{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:20:34Z","timestamp":1768454434965,"version":"3.49.0"},"reference-count":58,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative 2 Joint Undertaking","doi-asserted-by":"publisher","award":["777500"],"award-info":[{"award-number":["777500"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.<\/jats:p>","DOI":"10.3390\/ijms23158295","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"8295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development"],"prefix":"10.3390","volume":"23","author":[{"given":"Johannes","family":"van Niel","sequence":"first","affiliation":[{"name":"Mature Products Develoment, Gr\u00fcnenthal GmbH, 52099 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Bloms-Funke","sequence":"additional","affiliation":[{"name":"Translational Science & Intelligence, Gr\u00fcnenthal GmbH, 52099 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ombretta","family":"Caspani","sequence":"additional","affiliation":[{"name":"Mannheim Center for Translational Neurosciences (MCTN), Department of Neurophysiology, University of Heidelberg, 69120 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4437-7585","authenticated-orcid":false,"given":"Jose Maria","family":"Cendros","sequence":"additional","affiliation":[{"name":"Development DMPK, Welab Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9873-789X","authenticated-orcid":false,"given":"Luis","family":"Garcia-Larrea","sequence":"additional","affiliation":[{"name":"Lyon Neurosciences Center Research Unit Inserm U 1028, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Lyon 1 University, 69100 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Truini","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Sapienzia University, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Tracey","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Integrative Neuroimaging, FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonya C.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Arlington Square, Bracknell RG12 1PU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3526-8037","authenticated-orcid":false,"given":"Nicol\u00e1s","family":"Marco-Ari\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, 31009 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3700-8658","authenticated-orcid":false,"given":"I\u00f1aki F.","family":"Troconiz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, 31009 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Phillips","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Erl Wood, Bracknell GU20 6PH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5541-0240","authenticated-orcid":false,"given":"Nanna Brix","family":"Finnerup","sequence":"additional","affiliation":[{"name":"Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Mouraux","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience (IoNS), UCLouvain, B-1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf-Detlef","family":"Treede","sequence":"additional","affiliation":[{"name":"Mannheim Center for Translational Neurosciences (MCTN), Department of Neurophysiology, University of Heidelberg, 69120 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nrd.2017.87","article-title":"Breaking barriers to novel analgesic drug development","volume":"16","author":"Yekkirala","year":"2017","journal-title":"Nat. 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