Development and evaluation of translational pain models using objective neurophysiological markers

Acute pain plays a fundamental role in survival, providing protection from potentially damaging stimuli. However, chronic pain is much less useful and is hugely detrimental to quality of life. An inadequately low number of chronic pain patients get meaningful analgesic treatment benefit, and very few novel analgesics have become available in recent years. This is due in part to a high failure rate of new analgesics in early clinical trials. with a significant number of these failures being due to lack of efficacy, thus questioning whether current animal models, and/or how pain is assessed in these models, sufficiently predict clinical efficacy. Development of translational pain models will bridge this gap between preclinical animal and human clinical research by providing experimental models that have similar underlying mechanisms. Additionally. use of translational objective measures of pain as pharmocodynamic endpoints will aid drug development. The work described in this thesis aimed to address these two critical issues, namely that animal and human pain models are often mechanistically different and are quantified using different outcome measures. The main focus of this project was translational inflammatory pain models with a central sensitisation component, a cardinal clinical feature or chronic pain. As secondary mechanical hyperalgesia results from central sensitisation. the work focused on development of models ill which secondary mechanical hyperalgesia is exhibited, combined with objective assessment of this mechanical hyperalgesia. The key findings of this project were two-fold. Firstly, a novel objective neurophysiological measure of mechanical pain was developed and validated in healthy human volunteers. Secondly, the occurrence of secondary mechanical hyperalgesia was investigated in an established translational inflammatory pain model in the rat (the ultraviolet-B (UV -13) model). and in a novel model which combines UV-B with heat rekindling to prolong central sensitisation. Finally. to bring the two aspects of the project together. the objective measure of mechanical pain in humans was used to investigate secondary mechanical hyperalgesia in a translational experimental inflammatory pain model in healthy human volunteers. The development of translational experimental models of inflammatory pain. with emphasis on the clinically relevant phenomenon of central sensitisation, will improve transition of novel analgesics into the clinic. The objective measure of mechanical pain in humans described here is a neurophysiological technique that will aid future pain research when used alongside subjective measures of pain, creating a multidimensional approach to pain assessment. It also has the potential to be back-translated to the laboratory rat for future quantification of secondary mechanical hyperalgesia and central sensitisation ill translational models such as the UV-B model.EThOS - Electronic Theses Online ServiceGBUnited Kingdo