Reliable Biomarkers of Descending Pain Inhibition: A Laser-Evoked Potential and Behavioural Study.

BACKGROUND: Conditioned pain modulation (CPM) assesses descending pain inhibition, but behavioural approaches are limited by subjectivity and variable reproducibility. We tested a CPM protocol combining nociceptive-selective laser-evoked potentials (LEPs) with a repeated-trial design to determine whether neurophysiological markers complement behavioural measures and improve reliability. METHODS: Twenty-seven healthy adults (mean age 24.6 years; 14 female) completed two sessions ≥ 1 week apart. Nociceptive-selective laser stimuli were applied to the left hand before and after a cold pressor task, and EEG was recorded to extract LEP-N2P2 components. Temporal LEP-N1 was measured as a secondary outcome. Behavioural CPM (B_CPM) was indexed by pain ratings; neurophysiological CPM (N_CPM) was defined by reductions in LEP-N2P2 amplitude. RESULTS: Consistent behavioural responders were observed in 92.6% of participants, and N_CPM responder rates exceeded 74% across electrodes. B_CPM and N_CPM magnitudes correlated at C3, C4, and Cz (ρ = 0.54-0.56; FDR-adjusted p < 0.05). Test-retest reliability was good to excellent for B_CPM (ICC3,1 = 0.69; ICC3,2 = 0.81) and for N_CPM at Cz (ICC3,1 = 0.63; ICC3,2 = 0.77). N1_CPM showed mean attenuation but poorer test-retest reliability (ICC3,1 = -0.21; ICC3,2 = -0.51) and no significant correlation with B_CPM. Psychological measures were stable across visits and unrelated to outcomes in this cohort at baseline. CONCLUSION: The repeated-trial design enabled assessment of within-subject consistency via the B_CPM induction rate. Combining behavioural and neurophysiological measures in this dual-domain framework may improve interpretability and advance standardisation of CPM methodology. LEP-based N_CPM markers showed reproducibility across sessions and may contribute to the development of brain-based biomarkers for patient stratification and treatment selection in chronic pain. SIGNIFICANCE STATEMENT: This study establishes a reproducible dual-domain framework for assessing descending pain inhibition by integrating behavioural conditioned pain modulation with nociceptive-specific laser-evoked potentials. Using a repeated-trial design, both behavioural and cortical measures showed high responder rates, strong correlations, and good test-retest reliability. The findings advance standardisation of CPM methodology and demonstrate that LEP-based neurophysiological markers can objectively index inhibitory function, supporting the development of reliable, brain-based biomarkers to guide mechanism-driven pain assessment and personalised neuromodulation therapies.