Neural biomarkers in pulpitis and their associations with inflammation and pain perception: a systematic review and meta-analysis.

Pulpal nerves have been revealed to play a crucial role in regulating immune responses and pain perception in dental pulp inflammation. While the dynamic changes in inflammatory mediators during the progression of pulpitis have been extensively emphasized, neural biomarkers and pulpal nerve alterations have not been well summarized. The objective of this study was to synthesise evidence on the expression of molecular biomarkers associated with neural alterations during pulp inflammation, with particular emphasis on which molecules orchestrate inflammation and how they regulate pain perception. An electronic search was conducted across PubMed, Web of Science, MEDLINE, Scopus, Embase, and the Cochrane Library. Human studies published in English with full text available that investigated biomarkers associated with neural changes in pulpitis were included. The data extraction and quality assessment were conducted by calibrated assessors. Meta-analysis was performed on biomarkers for which data were available for synthesis; the standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed. Thirty-two case-control studies were identified, with a moderate risk of bias. A total of thirty-eight biomarkers were investigated in the included studies. Four studies on substance P (SP) and five on calcitonin gene-related peptide (CGRP) were included in the meta-analysis, respectively. A statistically significant increase in CGRP expression was observed in teeth with symptomatic irreversible pulpitis compared with healthy teeth; however, heterogeneity was high. CGRP also demonstrated a potential association with the incidence of pain in inflamed pulps. In contrast, the expression levels of SP remain inconclusive between inflamed and healthy pulps, as does its association with pain perception. Given the limitations of insufficient clinical data and methodological variability, the low-quality evidence suggests that neural biomarkers, particularly CGRP, may be associated with pulpal inflammation and pain perception.