Epidemiology of Chronic shoulder pain and associated risk factors in the United Kingdom: a population-based study of UK primary care data using clinical practice research datalink (CPRD) - Nouf Al-Otaibi
Knee pain and multimorbidity in retired male professional football players and general population control men
Retired professional footballers have a higher injury rate of lower limbs joints. These injuries might results to short and long-term effects such as chronic pain and osteoarthritis (OA). However, they may be less likely to have other long-term conditions such as diabetes, cardiovascular disease and cancer due to their levels of physical fitness but a higher prevalence of mental health problems. The presence of multimorbidity (≥2 long-term conditions) is increasing within the general population but whether footballers are more or less likely to have multimorbidity remains unknown. The association between professional footballers and risk of long-term health consequences, including OA and multimorbidity after retirement, is an important concern due to its impact on their health, wellbeing and quality of life. The aim of this PhD is to examine the incidence of knee pain (KP) and multimorbidity in male retired professional footballers compared to men in the general population.
Objectives
Investigating musculoskeletal pain and frailty
As the average lifespan increases, the number of years in good health struggles to keep pace. Accumulation of currently incurable conditions with increasing age leads to increasing health impairment and reduced quality of life. Musculoskeletal pain, for example, due to osteoarthritis, is increasingly prevalent, and, as well as directly causing distress, contributes to reduced independence and increases health care and societal costs. Knee osteoarthritis causes severe pain and reduced mobility, and reduced activity and increasing sedentary behaviour contribute to increased morbidity and mortality. Frailty is a vulnerability state seen in older people due to multi-organ age-associated decline and is characterised by homeostatic failure in response to challenge. Understanding the link between musculoskeletal pain and frailty may help develop and target treatments that facilitate healthy ageing.
This project takes advantage of the multidisciplinary research environment and patient cohorts developed in Nottingham within the NIHR Nottingham Biomedical Research Centre and Pain Centre Versus Arthritis. The Investigating Musculoskeletal Health and Wellbeing survey is a questionnaire-based research study which collects annual information from people with different degrees of pain and frailty.
Role of the gut microbiome and serum metabolome in knee pain in patients with Osteoarthritis
Knee osteoarthritis (OA) is a multifactorial disease initiated with inflammation and pain which later progress to joint deformation and disability. There has been an increase in the global burden of knee pain and OA reducing the quality of life over the past few years. The available treatments of pain-analgesics, however, have been reported to be having certain side effects. With the growing evidence of gut microbiome associated with many other inflammatory diseases, the gut microbiota has been regarded as a crucial contributing factor in the development of OA. It's already established that gut microbes are responsible for degrading the dietary compounds or the host-produced compounds and converting them to a diverse range of metabolites. This project aims to investigate the association of gut microbiome and serum metabolome with knee pain in OA patients. This is further explored by looking into the metabolic pathways that are relevantly involved in knee pain and OA that could be targeted for potential metabolites-based therapeutics.
Personalised approaches to the management of chronic musculoskeletal pain in people with Rheumatoid Arthritis
Chronic pain is a major cause of disability worldwide. There is discrepancy between the pain level and the actual tissue damage. Central sensitisation, defined by IASP as increased responsiveness of nociceptive neurons in CNS to their normal or subthreshold stimuli, has been implicated in this discrepancy. Various rheumatological conditions showed features of central sensitisation (CS) such as fibromyalgia, rheumatoid arthritis, and osteoarthritis. Central sensitisation is usually associated with poor treatment outcomes, so it is important to reduce it. Exercise has the potential to decrease CS. This effect is robust in pain-free population, however in people with chronic pain it might be more dependent on exercise dosage. Although the mechanisms underlying exercise-induced hypoalgesia are not completely understood, it was found by many researchers that it has a robust effect on the descending inhibitory pathways. Other studies showed that exercise inhibits the facilitatory pathway by investigating the effect of exercise on temporal summation. Additionally, it was observed by neuroimaging that exercise might have effects on brain neurobiology in a chronic musculoskeletal pain population. My hypothesis is that Exercise reduces central nervous system mechanisms that increase pain in people with rheumatoid arthritis. My aim is to design the optimal exercise program to reduce central sensitisation.I will start my research project by doing a systematic review to underpin the exercise intervention/s types and dosage/s associated with the greatest reductions in indices of CS. After that, an RCT in people with rheumatoid arthritis will be designed comparing exercise with control to explore the effect of the exercise therapy on central sensitisation mechanisms of pain in RA population.
