratively, with each cited study graded using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 Levels of Evidence framework to enable transparent calibration of confidence. Results: Available preliminary and largely extrapolated evidence supports PNS as a promising but not yet established useful adjunct in oncologic perioperative care; because cancer-specific data rest substantially on a single pilot study (n = 12), one retrospective review (n = 15), and extrapolation from non-cancer populations, these conclusions should be regarded as hypothesis-generating. Randomized controlled trial data from non-cancer cohorts demonstrate opioid consumption reductions of approximately 80–90% in the PAINfRE trial, while the post-amputation trial demonstrated ≥50% pain-relief responder rates and reductions in pain interference, with clinically meaningful improvements in pain and function. Oncologic-specific pilot and retrospective evidence confirms feasibility and a 58–67% success rate across diverse cancer pain subtypes. Conclusions: The opioid-sparing properties of PNS carry additional biological plausibility for preserving perioperative antitumor immune function. High-quality prospective trials specifically designed for oncologic surgical populations remain needed to establish evidence-based recommendations. Full article

Background: Chronic non-specific low back pain (CNSLBP) is highly disabling, and the efficacy of transcranial direct current stimulation (tDCS) remains uncertain. This systematic review and meta-analysis evaluated the effects of standalone and combined tDCS on pain and functional disability in adults with CNSLBP, with secondary comparisons between M1 and DLPFC stimulation. Methods: PubMed, Web of Science, Science Direct, China National Knowledge Infrastructure, Chinese Quarterly Virtual Information Platform, and Wanfang Data were searched up to February 2026. Randomized controlled trials of standalone or combined tDCS in adults with CNSLBP were included. Meta-analyses assessed pain intensity and functional disability, with subgroup analyses comparing stimulation targets and meta-regression exploring protocol parameters. Evidence certainty was evaluated using GRADE, and the protocol was registered with PROSPERO (CRD420261341095). Results: Meta-analysis of 17 trials showed that standalone tDCS did not significantly reduce pain intensity, whereas tDCS combined with peripheral interventions yielded a significant analgesic effect, and anodal stimulation over M1 significant reduced pain intensity. However, neither standalone nor combined tDCS significantly improved functional disability, subgroup differences between M1 and DLPFC were non-significant, and meta-regression identified no significant moderators. Descriptive findings showed potential benefits of tDCS for pain catastrophizing and postural control, with mild adverse events. Conclusions: Moderate-certainty evidence suggests that standalone tDCS is unlikely to provide clinically meaningful analgesia for CNSLBP. Low-certainty evidence indicates that anodal M1 tDCS combined with structured peripheral interventions, particularly exercise, may produce analgesic benefits, but this finding requires cautious interpretation. Full article

Background and Clinical Significance: Sickle cell vaso-occlusive crisis (VOC) may present with severe refractory pain that is difficult to control despite guideline-directed multimodal therapy and high-dose opioids. Case Presentation: We report an adult with VOC and severe, opioid-refractory anterior thigh and leg pain who was treated with bilateral, ultrasound-guided continuous femoral nerve catheters (0.5% bupivacaine bolus per side followed by infusion of 0.2% ropivacaine at 5 mL/h each). Twenty-four-hour opioid use decreased by 76% from 44 mg intravenous hydromorphone (880 MME) before block placement to 10.4 mg (208 MME) after catheter initiation. Pain scores declined significantly from 10/10 to 3/10, facilitating mobilization and expediting discharge of the patient. No local anesthetic systemic toxicity occurred, and transient quadriceps weakness was managed with fall-risk precautions. IRB approval for this case report was waived per our institution policy. Conclusions: In select adults with VOC and predominant anterior thigh/leg pain, bilateral continuous femoral nerve catheters may provide rapid analgesia and substantial opioid-sparing benefits as part of multidisciplinary care. These findings are hypothesis-generating and support prospective evaluation of continuous peripheral nerve block strategies in VOC. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Background/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine–ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable. Full article

Background: Mas-related G-protein-coupled receptor b4 (Mrgprb4)-lineage neurons in the peripheral nervous system are a type of C fibers in hairy skin. Our prior work demonstrated that these neurons respond to both noxious and innocuous mechanical and thermal stimuli. Ablating them eliminates the pleasant sensation elicited by gentle pressure on a mouse’s nape. However, their potential role in mitigating pain and pain-related negative emotions in response to somatic stimuli remains unclear. Methods: A CFA-induced chronic pain and anxiety comorbidity model was established in C57BL/6J mice. In vivo calcium imaging of dorsal root ganglia (DRG) neurons in Mrgprb4-GCaMP6s transgenic mice characterized neuronal responses to transcutaneous electrical nerve stimulation (TENS) at the Zusanli (ST36) acupoint. Optogenetic activation (Mrgprb4-ChR2 mice) and viral ablation of Mrgprb4-lineage neurons were employed to evaluate their role in mediating TENS effects on mechanical pain thresholds and anxiety-like behaviors. Results: In vivo calcium imaging revealed that 0.5 mA TENS preferentially activated Mrgprb4-lineage neurons compared to 2.0 mA TENS. In CFA model mice, 0.5 mA TENS at ST36 significantly increased mechanical pain thresholds and reduced anxiety-like behaviors in the open-field test. Optogenetic activation of Mrgprb4-lineage neurons at ST36 replicated these analgesic and anxiolytic effects, demonstrating the sufficiency of these neurons for therapeutic outcomes. Conversely, viral ablation of L3–L5 Mrgprb4-lineage neurons substantially attenuated the therapeutic effects of 0.5 mA TENS for both pain relief and anxiety reduction, indicating their necessity in mediating TENS efficacy. Conclusions: Mrgprb4-lineage neurons serve as critical peripheral mediators of TENS-induced analgesia and anxiolysis. These findings identify a specific neuronal population underlying the therapeutic effects of somatic stimulation at ST36, providing mechanistic insights that may guide optimization of TENS parameters for treating chronic pain and comorbid anxiety in clinical settings. Full article

Total knee arthroplasty (TKA) is one of the most performed surgical procedures in the United States and is often associated with moderate to severe postoperative pain. Multimodal postoperative analgesia following TKA is essential for optimizing postoperative recovery and enabling early postoperative mobilization. Regional anesthesia using ultrasound-guided peripheral nerve blocks plays an important part in perioperative pain management by targeting the femoral, obturator, and sciatic nerves of the knee joint. A variety of peripheral nerve block techniques have been described, which can be classified as either motor-blocking or motor-sparing techniques. Traditional motor-blocking regional anesthesia techniques, such as femoral and sciatic nerve blocks, provide excellent analgesia but can result in significant quadriceps weakness that delays ambulation after TKA. Motor-sparing regional anesthesia techniques, including the adductor canal block, iPACK block, and genicular nerve block, are becoming more widely used in enhanced postoperative recovery protocols for outpatient and short-stay inpatient TKAs. The peripheral nerve block technique can be selected according to the type of surgical procedure, the planned length of stay, rehabilitation goals, and patient comorbidities. Multiple peripheral nerve blocks provide better analgesia than single-injection blocks, and continuous catheter techniques are used for prolonging analgesia in select patients. An individualized multimodal regional anesthesia approach should be utilized to maximize analgesia after TKA to optimize postoperative outcomes. We present a narrative review of peripheral nerve block techniques and strategies for their use following inpatient or outpatient TKA. Full article