{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:59:58Z","timestamp":1785337198334,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly encountered in pain practice, but reported pain improvement may reflect direct antinociception, weight loss, metabolic change, or disease-specific effects. This structured narrative review examined these possibilities and relevant safety issues. Methods: PubMed\/MEDLINE, Embase, and Web of Science Core Collection were searched through 15 May 2026. Peer-reviewed human studies, key mechanistic preclinical studies, systematic reviews and meta-analyses, and professional guidance relevant to pain outcomes or procedural safety were considered. Metabolic-only and non-peer-reviewed reports were excluded, and human pain-primary evidence was prioritized. Results: Preclinical data support plausible mechanisms involving spinal microglia, interleukin-10, beta-endorphin, neuroinflammation, and sensory-neuron signaling, but direct analgesic efficacy at systemic clinical doses has not been demonstrated. In STEP 9 (n = 407), mean WOMAC pain scores at 68 weeks changed from baseline by \u221241.7 points with semaglutide 2.4 mg and \u221227.5 points with a placebo; body weight changed by \u221213.7% and \u22123.2%, respectively. Liraglutide produced additional weight loss without superior knee-pain reduction. Diabetic peripheral neuropathy evidence was mainly structural or neurophysiologic; idiopathic intracranial hypertension and ROSE-010-treated irritable bowel syndrome showed disease-specific signals, whereas fibromyalgia- and opioid-related findings remained observational or hypothesis-generating. Gastrointestinal dysmotility, reduced intake, and lean-mass loss may offset functional benefits. Conclusions: GLP-1RAs are not established analgesics. Current human signals are best interpreted as indirect metabolic\u2013functional or disease-specific effects. Future trials should use validated pain-primary outcomes, control for weight loss, and monitor treatment-related harms.<\/jats:p>","DOI":"10.3390\/jcm15155932","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"5932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glucagon-like Peptide-1 Receptor Agonists and Chronic Pain: Preclinical Antinociceptive Mechanisms, Indirect Metabolic\u2013Functional Effects, and Clinical Considerations\u2014A Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Sung-woo","family":"Hyung","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Eunpyeong St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ui Jin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Eunpyeong St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Hwan","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Uijeongbu St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7179-7235","authenticated-orcid":false,"given":"Siwook","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Eunpyeong St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"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 ICD-11","volume":"160","author":"Treede","year":"2019","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s10194-024-01821-3","article-title":"Glucagon-like peptide-1 receptor agonists for headache and pain disorders: A systematic review","volume":"25","author":"Halloum","year":"2024","journal-title":"J. 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