Peripheral contributions to the developing and maintenance of chronic pain in osteoarthritis in the knee joints
Practically I will aim to understand how pain progresses during the disease specifically in the peripheral nervous system in conjunction with the signalling to the CNS.
Moreover, given the inconsistency of the drugs that currently exist against OA, I will focus my research on understanding the basic mechanisms of VEGFA isoforms when used against OA, since there are evidence that targeting VEFGA can reduce pain. However the question of what happens to the inflammation still stands. Moving forward in the next steps of the PhD I will try to tackle the question of how inflammation progresses and alters in conjuction to pain.
Adrian Haywood
Contributions of spinal and supraspinal sites to the pain assocated with osteoarthritis
Adele Edwards
Developmental changes in neural stem cell responses in the spinal cord and the influence of painful stimulation
Amanda Lillywhite
Investigation of the influence of innate anxiety on functional connectivity in animal models of osteoarthritis pain
Junting Huang
Investigation of inflammatory mechanisms in models of osteoarthritic pain
Luting Xu (Tracey)
The role of TRPV1 signalling in osteoclastogenesis and pain in osteoarthritis
Kun Zuo
The contextual effect of treatment in osteoarthritis
Hamza Alshuft
Structural brain changes in chronic pain of knee osteoarthritis
Louis Brailsford
The role of lipid signalling in osteoclasts: contributions to osteoarthritic pain
Xi Chen
The placebo effect and its determinants in fibromyalgia
Charles Greenspon
Postnatal neurophysiological development of nociception: integration and representation into supraspinal networks
Fatimah Almahasneh
Role of prostaglandins in the periaqueductal gray in the central modulation of osteoarthritis pain
Meesawatsom Pongsatorn (Den)
Targeting the resolution of inflammation to reduce spinal excitability and pain
Lilian Nwosu
Structural pain modification in models of osteoarthritis
Monica Persson
Relative efficacy of topical NSAIDs and topical capsaicin in osteoarthritis and neuropathic pain
Laura Stoppiello
Structural associations of pain in human knee osteoarthritis
Subhashisa Swain
Commenced: 1 February 2018
Supervisors: Weiya Zhang, Carol Coupland and Mike Doherty
Epidemiology of Osteoarthritis and it’s comorbidities
Osteoarthritis (OA) is one of the common chronic conditions in older people and often causes chronic joint pain and disability. Despite the rise in multimorbidity there is little information available on the proportion of people with OA have multiple chronic conditions and how it changes with time. According to a recent research, three out of ten people in the UK have more than at least one long term condition. However, the pattern and association of these conditions with OA is not well understood.
This research aims to use advanced statistical techniques to understand the epidemiology of OA in the UK and multiple chronic conditions associated with. Furthermore, the risk, burden and impact of multiple chronic conditions in OA will be studied in detail.
Emma Battell
Commenced: 1 October 2017
Supervisors: Gareth Hathway and Lucy Donaldson
Supraspinal centres serve critical roles in producing behavioral responses to pain and modulating the excitability of spinal pain networks. This descending pain modulation system (DPMS) comprises several centres in the brain with the periaqueductal grey (PAG) serving as an integrative centre. The PAG hassignificant afferent input from the forebrain and limbic system and an efferent projection to the brainstem.
Significant postnatal changes occur in the PAG and brainstem that profoundly effect sensory processing. This project aims to detail changes in the function and connectivity of the PAG across postnatal development.
Afroditi Kouraki
Dates: 09/05/2019 - 01/08/2022
Supervisors: Professor Ana M. Valdes, Dr Tobias Bast, Professor Eamonn Ferguson
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.
