Mechanistic, translational, quantitative pain assessment tools in profiling of pain patients and for development of new analgesic compounds

Scandinavian Journal of Pain - Tập 4 - Trang 226-230 - 2013
Lars Arendt-Nielsen1, Michele Curatolo2
1Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
2Department of Anaesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

Tóm tắt

Abstract Background Mechanistic, translational, human experimental pain assessment technologies (pain bio markers) can be used for: (1) profiling the responsiveness of various pain mechanisms and pathways in healthy volunteers and pain patients, and (2) profiling the effect of new or existing analgesic drugs or pain management procedures. Translational models, which may link mechanisms in animals to humans, are important to understand pain mechanisms involved in pain patients and as tools for drug development. This is urgently needed as many drugs which are effective in animal models fail to be efficient in patients as neither the mechanisms involved in patients nor the drugs’ mechanistic actions are known. Aim The aim of the present topical review is to provide the basis for how to use mechanistic human experimental pain assessment tools (pain bio markers) in the development of new analgesics and to characterise and diagnose pain patients. The future aim will be to develop such approaches into individualised pain management regimes. Method Experimental pain bio markers can tease out mechanistically which pain pathways and mechanisms are modulated in a given patient, and how a given compound modulates them. In addition, pain bio markers may be used to assess pain from different structures (skin, muscle and viscera) and provoke semi-pathophysiological conditions (e.g. hyperalgesia, allodynia and after-sensation) in healthy volunteers using surrogate pain models. Results With this multi-modal, multi-tissue, multi-mechanism pain assessment regime approach, new opportunities have emerged for profiling pain patients and optimising drug development. In this context these technologies may help to validate targets (proof-of-concept), provide dose-response relationships, predicting which patient population/characteristics will respond to a given treatment (individualised pain management), and hence provide better understanding of the underlying cause for responders versus non-responders to a given treatment. Conclusion In recent years, pain bio markers have been substantially developed to have now a role to play in early drug development, providing valuable mechanistic understanding of the drug action and used to characterise/profile pain patients. In drug development phase I safety volunteer studies, pain bio marker scan provide indication of efficacy and later if feasible be included in clinical phase II, III, and IV studies to substantiate mode-of-action. Implications Refining and optimizing the drug development process ensures a higher success rate, i.e. not discarding drugs that may be efficient and not push non-efficient drugs too far in the costly development process. Mechanism-based pain bio markers can help to qualify the development programmes and at the same time help qualifying them by pain profiling (phenotyping) and recognising the right patients for specific trials. The success rate from preclinical data to clinical outcome may be further facilitated by using specific translational pain bio-markers. As human pain bio markers are getting more and more advanced it could be expected that FDA and EMA in the future will pay more attention to such mechanism-related measures in the approval phase as proof-of-action.

