This project utilised both advanced statistical analysis and clinical-based research to identify how psychological (anxiety and cognitive ability), social (social deprivation/isolation, education) and biological (genetics and the gut microbiome) factors interact in their contribution to chronic pain. 

We identified common threads that link cognitive ability and anxiety with social and biological factors regardless of whether we looked at a clinical sample, a longitudinal panel, or genetic and gut microbiome data. These multilevel findings link together the pathways through which psychological, social and biological factors contribute to pain mechanisms and pain-related outcomes and suggest that chronic pain is a complex phenomenon that we have to approach from a holistic point of view.  

Gout is one of the most common forms of inflammatory arthritis, with a prevalence of 2.49% in the UK. It is characterised by abrupt episodes of acute inflammation and severe pain in joints due to monosodium urate (MSU) crystals deposition as a consequence of hyperuricemia. Despite being crucial to gout, hyperuricemia does not necessarily cause the disease, but the reasons underlying the progress from asymptomatic crystal deposition in people with hyperuricemia to gout remains unclear. Moreover, clinical variation among patients with gout in terms of the age of onset, frequency of attacks and the development of tophi is still poorly understood.

Based on the fundamental role of the NLRP3 inflammasome and toll-like receptors (TLR) pathway in the immune response to MSU crystals, the aims of the present project is to analyse gene expression of inflammasome and TLR-related genes to: (1) evaluate if it is influenced by serum uric acid levels, (2) evaluate whether a differential expression is associated to the development of symptomatic gout, and (3) explore the expression profile during acute and intercritical gout. In addition, polygenic risk models will be developed to distinguish gout cases vs controls, and to determine risk for gout in people with hyperuricaemia who has not developed gout.

Fibromyalgia (FM) is a common chronic condition that manifests with chronic widespread pain or multiple regional pain, and with other associated core symptoms of fatigue, non-restorative sleep and cognitive dysfunction. After osteoarthritis, FM is the second most common rheumatologic condition, and affects 2-8% of the whole population. Universally guidelines on the management of FM support a multi-faceted approach combining non-pharmacological interventions as first-line therapy and pharmacological interventions as adjunctive treatment, with an emphasis on an individualised patient-centred approach.

The overall purpose of the research project is the development of an optimal non-pharmacological treatment package for FM. It primarily aims to estimate the efficacy and relative efficacy of all non-pharmacological interventions, select the most efficacious, accessible and applicable interventions and bring them together as a package of care. Firstly, studies comparing a non-pharmacological intervention versus a non-intervention will be used to calculate overall effect sizes for each non-pharmacological treatment by conducting a conventional meta-analysis. Secondly, these treatments will be prioritised by Network Meta-Analysis using direct and indirect evidence. Finally, a Delphi exercise (consensus building) will be undertaken among patients and healthcare professionals to select the most effective and accessible interventions.  

Chronic pain is a major worldwide health burden with an asymmetry between prevalence and effective treatments. Additionally, chemotherapy induced peripheral neuropathy (CIPN) is emerging as a major contributor to the aforementioned burden, and a limiting factor in the supply of chemotherapy regimens. Thus, there is a large demand for the rapid development of novel analgesic drugs with which to counter the growing requirement for efficacious therapeutics.

One such approach is modulation of Vascular Endothelial Growth Factor (VEGF) synthesis. Different
isoforms of VEGF have profound neuroprotective and anti-nociceptive functions. Therefore, my project is centred on developing a series of potential therapeutics that would initiate synthesis of these VEGF isoforms over those that normally predominate in pain states. This provides a new and innovative approach to pain management therapy.

The project investigated the placebo effect in fibromyalgia and its potential determinants in randomized controlled trials. Meta-analysis was used to summarise the placebo and nocebo effects for different types of placebos. The effect sizes were compared between fibromyalgia and osteoarthritis. The duration of the placebo effect and associated factors were examined.

Kun undertook a project to examine the relative effect of placebo (contextual effect) in complementary therapy in osteoarthritis (OA). The PhD project investigated the effect size of the contextual effect for each complimentary treatment modality. Comparisons were made between treatments, as well as between OA and other chronic painful conditions (fibromyalgia and rheumatoid arthritis). Meta-analysis was used to combine results and different treatment categories and determinants of the contextual effect and related adverse events (nocebo effects) were also examined.

A comparison of structural and biochemical factors in joint tissues from knees of patients undergoing joint replacement surgery for OA pain with those with similar degrees of chondropathy that have been obtained post mortem from people who have not sought help for knee pain. The development of key structural and biochemical changes with OA disease progression will be determined by comparing human tissues to OA models. Knee joint structural and biochemical changes predicting pain phenotype will be explored. Finally, one key molecular or structural target emerging from these studies will be tested in interventional studies in an appropriately validated model.

The project aimed to better understand the mechanism of pain in osteoarthritis. It did so  by identifying treatment responders, making comparisons between treatments with different mechanisms of action, and between osteoarthritic and neuropathic pain. Conventional, network, and individual patient data meta-analyses of randomised controlled trials evaluating the efficacy of topical NSAIDs and topical capsaicin in osteoarthritis were conducted. The relative efficacy of both treatments was assessed in osteoarthritis, and treatment responders was identified. Comparisons were made with randomised controlled trials of neuropathic pain.