Khalid Yaseen
Supervisors: Abhishek Abhishek, Michelle Hall, Mike Doherty and Weiya Zhang
Polykarpos Angelos Nomikos
Commenced: 1 December 2017
Supervisors: Abhishek Abhishek, Michelle Hall, Roshan das Nair and Ana Waldes
Knee OA manifests clinically with pain, stiffness and disability. Knee pain is a common problem, with 25% of the population older than 55 years in age having persistent knee pain and knee pain present on most days of the previous month, is present in one in five adults over the age of 40 years.
National Institute for Health and Care Excellence (NICE) have recommended core, adjunctive non-pharmacological and pharmacological treatments for OA. However, core treatments suggested by NICE are under-utilised as both doctors and patients often focus predominantly on pharmacological systemic analgesics alone. Doctors do not appear to be best suited for managing knee pain due to OA. Even enhanced GP consultations based on an OA guidebook followed by referral to a practice nurse-led OA clinic and provision of a written information on OA did not improve several quality indicators for knee OA.
The overall purpose of the study is to test the feasibility of conducting a RCT of a nurse-led complex intervention comprising education, non-pharmacological and pharmacological principles of management of OA and knee pain.
Gabriela Sandoval-Plata
Commenced: 1 October 2018
Supervisors: Abhishek Abhishek and Kevin Morgan
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.
Asta Tranholm
Supervisor: Cornelia de Moor
Sameer Gohir
Commenced: 1 January 2018
Supervisors: Paul Greenhaff, Ahbishek Abhishek and Ana Valdes
Burak Kundakci
Commenced: 1 April 2017
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.
Arman Tadjibaev
Commenced: 1 October 2016
Supervisors: Dorothee Auer and Sarina Iwabuchi
A link between chronic pain and anxiety
Incidence of anxiety disorders among chronic pain patients is disproportionately higher than in general population. Anxious pain patients are characterized by decreased pain thresholds, increased pain levels, more daily complaints, poorer quality of life and worse outcome of treatment. Underlying mechanisms of negative influence of anxiety on pain are still poorly understood.
The main aim of my research is to understand neural mechanisms of coexistence of two disorders and to suggest new methods of treatment and management of chronic pain conditions with co-morbid anxiety.
Commenced: 1 September 2015
Supervisor: Victoria Chapman
Matthew Swift
Commenced: September 2016
Supervisors: Lucy Donaldson and David Bates
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. Differentisoforms 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.
Amer Imraish
Commenced: 1 October 2014
Supervisor: Gareth Hathway
Age-related Changes in the Phenotype of Spinal Microglia
Lydia Sinnett-Smith
Sara Gonçalves
Commenced: 1 September 2016
Supervisors: Vicky Chapman, Gareth Hathway and Tobias Blast
Emma Dayman
Pain pathways mature over the first weeks and months of life in rodents, and years in humans. In early life, thresholds to painful stimuli are lowered and behavioural responses to noxious stimuli are altered. Previous work has demonstrated that inflammatory stimulus leads to different nociceptive responses in the early life, compared with adulthood.
My research aims to characterise the ability of various inflammatory stimuli to prime the nociceptive pathways in early life, and identify key differences in immunological and pain responses between neonates and adults. Furthermore, we will determine the impact this has on the response of the nociceptive system to re-exposure to inflammatory signals later in life. This project will use a range of in vivo and in vitro approaches to compare inflammatory processes in response to single and repeat inflammation in cutaneous tissue at different postnatal ages in rats. Techniques including FACS analysis, immunohistochemistry linked to fluorescence microscopy and pain behaviour assays will be utilised. We will also perform quantification of alterations in the expression of key genes involved in inflammatory processing in isolated inflammatory cells.
Alexandra Durrant
Supervisors: Lucy Donaldson and Nick Beazley-Long
Vasileios Georgopoulos
Supervisor: David Walsh
Vicki Simmonds
Commenced: 1 October 2013
Supervisors: John Harris and Carl Stevenson
Siew Li Goh
Commenced: 1 October 2015
Supervisors: Weiya Zhang, Mike Doherty and Michelle Hall
Kehinde Akin-Akinyosoye
Commenced: 1 October 2015.
