{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:18:27Z","timestamp":1792696707919,"version":"4.5.0"},"reference-count":61,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Pain is one of the most common complaints leading to a pediatric emergency department visit and is associated with various painful procedures, leading to increased anxiety and stress. Assessing and treating pain in children can be challenging, so it is crucial to investigate new methods for pain diagnosis. The review aims to summarize the literature on non-invasive salivary biomarkers, such as proteins and hormones, for pain assessment in urgent pediatric care settings. Eligible studies were those that included novel protein and hormone biomarkers in acute pain diagnostics and were not older than 10 years. Chronic pain studies were excluded. Further, articles were divided into two groups: studies in adults and studies in children (&lt;18 years). The following characteristics were extracted and summarized: study author, enrollment date, study location, patient age, study type, number of cases and groups, as well as tested biomarkers. Salivary biomarkers, such as cortisol, salivary \u03b1-amylase, and immunoglobulins, among others, could be appropriate for children as saliva collection is painless. However, hormonal levels can differ among children in different developmental stages and with various health conditions, with no predetermined levels of saliva. Thus, further exploration of biomarkers in pain diagnostics is still necessary.<\/jats:p>","DOI":"10.3390\/diagnostics13111929","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T01:40:56Z","timestamp":1685583656000},"page":"1929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Exploring Non-Invasive Salivary Biomarkers for Acute Pain Diagnostics: A Comprehensive Review"],"prefix":"10.3390","volume":"13","author":[{"given":"Laura","family":"Stendelyte","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mantas","family":"Malinauskas","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5380-3776","authenticated-orcid":false,"given":"Dovile Evalda","family":"Grinkeviciute","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Jankauskaite","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"},{"name":"Department of Pediatrics, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","unstructured":"IASP (2022, April 13). Announces Revised Definition of Pain\u2014International Association for the Study of Pain (IASP). Available online: https:\/\/www.iasp-pain.org\/publications\/iasp-news\/iasp-announces-revised-definition-of-pain\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","article-title":"The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises","volume":"161","author":"Raja","year":"2020","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s12630-013-0076-7","article-title":"Not small adults: The emerging role of pediatric pain services","volume":"61","author":"Finley","year":"2014","journal-title":"Can. J. Anaesth. J. Can. D\u2019anesthesie"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1155\/2008\/478102","article-title":"Pain in hospitalized children: A prospective cross-sectional survey of pain prevalence, intensity, assessment and management in a Canadian pediatric teaching hospital","volume":"13","author":"Taylor","year":"2008","journal-title":"Pain Res. Manag. J. Can. Pain Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jpain.2019.07.002","article-title":"Assessment and Treatment Recommendations for Pediatric Pain: The Influence of Patient Race, Patient Gender, and Provider Pain-Related Attitudes","volume":"21","author":"Miller","year":"2020","journal-title":"J. Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1097\/01.NAJ.0000370157.33223.6d","article-title":"Culture\u2019s effects on pain assessment and management","volume":"110","author":"Narayan","year":"2010","journal-title":"Am. J. Nurs."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1097\/AJP.0000000000000947","article-title":"Perceived Injustice Is Associated with Pain-related Function and Mood in Youth with Acute Musculoskeletal Pain","volume":"37","author":"Battison","year":"2021","journal-title":"Clin. J. Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/ped.13724","article-title":"Neonatal pain: Knowledge and perception among pediatric doctors in Malaysia","volume":"61","author":"Ishak","year":"2019","journal-title":"Pediatr. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1002\/ejp.1527","article-title":"Evolution in acute pain assessment and treatment in the paediatric emergency department of a tertiary health care centre","volume":"24","author":"Ganzijeva","year":"2020","journal-title":"Eur. J. Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1460-9592.2012.03881.x","article-title":"The pain-free ward: Myth or reality","volume":"22","author":"Morton","year":"2012","journal-title":"Paediatr. Anaesth."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1080\/15360288.2019.1686100","article-title":"Doctors and Nurses\u2019 Knowledge and Attitudes towards Pediatric Pain Management: An Exploratory Survey in a Children\u2019s Hospital","volume":"33","author":"Vagnoli","year":"2019","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s00431-017-2944-6","article-title":"Acute pain management: Acetaminophen and ibuprofen are often under-dosed","volume":"176","author":"Milani","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13052-019-0754-3","article-title":"Acute pain management in children: A survey of Italian pediatricians","volume":"45","author":"Marseglia","year":"2019","journal-title":"Ital. J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1017\/cem.2018.11","article-title":"Is caregiver refusal of analgesics a barrier to pediatric emergency pain management? A cross-sectional study in two Canadian centres","volume":"20","author":"Whiston","year":"2018","journal-title":"CJEM"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13049-015-0166-3","article-title":"Assessment of pain in a Norwegian Emergency Department","volume":"23","author":"Dale","year":"2015","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.pmn.2018.04.006","article-title":"Nurses\u2019 Knowledge, Attitudes and Clinical Practice in Pediatric Postoperative Pain Management","volume":"19","author":"Smeland","year":"2018","journal-title":"Pain Manag. Nurs."