Cold induced pain elicits reproducible breath metabolomic responses across geographically distinct populations
M. Richard, K.D. Singh, D. Sezer, S. Buergler, L. Palermo, Y. Schulz, Z. Tang, X. Luo, U. Frey, P. C. Cattin, X. Li, J. Gaab, P. Sinues
Abstract
Breath metabolomics for real-time detection of acute pain responses
Cold-induced pain produces rapid physiological changes that are difficult to assess objectively, especially in vulnerable or non-communicative patients. This study investigates whether real-time breath metabolomics using SESI-HRMS can detect metabolic responses to the cold pressor test, a standardized model of acute nociceptive and sympathetic activation. Across two independent cohorts from Switzerland and China, the intervention induced reproducible shifts in the exhaled metabolome, with more than 400 upregulated features shared between both populations. Pathway analyses linked these changes mainly to amino acid metabolism, energy regulation, oxidative stress, and vascular responses. In addition, a neural network model classified pre- and post-pain breath fingerprints with an AUC of 0.856 and 78% accuracy. Overall, the study supports exhaled breath analysis as a promising non-invasive and observer-independent approach for monitoring short-term physiological responses related to pain.