Dates: April 2010 - Mar 2014
Supervisor: R Dineen
Hamza was appointed to investigate the structural brain changes associated with chronic pain of knee osteoarthritis. Up-to-date structural image analysis tools were used to quantitatively analyse high-resolution brain images obtained using advanced MRI scanning techniques.
Dates: January 2011 - December 2014
Supervisor: A Bennett
Osteoclasts have an important role in bone remodelling and have been shown to contribute to bone cancer induced pain. Both clinical and preclinical evidence supports a role of osteoclasts in osteoarthritis, which is associated with bone remodelling and chronic pain. This project investigated the signalling pathways which mediate osteoclastogenesis using a combination of molecular biology, primary cell culture, mass spectrometry and fluorescence imaging techniques. The potential interactions of these signalling pathways with peripheral pain mechanisms were assessed in models of osteoarthritic pain.
Dates: November 2011 - October 2014
Supervisor: W Zhang
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.
Dates: September 2011 - July 2014
Supervisor: V Chapman
The contribution of peripheral and central inflammatory responses to pain responses associated with osteoarthritis (OA) will be studied in models of OA pain. Techniques will include behavioural studies of pain responses and ex vivo analysis of tissues from these models. Immunohistochemistry, western blotting and RT-PCR will be used to investigate expression levels of receptors, cytokines and other pro- and anti-inflammatory mediators in these models of OA pain.
Dates: October 2010 - Sept 2014
Luting (Tracey) focused on elucidating the mechanism underlying the formation of osteoclast in OA and how it was associated with OA pain. Molecular biology, gene expression analysis and cytohisochemistry techniques were employed. The PhD programme focusses on the TRPV1 signaling pathway, modulation by lipid metabolism and its relationship with pathological bone remodeling in osteoarthritic joints.
Dates: October 2011 - July 2014
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.
Dates: October 2011 - October 2015
Supervisor: D Walsh
Laura Wyatt (nee Stoppiello)
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.
Dates: January 2015 - May 2018
Supervisor: G Hathway
My project aimed to understand fundamental physiological aspects of chronic pain by understanding how both the spinal cord and brain respond and adapt to it. This was done using a model of arthritis so that any discoveries made are relevant to many people who are in pain. The techniques that this project developed should provide a framework for further comprehensive work to be done that may be more relevant in a clinical setting. Furthermore, this project was particularly interested in how the pathways and networks that are relevant to chronic pain develop in adolescence. Significant work was done to measure and understand how neural nociceptive-evoked activity changes over development.
Dates: April 2014 - March 2018
Supervisor: L Donaldson
The experience of pain in osteoarthritis (OA) is significantly affected by central pathways of pain modulation, where the midbrain periaqueductal gray (PAG) is known to play a crucial role through central sensitization and hyperalgesia. Prostaglandins (PGs) enhance nociceptive transmission both peripherally and centrally, and have been recognized as mediators of PAG-facilitated modulation of pain.
This study aims to look into the role of PGs in the PAG in the descending facilitation of nociception in OA using the monoiodoacetate (MIA) model, as well as the complete Freud's adjuvant (CFA) model of inflammatory arthritis, and conduct a comparison between the two models. Techniques such as PCR, immunofluorescence and electromyography (EMG) recording will be used in this project.
Dates: October 2013 - September 2017
Nuria Casanova Vallve
Dates: January 2015 - September 2019
Catherine Owles
Dates: May 2015 - September 2019
Investigations of the origins of altered pain perception in a commercial pig strain
This project examined the relationship between degenerative joint disease (osteoarthritis) and pain in commercial breeder pigs. Pain behaviours were evaluated in commercial pigs and the relationship to joint disorders evaluated by assessing joint chondropathy, changes in the phenotype of sensory nerves innervating the affected joint, changes in the spinal cord and changes in the synovium and synovial fluid. The results found in pigs were then compared to a well validated rodent model of osteoarthritis pain, with a secondary aim of the project to evaluate pig joint disease as a model of human osteoarthritis.
Dates: October 2015 - September 2019
Supervisors: Weiya Zhang
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.
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