BJA/RCoA Project Grants

University of Dundee

Title
Early life adversity programs pain vulnerability and aberrant responses to opioids

Amount
£70,000

Scientific Abstract
Opioid tolerance, the requirement for escalating doses to maintain analgesia, is a complicating factor in the management of chronic pain. Tolerance, dependence and withdrawal contribute to the development of opioid addiction, which underlies the crisis of prescription opioid misuse in the USA. A similar scenario threatens the UK, where there are increasing opioid prescribing rates and opioid-associated deaths. In Scotland, as elsewhere, prescribing and opioid deaths are highest within the most deprived communities. Deprivation during early life may cause pain vulnerability and alter opioid analgesic responses in later life. Indeed, our preliminary findings suggest that mice exposed to fragmented maternal care, a form of early life deprivation, develop altered pain sensitivity coupled with low potency morphine analgesia, rapid development of morphine tolerance and hyperalgesia. Our aim is to determine the role of opioid receptors in this process. We hypothesise that fragmented maternal care enhances delta opioid receptor expression. We will test this using behavioural and biochemical experiments in wild type and delta receptor knockout mice. An understanding of the mechanism by which early life adversity affects pain sensitivity and responses to opioids may provide a strategy for future stratification of chronic pain management.

University College London

Title
Post-Operative Morbidity Electronic Linkage Observational study (POMELO)

Amount
£69,120

Scientific Abstract
Occurring in 20% of adults undergoing major surgery, perioperative complications have important implications for patients and the NHS: increased healthcare resource utilisation (HCRU); reduced quality of life; reduced long-term survival. Collecting patient data on postoperative complications is burdensome and costly. The Hospital Episode Statistics (HES) coding system does not differentiate between pre-existing comorbidities and complications sustained during a hospital episode. Furthermore, little is known about the prevalence, magnitude and cost of complications which develop or continue after discharge from hospital and are managed in primary care.

We aim to determine the feasibility, validity and utility of linking primary care electronic health records from the Clinical Practice Research Datalink (CPRD) with HES to identify complications occurring after major surgery. We will develop coding algorithms to identify HES discharge diagnoses not present pre-operatively within HES or CPRD, thereby identifying complications. We will investigate the trajectory, magnitude and determinants of HCRU before and after surgery, and identify patient risk factors that have the greatest impact on different outcomes. Achieving a more complete overview of the perioperative pathway by linking patient records could not only improve knowledge, but also reduce the burden of data collection on the NHS therefore saving time, resources and money.

University of Oxford

Title
Biomarkers of musculoskeletal pain: towards personalised medicine in chronic widespread and localised musculoskeletal pain using cerebrospinal fluid proteomics

Amount
£68,631

Scientific Abstract
Chronic pain is one of the substantial medical challenges nowadays and causes of disability worldwide. It comes with an immense burden, but underlying pathophysiology is poorly understood with direct consequences in inadequate treatment. Half of the chronic pain conditions is related to chronic musculoskeletal pain, and the most common diseases related to musculoskeletal pain are osteoarthritis (OA) and fibromyalgia. Although first localised, and second widespread, the common phenomenon to both is that intensity of peripheral nociceptive input is not directly related to reported pain, and it is proposed to be due to central modulation or sensitisation. In this study, we aim to undertake a state-of-the-art approach, using in-depth proteomics analysis, into proteins in cerebrospinal fluid of patients with fibromyalgia, OA and healthy controls. With this, we expect to identify proteins that are up or down-regulated due to the central modulation of nociception in chronic widespread and localised musculoskeletal pain compared to healthy people, as well as fingerprints of the localised and widespread musculoskeletal pain. Further, these protein biomarkers can point out to pathophysiological processes with the potential to improve pain understanding and disease treatment, or after validation in blood samples for use as diagnostic, prognostic or predictive biomarkers.

University College Dublin

Title
Dependence of endothelial integrity and oedema formation on the viscosity of the perfusing solution

Amount
£28,240

Scientific Abstract
Interstitial oedema is detrimental to organ perfusion, tissue oxygenation and increases patient mortality. Preventing oedema formation requires the maintenance of normal endothelial function and an intact endothelial glycocalyx layer (EGL). Normal shear stress is needed to maintain the EGL and is dependent on the viscosity of the perfusing blood. Recent evidence shows that perfusion solutions whose viscosity is less than the viscosity of blood cause endothelial barrier dysfunction and oedema formation.

Aims:
(1) To identify the optimum viscosity of a perfusate that limits oedema formation in the lungs.
(2) To identify the mechanisms by which optimal viscosity solution prevents endothelial leak (3) to test the ability of optimal viscosity perfusate to attenuate oedema formation in injured lungs.

This interventional laboratory study will be undertaken using isolated, ventilated, perfused mouse lungs. This preparation allows precise control of haemodynamic and ventilator variables, thus permitting the examination of the direct effect of viscosity on endothelial leak. The demonstration that the viscosity of a perfusate has a beneficial effect on endothelial barrier leak would identify a novel therapeutic target for use in fluid therapy of critically ill patients, and in ex vivo organ perfusion to allow the reconditioning of organs.