# Circulating microRNAs differentiate nociceptive and nociplastic pain: An exploratory study

## TL;DR

This study explores how specific microRNAs in the blood can help distinguish between two types of pain and track treatment responses.

## Contribution

The study identifies miR-16, miR-26a, and Let-7a as novel biomarkers for differentiating nociceptive and nociplastic pain mechanisms.

## Key findings

- Let-7a is associated with joint degeneration but not subjective pain ratings.
- MiR-16 decreases after cognitive behavioral therapy, indicating neuroplastic adaptation.
- A decision tree model using miRNA markers achieved high accuracy (AUC > 0.94) in pain classification.

## Abstract

•Let-7a, miR-26a, and miR-16 differentiate nociceptive and nociplastic pain.•Let-7a tracks joint degeneration, not subjective pain.•MiR-16 decrease after CBT reflects neuroplastic adaptation.•Decision tree model achieved AUC > 0.94 using miRNA markers.•Circulating miRNAs show diagnostic potential in pain classification.

Let-7a, miR-26a, and miR-16 differentiate nociceptive and nociplastic pain.

Let-7a tracks joint degeneration, not subjective pain.

MiR-16 decrease after CBT reflects neuroplastic adaptation.

Decision tree model achieved AUC > 0.94 using miRNA markers.

Circulating miRNAs show diagnostic potential in pain classification.

Nociceptive and nociplastic pain arise from distinct biological mechanisms, yet their differentiation remains clinically challenging. Circulating microRNAs (miRNAs) are promising candidates for objective, mechanism-based pain classification.

To explore whether specific circulating miRNAs can differentiate nociceptive pain in patients with hip osteoarthritis (HO) from nociplastic pain in patients with chronic primary pain (CPP), and to assess their relationship with clinical and psychological outcomes.

In this exploratory, single-center study, plasma samples were collected from patients with HO (n = 13), CPP (n = 11), and healthy controls (n = 7). Microarray screening identified candidate miRNAs, which were validated via real-time PCR. Pain intensity (NRS), disability (PDAS), quality of life (EQ-5D), and psychological factors (PCS, PSEQ, TSK-11, PHQ-9) were assessed. Classification accuracy was evaluated using decision tree modeling and ROC analysis.

Let-7a, miR-26a, and miR-16 showed distinct expression profiles and contributed to a predictive model with strong performance (R2 = 0.677; AUC > 0.94). Let-7a expression was associated with structural joint changes in HO but not subjective pain ratings. MiR-26a correlated with cognitive-affective pain traits in CPP, and miR-16 decreased following CBT, suggesting a role in treatment-related neuroplasticity. MiR-126 and miR-146a were linked to reductions in pain intensity post-surgery in the HO group. QOL improved in HO, while psychological factors remained prominent in CPP.

This pilot study suggests that circulating miRNAs may aid in differentiating nociceptive and nociplastic pain mechanisms and tracking treatment effects. While preliminary, these findings support the potential utility of miRNA-based biomarkers in precision pain diagnostics and personalized management strategies.