Cold induced pain elicits reproducible breath metabolomic responses across geographically distinct populations.

Overview

1. University Children’s Hospital Basel (UKBB), Spitalstrasse 33, 4031 Basel, Switzerland
2. Department of Biomedical Engineering, University of Basel, Hegenheimermattweg 167b, 4123 Allschwil, Switzerland
3. Faculty of Psychology, University of Basel, Missionsstrasse 60/62, 4055 Basel, Switzerland
4. University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
5. College of Environment and Climate, Institute of Mass Spectrometry and Atmospheric Environment, Guangdong Provincial Key Laboratory of Speed Capability Research, Jinan University, Guangzhou 510632, China

Abstract

Observer-independent assessment of nociceptive states is particularly important in non-communicative or vulnerable patient populations, where self-report is unavailable. In this proof-of-concept study, we explored whether exhaled breath metabolomics, measured in real time using secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS), can capture rapid physiological responses to the cold pressor test (CPT), a standardized model of acute sympathetic and nociceptive activation. Forty healthy adults (n = 19 in Switzerland, n = 21 in China) underwent four breath measurements: two pre- and two post-CPT intervention. Mass spectral data revealed a reproducible and rapid metabolic shift, with over 400 upregulated features consistently observed across both cohorts. Pathway enrichment and correlation analyses implicated amino acid metabolism (e.g., glutamate, arginine, and threonine) and stress-related pathways (e.g., creatine, butanoate, and citric acid cycle intermediates). A neural network classifier distinguished pre-vs. post-CPT states (AUC = 0.856, 78% accuracy). Our findings support real-time breath analysis as a non-invasive method for detecting short-term physiological responses.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

• doi:10.17632/9g3nthjf2z.2, at the source; found in “Data and code availability”

Data and code availability

Raw breath metabolomics data and associated metadata have been deposited at Mendeley Data as Mendeley Data: https://doi.org/10.17632/9g3nthjf2z.2 and are publicly available as of the date of publication. The dataset includes raw SESI-HRMS files, Exhalion files, subject metadata, measurement conditions, instrumental parameters, and CPT response times for both the discovery and validation cohorts.

This paper does not report original code. All data processing and analysis steps are fully described in the STAR Methods and supplemental information.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 6 keywords, 5 funders, 77 references.

Cite

This paper

Richard, M., Singh, K. D., Sezer, D., Buergler, S., Palermo, L., Schulz, Y., Tang, Z., Luo, X., Frey, U., Cattin, P. C., Li, X., Gaab, J., & Sinues, P. (2026). Cold induced pain elicits reproducible breath metabolomic responses across geographically distinct populations. iScience, 29(6), 115857. https://doi.org/10.1016/j.isci.2026.115857

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