Tài liệu tham khảo

Sindrup SH, Finnerup NB, Jensen TS. Tailored treatment of peripheral neuropathic pain. Pain 2012;153:1781-2. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287-333. Robinson I, Dowdall T, Meert TF. Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats. Neurosci Lett 2004;368:107-11. Christoph T, Kogel B, Schiene K, Mèen M, De Vry J, Friderichs E. Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain. Eur J Pharmacol 2005;507:87-98. Kontinen VK, Meert TF. Predictive validityof neuropathic pain models in pharmacological studies with a behavioral outcome in the rat: a systematic review. In: Dostrovsky J, Carr DB, Koltzenburg M, editors. 10th World Congress on Pain. San Diego: IASP Press; 2003. p. 489-98. Quessy SN. The challenges of translational research foranalgesics: the state of knowledge needs upgrading and some uncomfortable deficiencies remain to be urgently addressed. J Pain 2010;11:698-700. Mao J. Translational pain research: achievements and challenges. J Pain 2009;10:1001-11. Arrowsmith J. Trial watch: phase II failures: 2008-2010. Nat Rev Drug Discov 2011;10:328-9. Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008;139:243-7. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg 2010;110:780-9. Dray A. Neuropathic pain: emerging treatments. Br J Anaesth 2008;101:48-58. Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 2009;10:556-72. Arendt-Nielsen L, Hoeck HC. Optimizing the early phase development of new analgesics by human pain bio markers. Expert Rev Neurother 2011;11:1631-51. Woolf CJ. Overcoming obstacles to developing new analgesics. Nat Med 2010;16:1241-7. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol 2010;6:599-606. Klein T, Magerl W, Rolke R. Human surrogate models of neuropathic pain. Pain 2005;115:227-33. Fimer I, Klein T, Magerl W. Modality-specific somatosensory changes in a human surrogate model of postoperative pain. Anesthesiology 2011;115:387-97. Sandkuhler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009;89:707-58. Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 2009;68:322-41. Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review. Br J Clin Pharmacol 2009;68:149-68. Brock C, Arendt-Nielsen L, Wilder-Smith O, Drewes AM. Sensory testing ofthe human gastrointestinal tract. World J Gastroenterol 2009;15:151-9. Wise RG, Tracey I. The role of fMRI in drug discovery. J Magn Reson Imaging 2006;23:862-76. Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, Gierthmühlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihöfner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uçeyler N, Valet M, Wasner G, Treede RD. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010;150:439-50. Arendt-Nielsen L, Graven-Nielsen T. Translational musculoskeletal pain research. Best Pract Res Clin Rheumatol 2011;25:209-26. Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SD. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today 2012;17:419-24. Wei H, Viisanen H, Pertovaara A. Descending modulation of neuropathic hyper sensitivity by dopamine D2 receptors in or adjacent to the hypothalamic A11 cell group. Pharmacol Res 2009;59:355-63. Oono Y, Nie H, Matos RVL, Wang K, Arendt-Nielsen L. The inter-and intra-individual variance in descending pain modulation evoked by different conditioning stimuli in healthy men. Scand J Pain 2011;2:162-9. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. Pain 2010;149:573-81. Chizh BA, Sang CN. Use of sensory methods for detecting target engagement in clinical trials of new analgesics. Neurotherapeutics 2009;6:749-54. Chizh BA, O'Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bull-man JN, Gray EJ, Lai RY, Williams PM, Appleby JM. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 2007;132:132-41. Freund B, Schwartz M. Temporal relationship of muscle weakness and pain reduction in subjects treated with botulinum toxin A. J Pain 2003;4:159-65. Bach-Rojecky L, Relja M, Lackovic Z. Botulinum toxin type A in experimental neuropathic pain. J Neural Transm 2005;112:215-9. Gazerani P, Staahl C, Drewes AM, Arendt-Nielsen L. The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization. Pain 2006;122:315-25. Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L. Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain 2009;141:60-9. Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L, Drewes AM. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006;123:28-36. Staahl C, Dimcevski G, Andersen SD, Thorsgaard N, Christrup LL, Arendt-Nielsen L, Drewes AM. Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study. Scand J Gastroenterol 2007;42:383-90. Koppert W, Ihmsen H, Körber N, Wehrfritz A, Sittl R, Schmelz M, Schüttler J. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005;118:15-22. Koivisto A, Pertovaara A. Transient receptor potential ankyrin 1 (TRPA1) ion channel inthe pathophysiology of peripheral diabetic neuropathy. Scand J Pain 2013;4:129-36. Jensen TS. New understanding of mechanisms of painful diabetic neuropathy: a pathto preventionand better treatment? Scand J Pain 2013;4:127-8. Rice ASC, Morland R, Huang W, Currie GL, Sena ES, Macleod MR. Transparency in the reporting of in vivo pre clinical pain research: the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. Scand J Pain 2013;4:58-62. Kontinen V. From clear reporting to better research models. Scand J Pain 2013;4:57.
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Scandinavian Journal of Pain

Tập 4

226-230

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