eprintid: 1561318 rev_number: 89 eprint_status: archive userid: 608 dir: disk0/01/56/13/18 datestamp: 2017-07-12 16:18:40 lastmod: 2025-04-28 16:30:39 status_changed: 2017-07-12 16:18:40 type: article metadata_visibility: show creators_name: Taneja, A creators_name: Della Pasqua, OE creators_name: Danhof, M title: Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D10 divisions: G10 keywords: neuropathic pain, inflammatory pain, chronic pain, hyperalgesia, analgesics, PKPD modelling, drug development note: Copyright© The Author(s) 2017 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. abstract: Aim: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs.// Methods: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on (1) disease mechanisms leading to chronic/neuropathic pain and (2) druggable targets which are currently under evaluation in drug development. Attention was also given to the role of biomarkers and pharmacokinetic-pharmacodynamic modelling.// Results: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti-inflammatory drugs (NSAIDs).// Conclusion: A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials. date: 2017-10 publisher: Springer Verlag official_url: https://doi.org/I 10.1007/s00228-017-2301-8 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1300683 doi: 10.1007/s00228-017-2301-8 lyricists_name: Della Pasqua, Oscar lyricists_id: ODELL25 actors_name: Della Pasqua, Oscar actors_name: Harris, Jean actors_id: ODELL25 actors_id: JAHAR68 actors_role: owner actors_role: impersonator full_text_status: public publication: European Journal of Clinical Pharmacology volume: 73 pagerange: 1219-1236 issn: 0031-6970 citation: Taneja, A; Della Pasqua, OE; Danhof, M; (2017) Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm. European Journal of Clinical Pharmacology , 73 pp. 1219-1236. 10.1007/s00228-017-2301-8 <https://doi.org/10.1007/s00228-017-2301-8>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/38/Taneja_Challenges_translational_drug_research_Tables.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/23/fig1%20rev%20%281%29.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/40/Taneja_Challenges_translational_drug_research_Fig2.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/39/Taneja_Challenges_translational_drug_research_Fig3.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/41/Taneja_Challenges_translational_drug_research_Fig4.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/42/Taneja_Challenges_translational_drug_research_Fig5.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/64/Taneja_challenges_in_translational_drug_research.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1561318/70/Della%20Pasqua_s00228-017-2301-8.pdf