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.pmn.2018.03.002","article-title":"Nurses\u2019 Knowledge and Attitudes Regarding Pediatric Pain Management in Western Australia","volume":"19","author":"Peirce","year":"2018","journal-title":"Pain Manag. Nurs."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1038\/s41598-022-08657-4","article-title":"Relevance of cortisol and copeptin blood concentration changes in an experimental pain model","volume":"121","author":"Blum","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1097\/MOP.0000000000000347","article-title":"Management of acute pediatric pain in the emergency department","volume":"28","author":"Ruest","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1145","DOI":"10.1097\/PEC.0000000000001930","article-title":"Pain Assessment in Pediatric Emergency Departments: A National Survey","volume":"37","author":"Haupt","year":"2021","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4037\/ccn2019713","article-title":"Using Valid and Reliable Tools for Pain and Sedation Assessment in Pediatric Patients","volume":"39","year":"2019","journal-title":"Crit. Care Nurse"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1111\/anae.13018","article-title":"Assessing pain objectively: The use of physiological markers","volume":"70","author":"Cowen","year":"2015","journal-title":"Anaesthesia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1097\/AJP.0000000000000165","article-title":"A debate on the proposition that self-report is the gold standard in assessment of pediatric pain intensity","volume":"31","author":"Twycross","year":"2015","journal-title":"Clin. J. Pain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.psyneuen.2014.09.018","article-title":"Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress","volume":"51","author":"Brummelte","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2018409118","DOI":"10.1073\/pnas.2018409118","article-title":"Storytelling increases oxytocin and positive emotions and decreases cortisol and pain in hospitalized children","volume":"118","author":"Brockington","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00056-021-00311-4","article-title":"Assessment of salivary stress and pain biomarkers and their relation to self-reported pain intensity during orthodontic tooth movement: A longitudinal and prospective study","volume":"83","author":"Bozkaya","year":"2022","journal-title":"J. Orofac. Orthop."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e26973","DOI":"10.1002\/pbc.26973","article-title":"Emotion regulation and positive affect in the context of salivary alpha-amylase response to pain in children with cancer","volume":"65","author":"Jenkins","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/pme.12545","article-title":"Can biomarkers differentiate pain and no pain subgroups of nonverbal children with cerebral palsy? A preliminary investigation based on noninvasive saliva sampling","volume":"16","author":"Symons","year":"2015","journal-title":"Pain Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17301","DOI":"10.1038\/s41598-021-96840-4","article-title":"Maternal speech decreases pain scores and increases oxytocin levels in preterm infants during painful procedures","volume":"11","author":"Filippa","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_30","first-page":"CR405","article-title":"Influence of salivary secretory immunoglobulin A level on the pain experienced by orthodontic patients","volume":"16","author":"Campos","year":"2010","journal-title":"Med. Sci. Monit."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1136\/archdischild-2021-321593","article-title":"Saliva cortisol diurnal variation and stress responses in term and preterm infants","volume":"107","author":"Stoye","year":"2022","journal-title":"Arch. Dis. Child Fetal Neonatal Ed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1093\/jbcr\/irab147","article-title":"An Exploratory Study Demonstrating That Salivary Cytokine Profiles Are Altered in Children With Small Area Thermal Injury","volume":"43","author":"Carlton","year":"2022","journal-title":"J. Burn Care Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.bbi.2022.04.010","article-title":"Secretory immunoglobulin A (s-IgA) reactivity to acute psychosocial stress in children and adolescents: The influence of pubertal development and history of maltreatment","volume":"103","author":"Romero","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/AJP.0b013e31822cf542","article-title":"Enhanced cortisol increase upon awakening is associated with greater pain ratings but not salivary cortisol or soluble tumor necrosis factor-\u03b1 receptor II responses to acute pain","volume":"28","author":"Goodin","year":"2012","journal-title":"Clin. J. Pain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1111\/j.1365-2044.2012.07267.x","article-title":"Modulation of pain sensation by stress-related testosterone and cortisol","volume":"67","author":"Choi","year":"2012","journal-title":"Anaesthesia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3349\/ymj.2014.55.1.216","article-title":"Effects of seasonal differences in testosterone and cortisol levels on pain responses under resting and anxiety conditions","volume":"55","author":"Choi","year":"2014","journal-title":"Yonsei Med. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/AJP.0000000000000398","article-title":"Dexamethasone-suppressed Salivary Cortisol and Pain Sensitivity in Female Twins","volume":"33","author":"Godfrey","year":"2017","journal-title":"Clin. J. Pain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"46","DOI":"10.2344\/0003-3006-60.2.46","article-title":"Salivary cortisol, salivary alpha amylase, and the dental anxiety scale","volume":"60","author":"Sadi","year":"2013","journal-title":"Anesth. Prog."