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Elevated pro-inflammatory cytokines (IL-1\u03b2, IL-6, IL-10, TNF-\u03b1), neurodegenerative markers (tau, \u03b2-amyloid 42), metabolic hormones, and fasting glucose have been consistently associated with both objective and subjective sleep impairments in chronic pain conditions. Pharmacological agents such as melatonin and opioids exhibit heterogeneous effects on neurophysiological pathways, reflecting differences in mechanisms of action and their modulation of biological processes. Rather than offering therapeutic recommendations, this review aims to clarify how these mediators and drugs shape the complex interplay between pain and sleep. Overall, the evidence suggests that persistent dysregulation of inflammatory, neurodegenerative, and metabolic pathways may drive the reciprocal and detrimental interaction between chronic pain and sleep disturbances, highlighting opportunities for targeted research and integrated clinical strategies.<\/jats:p>","DOI":"10.3390\/biomedicines14010116","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:09:36Z","timestamp":1767712176000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarkers and Breakdowns: Neuroinflammatory Drivers Linking Sleep Disorders and Chronic Pain"],"prefix":"10.3390","volume":"14","author":[{"given":"Bento","family":"Alves","sequence":"first","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5696-1239","authenticated-orcid":false,"given":"Isaura","family":"Tavares","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"Institute for Research and Innovation in Health and IBMC, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-4479","authenticated-orcid":false,"given":"Daniel Humberto","family":"Pozza","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"Institute for Research and Innovation in Health and IBMC, University of Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/j.pain.0000000000001384","article-title":"Chronic pain as a symptom or a disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11)","volume":"160","author":"Treede","year":"2019","journal-title":"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":"5","DOI":"10.1002\/ejp.1090","article-title":"Chronic widespread pain prevalence in the general population: A systematic review","volume":"22","author":"Andrews","year":"2018","journal-title":"Eur. 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