{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:14:01Z","timestamp":1790680441510,"version":"4.1.0"},"reference-count":274,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003529","name":"European Union Agency for Cybersecurity","doi-asserted-by":"publisher","award":["RRF\u20102.3.1\u201021\u20102022\u201000015"],"award-info":[{"award-number":["RRF\u20102.3.1\u201021\u20102022\u201000015"]}],"id":[{"id":"10.13039\/501100003529","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"abstract":"Abstract<\/jats:title>\n \n Chronic primary pain (CPP) persisting for more than 3\u2009months, associated with significant emotional distress without any known underlying cause, is an unmet medical need. Traditional or adjuvant analgesics do not provide satisfactory pain relief for a great proportion of these patients. Therefore, identifying novel therapeutic targets and determining new treatments is important. In the present systematic review, we provide a comprehensive summary of Phases 1\u20133 clinical trials conducted between 01 January 2014 and 31 July 2024, available on\n clinicaltrials.gov<\/jats:ext-link>\n ,\n clinicaltrialsregister.eu<\/jats:ext-link>\n and PubMed, concerning both original drug development approaches and repurposing for the important widespread and regional musculoskeletal CPP conditions fibromyalgia (FM), complex regional pain syndrome and chronic low back pain. Unfortunately, there has not been a breakthrough in the pharmacotherapy of these conditions. This may be related to (i) the unsuccessful approaches to reveal pathophysiological mechanisms and identifying novel targets, with the lack of appropriate preclinical animal models with translational relevance, and (ii) the heterogeneity of these patient populations with several co\u2010morbidities. Alongside innovative drug developmental concepts such as TRPA1 and the P2X7 purine receptor inhibition and somatostatin SST\n 4<\/jats:sub>\n receptor activation, most trials have focussed on repurposing antidepressants, antiepileptics, psychedelics, immune modulators, or suppressants. The most promising candidates have targeted cannabinoid, glutamate, GABAergic, neuroinflammatory and immune mechanisms, because several studies were initiated focussing on these pathways and proving their efficacy and safety. Only cannabidiol (CBD) and (es)ketamine have been tested for all three CPPs despite similar etiological factors and mechanisms related to stress\u2010pain interactions.\n <\/jats:p>","DOI":"10.1111\/bph.70228","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T06:59:17Z","timestamp":1763189957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel approaches for drug development against chronic primary pain: A systematic review"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2918-4475","authenticated-orcid":false,"given":"Val\u00e9ria","family":"T\u00e9kus","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School University of P\u00e9cs P\u00e9cs Hungary"},{"name":"PharmInVivo Ltd. P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1234-4391","authenticated-orcid":false,"given":"\u00c9va","family":"Borb\u00e9ly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School University of P\u00e9cs P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3763-8206","authenticated-orcid":false,"given":"Andreas","family":"Goebel","sequence":"additional","affiliation":[{"name":"Department of Pain Medicine Walton Centre NHS Foundation Trust Liverpool UK"},{"name":"Pain Research Institute University of Liverpool Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9492-4698","authenticated-orcid":false,"given":"Ralf","family":"Baron","sequence":"additional","affiliation":[{"name":"Division of Neurological Pain Research and Therapy, Department of Neurology Christian\u2010Albrechts\u2010Universitaet Kiel Kiel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4421-0150","authenticated-orcid":false,"given":"Zs\u00f3fia","family":"Hajna","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School University of P\u00e9cs P\u00e9cs Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2435-4367","authenticated-orcid":false,"given":"Zsuzsanna","family":"Helyes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School University of P\u00e9cs P\u00e9cs Hungary"},{"name":"PharmInVivo Ltd. P\u00e9cs Hungary"},{"name":"Hungarian Research Network\u2010University of P\u00e9cs Chronic Pain Research Group Hungary"},{"name":"National Laboratory for Drug Research and Development Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/ejp.907","article-title":"Efficacy and tolerability of muscle relaxants for low back pain: Systematic review and meta\u2010analysis","volume":"21","author":"Abdel Shaheed C.","year":"2017","journal-title":"European Journal of Pain"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","DOI":"10.1080\/07853890.2024.2334398","article-title":"A brief review of complex regional pain syndrome and current management","volume":"56","author":"Abd\u2010Elsayed A.","year":"2024","journal-title":"Annals of Medicine"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"5741","DOI":"10.3390\/jcm13195741","article-title":"Nociplastic pain: A critical paradigm for multidisciplinary recognition and management","volume":"13","author":"Ablin J. 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