Recommendations for the Neurophysiological Assessment of Conditioned Pain Modulation: A Systematic Review of Nociceptive Blink Reflex and Nociceptive Withdrawal Reflex Protocols.

BACKGROUND AND OBJECTIVE: The nociceptive blink reflex (NBR) and nociceptive withdrawal reflex (NWR) are increasingly used as neurophysiological test stimuli to assess conditioned pain modulation (CPM). However, methodological inconsistencies limit reproducibility and cross-study comparison. This systematic review aimed to evaluate experimental protocols and outcome measures used in CPM studies employing NBR or NWR, and to propose recommendations for standardisation. DATABASES AND DATA TREATMENT: Following PRISMA guidelines, a systematic search of PubMed, Cochrane and Ovid databases was conducted. Studies were included if they assessed CPM in healthy adults using NBR or NWR. Data were extracted on stimulation parameters, electrode configuration, participant positioning, data acquisition, signal processing and CPM protocols. Sixteen studies met inclusion criteria (6 NBR, 10 NWR). RESULTS: Across studies, stimulation protocols varied in frequency, pulse duration and threshold calibration. Electrode placements and participant positioning were often inconsistently reported. Data acquisition methods differed in sampling rates and filtering, and analysis windows were not always defined. CPM protocols included cold pressor, heat and electrocutaneous stimulation. Outcome measures included both amplitude- and threshold-based metrics. CONCLUSIONS: This review highlights significant methodological heterogeneity in reflex-based CPM research in healthy participants. Standardisation of stimulation parameters, recording techniques, and CPM protocols is needed to enhance comparability and reproducibility across studies. To address this, we provide structured recommendations, based on GRADE classifications, for standardising protocols related to experimental setup, data acquisition and CPM outcome measures for both the NBR and NWR. SIGNIFICANCE STATEMENT: Reflex-based conditioned pain modulation demonstrates methodological inconsistencies, highlighting the need for standardised protocols. With standardised protocols recommended in this review, future efforts should focus on enhancing its reliability, reproducibility and clinical applicability.