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 (ICC 3,1 = 0.69; ICC 3,2 = 0.81) and for N_CPM at Cz (ICC 3,1 = 0.63; ICC 3,2 = 0.77). N1_CPM showed mean attenuation but poorer test–retest reliability (ICC 3,1 = −0.21; ICC 3,2 = −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.