Orofacial pain (OFP) includes chronic pain conditions categorized into musculoskeletal (MS), neurovascular (NV), and neuropathic (NP) pain types, encompassing temporomandibular disorders (TMD), migraines, trigeminal neuralgia (TN), post-traumatic neuropathies, and burning mouth syndrome (BMS). These conditions significantly affect quality of life
yet, their underlying metabolic disruptions remain inadequately explored. Salivary metabolomics provides a non-invasive method to investigate biochemical alterations associated with OFP subtypes. This study aimed to identify pain-specific salivary metabolites across chronic OFP types and examine their correlations with clinical characteristics. Saliva samples from 63 OFP patients (TMD, migraines, TN, post-traumatic neuropathies, BMS) and 37 pain-free controls were analyzed using liquid chromatography-mass spectrometry (LC-MS) targeting 28 metabolites linked to pain. Statistical analyses determined significant metabolite changes and associations with pain subtypes and patient characteristics. Among the 28 analyzed metabolites, 18 showed significant differences between OFP patients and controls. Key amino acids, including DL-glutamic acid, DL-aspartic acid, DL-citrulline, spermidine, and DL-ornithine, were significantly elevated in MS, NV, and NP pain types compared to controls. Additionally, DL-glutamine, DL-valine, and DL-phenylalanine were distinctively elevated in TMD and migraine patients. BMS displayed fewer alterations, with significantly lower levels of DL-proline, DL-tryptophan, DL-glutamic acid, DL-asparagine, and DL-aspartic acid compared to other pain types but elevated spermidine levels relative to controls. Salivary metabolomics revealed distinct metabolic alterations in OFP subtypes, providing insights into potential biomarkers for diagnosis and monitoring. These findings offer a foundation for personalized approaches in OFP management, although further research is required to validate and expand these results.