Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of pharmacological therapies and determine the best strategy for CRPS. We searched the databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov, for published eligible randomized controlled trials (RCTs) comparing pharmacological treatment with placebo in CRPS patients. Target patients were diagnosed with CRPS according to Budapest Criteria in 2012 or the 1994 consensus-based IASP CRPS criteria. Finally, 23 RCTs comprising 1029 patients were included. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty (confidence in evidence and quality of evidence). Direct meta-analysis showed that using bisphosphonates (BPs) (mean difference [MD] −2.21, 95% CI −4.36–−0.06, p = 0.04, moderate certainty) or ketamine (mean difference [MD] −0.78, 95% CI −1.51–−0.05, p = 0.04, low certainty) could provide long-term (beyond one month) pain relief. However, there was no statistically significant difference in the efficacy of short-term pain relief. Ketamine (rank p = 0.55) and BPs (rank p = 0.61) appeared to be the best strategies for CRPS pain relief. Additionally, BPs (risk ratio [RR] = 1.86, 95% CI 1.34–2.57, p < 0.01, moderate certainty) and ketamine (risk ratio [RR] = 3.45, 95% CI 1.79–6.65, p < 0.01, moderate certainty) caused more adverse events, which were mild, and no special intervention was required. In summary, among pharmacological interventions, ketamine and bisphosphonate injection seemed to be the best treatment for CRPS without severe adverse events.

Complex regional pain syndrome (CRPS) is a chronic pain that affects the extremities after a trauma or nerve injury with no definite established treatment. The mechanisms mediating CRPS are not completely elucidated. Thus, we conducted a bioinformatics analysis to identify hub genes and key pathways to determine strategies for more effective treatments of CRPS. Finally, there is only one expression profile of GSE47063 in terms of homo sapiens-based CRPS from the Gene Expression Omnibus (GEO) database, which included four patients and five controls. We explored the differentially expressed genes (DEGs) in the dataset and conducted Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the potential hub genes. A protein–protein interaction (PPI) network was also established; then, according to the score of each hub genes, we used R software to draw the nomogram model to predict the rate of CRPS. Furthermore, GSEA analysis was estimated and assessed by the normalized enrichment score (NES). From the GO and KEGG analysis, we identified the top five hub genes (MMP9, PTGS2, CXCL8, OSM, TLN1); all of the selected DEGs were mainly enriched in their inflammatory response. In addition, the GSEA analysis showed complement and coagulation cascades also play an important role in CRPS. This study, to our knowledge, is the first to conduct further PPI network and GSEA analyses. Thus, targeting excessive inflammation could offer new therapeutic methods for CRPS and related physical and psychiatric disorders.

Complex regional pain syndrome (CRPS), a type of primary chronic pain, occurs following trauma or systemic disease and typically affects the limbs. CRPS-induced pain responses result in vascular, cutaneous, and autonomic nerve alterations, seriously impacting the quality of life of affected individuals. We previously identified the involvement of keratinocyte N-methyl-d-asparagic acid (NMDA) receptor subunit 2 B (NR2B) in both peripheral and central sensitizations in CRPS, although the mechanisms whereby NR2B functions following activation remain unclear. Using an in vivo male rat model of chronic post-ischemia pain (CPIP) and an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) cell model, we discovered that oxidative injury occurs in rat keratinocytes and HaCaT cells, resulting in reduced cell viability, mitochondrial damage, oxidative damage of nucleotides, and increased apoptosis. In HaCaT cells, OGD/R induced increases in intracellular reactive oxygen species levels and disrupted the balance between oxidation and antioxidation by regulating a series of antioxidant genes. The activation of NMDA receptors via NMDA exacerbated these changes, whereas the inhibition of the NR2B subunit alleviated them. Co-administration of ifenprodil (an NR2B antagonist) and NMDA (an NMDA receptor agonist) during the reoxygenation stage did not result in any significant alterations. Furthermore, intraplantar injection of ifenprodil effectively reversed the altered gene expression that was observed in male CPIP rats, thereby revealing the potential mechanisms underlying the therapeutic effects of peripheral ifenprodil administration in CRPS. Collectively, our findings indicate that keratinocytes undergo oxidative injury in CRPS, with NMDA receptors playing regulatory roles.

Neuropathic pain (NP) is a debilitating chronic pain condition with complex molecular mechanisms and inadequate therapeutic solutions. This study aims to identify temporal transcriptomic changes in NP using multiple bioinformatics and machine learning algorithms. A total of 10 mouse samples (5 per group) were harvested at each time point (day three, day seven, and day fourteen), following spared nerve injury and a sham operation. Differentially expressed gene (DEG) analysis and an intersection among the three time-point groups revealed 54 common DEGs. The GO and KEGG analyses mainly showed enrichment in terms of immune response, cell migration, and signal transduction functions. In addition, the interaction of the LASSO, RF, and SVM-RFE machine learning models on 54 DEGs resulted in Ngfr and Ankrd1. The cyan module in WGCNA was selected for a time-dependent upward trend in gene expression. Then, 172 genes with time-series signatures were integrated with 54 DEGs, resulting in 11 shared DEGs. Quantitative RT-PCR validated the temporal expressions of the above genes, most of which have not been reported yet. Additionally, immune infiltration analysis revealed significant positive correlations between monocyte abundance and the identified genes. The TF-mRNA-miRNA network and drug-target network revealed potential therapeutic drugs and posttranscriptional regulatory mechanisms. In conclusion, this study explores genes with time-series signatures as biomarkers in the development and maintenance of NP, potentially revealing novel targets for analgesics.

General anesthetics were first used over 170 years ago; however, the mechanisms of how general anesthetics induce loss of consciousness (LOC) remain unclear. Ciprofol, a novel intravenous anesthetic, has been developed by incorporating cyclopropyl into the chemical structure of propofol. This modification offers the benefits of rapid onset and minimal injection pain. Recent studies have revealed that the glutamatergic neurons of the lateral habenula (LHb) play a crucial role in modulating the LOC induced by propofol and sevoflurane. Nevertheless, the specific involvement of LHb in the anesthetic effects of ciprofol remains uncertain. Here, using targeted recombination in active populations (TRAP) combined with electroencephalogram/electromyography recordings and the righting reflex behavioral test, our study revealed that intravenous infusion of ciprofol for 1 h could lead to the induction of c-Fos expression in the LHb in mice. The combination of TRAP and gene ablation, aimed at selectively ablating ciprofol-activated neurons in the LHb, has been shown to facilitate the emergence of ciprofol anesthesia and decrease the proportion of delta waves during the emergence phase. Chemogenetic inhibition of these neurons produced a comparable effect, whereas chemogenetic activation resulted in the opposite outcome. Chemogenetic activation of ciprofol-activated neurons in the LHb delays the emergence of anesthesia and induces a deep hypnotic state during the emergence phase. Taken together, our findings suggest that LHb ciprofol-activated neurons modulate the state of consciousness and could potentially be targeted to manipulate consciousness during ciprofol anesthesia.