| Summary: | Pain is a leading cause of morbidity in neuro-orthopaedic conditions, and remains an unmet clinical need. In this study, I aimed to advance the assessment of the pain states using novel objective methods in patients with neuro-orthopaedic disorders, and to develop biomarkers that could be useful in clinical trials of new therapies. Quantitative sensory testing, the current method of assessment of small fibre (nociceptor) function, was compared to novel objective methods including skin biopsy, contact heat evoked potentials (CHEPS) and functional magnetic resonance imaging (fMRI), in human volunteer models and patients. The clinical conditions studied were congenital insensitivity to pain presenting as orthopaedic disorders, complex regional pain syndrome, osteoarthritis, small-fibre pain syndromes, nerve and spinal root injuries. Cutaneous sensitisation biomarkers and mechanisms were identified in topical capsaicin pain models in human volunteers with study of skin biopsies, contact heat and laser evoked cerebral potentials, and fMRI. The models showed features observed in patients with neurogenic hypersensitivity, including hypersensitivity associated with regenerating nerve fibres. In patient groups, congenital insensitivity of pain patients showed absent CHEPS and lack of intra-epidermal nerve fibres, a novel finding. In patient groups with pain / hypersensitivity, CHEPS distinguished neuropathic from inflammatory mechanisms, while skin biopsies showed changes in nerve fibre density, particularly of nerve fibres positive for GAP43, a marker of regenerating nerve fibres, and of TRPV1, the heat and capsaicin receptor. As these changes require p38 MAP kinase activation in neurons, an inhibitor of p38MAP kinase was studied in a neuropathic pain clinical trial, which showed efficacy and support of the biomarkers. fMRI studies showed increased activation in regions of the brain associated with pain processing in the capsaicin model and painful osteoarthritis affecting the hand. These findings advance the assessment and understanding of pain disorders, and provide biomarkers for the development of new analgesics.
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