Pain induces a rapid characteristic metabolic signature detectable in breath
Pablo Sinues, Melina Richard, Kapil Singh, Dilan Sezer, Sarah Buergler, Luana Palermo, Yannick Schulz, Zhifeng Tang, Xin Luo, Urs Frey,Philippe Cattin, Xue Li, Jens Gaab
Abstract
The objectification of pain presents a significant clinical challenge, particularly in children, elderly individuals, patients with disabilities and unconscious patients. It is critically important to accurately assess pain in these populations due to the heightened risk of undertreatment. Using the cold pressor test (CPT) as a pain induction model, we combined real-time breath metabolomics with pathway analysis to uncover metabolic shifts. Exhaled breath was analyzed in a discovery cohort (n=19) and validated in an independent cohort (n=21) using secondary electrospray ionization-high-resolution mass spectrometry (SESI-HRMS). Within 15 minutes of CPT, over 400 conserved mass spectral features were significantly altered across both cohorts. Pathway analysis highlighted shifts in aminoacyl-tRNA biosynthesis, cysteine/methionine metabolism, butanoate metabolism, and arginine/proline metabolism. Arginine and glutamate, key contributors to nitric oxide production and nociceptive signaling, exhibited consistent upregulation. Neural network classifiers achieved robust differentiation between pre- and post-CPT profiles (AUC=0.856), showcasing breath metabolomics as a promising observer independent, and objective tool for real-time pain assessment. To validate universal mechanistic relevance of the findings, we compared them to findings of chronic pain studies revealing consistencies in amino acid and neurotransmitter-related pathways. This study provides novel insights into the metabolic basis of acute pain and positions breath metabolomics as a viable approach for dynamic, observer independent monitoring pain in vulnerable patient groups. Future research must determine if these new insights into mechanistic pathways can inform patient- and disease-specific pain management strategies.