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sobas, E.M., Reinoso, R., Cuadrado-Asensio, R., Fern\u00e1ndez, I., Maldonado, M.J., and Pastor, J.C. (2016). Reliability of Potential Pain Biomarkers in the Saliva of Healthy Subjects: Inter-Individual Differences and Intersession Variability. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166976"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1016\/j.joms.2012.03.005","article-title":"Utility of saluvary biosensor for objective assessment of surgery-related stress","volume":"70","author":"Robles","year":"2012","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"722","DOI":"10.3390\/diagnostics10090722","article-title":"Salivary Alpha-Amylase in Experimentally-Induced Muscle Pain","volume":"10","author":"Christidis","year":"2020","journal-title":"Diagnostics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3389\/fpubh.2014.00121","article-title":"Alpha amylase as a salivary biomarker of acute stress of venepuncture from periodic medical examinations","volume":"2","author":"Koh","year":"2014","journal-title":"Front. Public Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"613","DOI":"10.2147\/OPTH.S225603","article-title":"Evaluation of Potential Pain Biomarkers in Saliva and Pain Perception after Corneal Advanced Surface Ablation Surgery","volume":"14","author":"Sobas","year":"2020","journal-title":"Clin. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.archoralbio.2018.12.006","article-title":"Salivary opiorphin in dental pain: A potential biomarker for dental disease","volume":"99","author":"Ozdogan","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"133","DOI":"10.5603\/EP.a2021.0004","article-title":"An assessment of the effectiveness of regional analgesia after VATS measured by an objective method for assessing testosterone, cortisol, \u03b1-amylase, sIgA, and \u03b2-endorphin levels\u2014A randomised controlled trial","volume":"72","author":"Bialka","year":"2021","journal-title":"Endokrynol. Pol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/PSY.0000000000000759","article-title":"Placebo Effects in the Neuroendocrine System: Conditioning of the Oxytocin Responses","volume":"82","author":"Skvortsova","year":"2020","journal-title":"Psychosom. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"22","DOI":"10.2344\/anpr-63-03-02","article-title":"Salivary Alpha Amylase, Dental Anxiety, and Extraction Pain: A Pilot Study","volume":"64","author":"Lee","year":"2017","journal-title":"Anesth. Prog."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.4103\/jfmpc.jfmpc_357_19","article-title":"Evaluation of levels of Interleukin-1b, intensity of pain and tooth movement during canine retraction using different magnitudes of continuous orthodontic force","volume":"8","author":"Singh","year":"2019","journal-title":"J. Fam. Med. Prim. Care"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1038\/s41598-018-21131-4","article-title":"Saliva as a medium to detect and measure biomarkers related to pain","volume":"8","author":"Jasim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1111\/joor.12977","article-title":"Daytime changes of salivary biomarkers involved in pain","volume":"47","author":"Jasim","year":"2020","journal-title":"J. Oral Rehabil."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1378\/chest.11-0448","article-title":"Salivary Cortisol Can Replace Free Serum Cortisol Measurements in Patients with Septic Shock","volume":"140","author":"Orlander","year":"2011","journal-title":"Chest"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40101-015-0068-0","article-title":"Distribution characteristics of salivary cortisol measurements in a healthy young male population","volume":"34","author":"Kobayashi","year":"2015","journal-title":"J. Physiol. Anthropol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"20401","DOI":"10.3402\/jom.v5i0.20401","article-title":"Secretory immunity with special reference to the oral cavity","volume":"5","author":"Brandtzaeg","year":"2013","journal-title":"J. Oral Microbiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e032927","DOI":"10.1136\/bmjopen-2019-032927","article-title":"Correlation between biomarkers of pain in saliva and PAINAD scale in elderly people with cognitive impairment and inability to communicate: Descriptive study protocol","volume":"9","year":"2019","journal-title":"BMJ Open"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3389\/fendo.2020.00335","article-title":"Cumulative Risk on Oxytocin-Pathway Genes Impairs Default Mode Network Connectivity in Trauma-Exposed Youth","volume":"11","author":"Levy","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.2147\/JPR.S247472","article-title":"Nerve Growth Factor Signaling and Its Contribution to Pain","volume":"13","author":"Barker","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/ejp.941","article-title":"The interaction between NGF-induced hyperalgesia and acid-provoked pain in the infrapatellar fat pad and tibialis anterior muscle of healthy volunteers","volume":"21","author":"Munkholm","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jpain.2009.06.012","article-title":"Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity","volume":"10","author":"Latremoliere","year":"2009","journal-title":"J. Pain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.tips.2005.12.001","article-title":"Novel class of pain drugs based on antagonism of NGF","volume":"27","author":"Hefti","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s10194-020-01160-z","article-title":"Altered levels of salivary and plasma pain related markers in temporomandibular disorders","volume":"21","author":"Jasim","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41587-019-0045-y","article-title":"Wearable biosensors for healthcare monitoring","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/11\/1929\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:46:26Z","timestamp":1760125586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/11\/1929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":61,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["diagnostics13111929"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics13111929","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]}}}