Modality and Calculation Method Influence Conditioned Pain Modulation Outcomes—An International Multisite Study
Jens Frøjk Axel Dixen, Emma Hertel, Monique van Velzen, Cornelis Jan van Dam, Marieke Niesters, Megan McPhee, Lars Arendt‐Nielsen, David Yarnitsky, Thomas Graven‐Nielsen, Kristian Kjær‐Staal PetersenABSTRACT
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.