Modality and Calculation Method Influence Conditioned Pain Modulation Outcomes—An International Multisite Study

European Journal of Pain, vol. 30, pp. e70394

Abstract

BACKGROUND: Conditioned pain modulation (CPM) is a human surrogate marker reflecting the net efficacy of descending noxious inhibitory and facilitatory control systems, but substantial variability exists. This multicenter study examined (1) associations between heat- and pressure-based CPM outcomes, (2) associations between relative and absolute CPM assessments within each pain sensitivity modality, and (3) differences in CPM effects across three countries. METHODOLOGY: A total of 103 participants were recruited from Denmark (n = 32), the Netherlands (n = 40), and Israel (n = 31). CPM was assessed using pressure pain thresholds (PPTs) and tonic heat as test stimuli, respectively, with the cold pressor test as the conditioning stimulus. The CPM effect was calculated as absolute and relative changes during the conditioning stimulus compared with baseline. CPM responders were defined as having a CPM larger than the lower bounds of the CPM effect's 95% confidence interval. RESULTS: No correlations between heat- and pressure-based CPM outcomes were found using either absolute or relative calculations. In contrast, absolute and relative CPM effects were strongly correlated within the heat (r = 0.816, p < 0.001) and pressure (r = 0.863, p < 0.001) modalities. CPM responder classification was also not associated between pressure and heat test stimuli. Relative pressure CPM differed between countries (p = 0.009), whereas the remaining CPM outcomes did not. CONCLUSION: Using a standardized protocol across three international centers, the present findings indicate that pressure- and heat-based CPM outcomes may not be directly comparable, with significant between-country differences observed only for relative pressure CPM. SIGNIFICANCE STATEMENT: This multicenter study shows that conditioned pain modulation depends on both the type of test stimulus and how it is quantified. The findings indicate that CPM may be a more complex phenomenon and that results obtained using heat and pressure test stimuli are not directly comparable, challenging the assumption that CPM is interchangeable across methods. This methodological difference may help explain inconsistencies across previous studies. Furthermore, the data suggest that absolute pressure CPM and relative heat CPM provide more stable measures for future research.

Authors 10

1. Jens Frøjk Axel Dixen

   Aalborg University

   Affiliation as printed

   Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark

2. Emma Hertel

   Aalborg University

   Affiliation as printed

   Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Department of Material and Production, Faculty of Engineering and Science Aalborg University Aalborg Denmark

   Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark

3. Monique van Velzen Aachen Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center

   Affiliation as printed

   Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden the Netherlands

4. Cornelis Jan van Dam Aachen Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center

   Affiliation as printed

   Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden the Netherlands

5. Marieke Niesters Aachen Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center

   Affiliation as printed

   Department of Anesthesiology and Pain Medicine Leiden University Medical Center Leiden the Netherlands

6. Megan E. McPhee

   Aalborg University

   Affiliation as printed

   Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark

7. Lars Arendt‐Nielsen

   Aalborg University

   Affiliation as printed

   Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark

8. David Yarnitsky

   Technion – Israel Institute of Technology · Rambam Health Care Campus

   Affiliation as printed

   Department of Neurology, Rambam Health Care Campus Technion‐Israel Institute of Technology Haifa Israel

9. Thomas Graven‐Nielsen corresponding

   Aalborg University

   Affiliation as printed

   Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark

10. Kristian Kjær-Staal Petersen

    Aalborg University

    Affiliation as printed

    Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Department of Material and Production, Faculty of Engineering and Science Aalborg University Aalborg Denmark

    Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine Aalborg University Aalborg Denmark