BJA/RCoA Project Grants

Background
Chronic pain, including persistent postsurgical pain affects 20-50% of the world's population, but unfortunately the available pain killers are not always effective. Opioid analgesics, including morphine, are effective against short-term severe pain. However, opioids only provide limited benefit for people with long-lasting pain. The actions of morphine and other opioids wear off when they are taken repeatedly, through a process known as tolerance. In addition, opioid pain killers have side effects such as nausea and constipation; they reduce resistance to infection and weaken breathing when taken in excess. Opioid pain killers are also habit forming in some people and this can lead to addiction. Despite efforts to develop better drugs to treat severe pain, there are none as effective as opioids. Studies in the USA reveal that even with their limited ability to reduce persistent pain and their troubling side effects, opioids are being prescribed to an increasing number of patients suffering from chronic pain. Our recent research reveals a similar upward trend in opioid prescribing in Scotland, particularly among patients living in the most deprived communities. The same communities suffer disproportionately from the impact of opioid misuse, with increasing numbers of opioid-related deaths.

Deprivation during early life may affect pain vulnerability and responses to analgesic opioids in later life and this may contribute to the escalating pattern of opioid prescribing and misuse. In keeping with this, 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.

Aims and approach
We are seeking to understand the mechanism by which deprivation during early life affects pain vulnerability and responses to opioid analgesics in adulthood. We hypothesise that exposure of neonatal mice to fragmented care by their mother programs aberrant responses to persistent pain and opioid analgesics later in life. Our preliminary data indicate that fragmented care may alter opioid receptor number. We hypothesise that a change in the number of delta receptors in key brain regions, leads to reduced resilience to persistent pain through enhanced tolerance to the body's natural pain killing opioids and analgesic opioid drugs.

We will establish how fragmented care affects wild type mice and mice that lack delta receptors examining:
1) Acute and persistent pain
2) Morphine analgesia, tolerance and hyperalgesia
3) The potential for opioid misuse

An understanding of the way in which early life adversity affects pain sensitivity and responses to opioids may provide a strategy for stratifying chronic pain management.

Around one million major operations take place in the NHS each year. Complications after major surgery are common, occurring in around one in five patients. Patients who develop complications are at increased risk of early death, tend to stay in hospital for longer and are at higher risk of being re-admitted after discharge home and of not returning to their baseline independence. Additionally, complications lead to increased NHS costs and resource use. The risk of complications occurring depends upon a patient's health and fitness, as well as the extent and severity of surgery.

Significant public resources are invested in national audits and research studies to better understand the long-term effects of surgery. These projects require clinicians to measure and manually record information about patients' health, quality of care and what happens to them after their hospital stay. Much of this information already exists somewhere within the NHS, in the electronic patient health records held by general practitioners (GPs) or in the routine data collected in hospitals. However, the computer systems used across these various care environments do not routinely communicate or share patient data with each other. Thus, there is a lot of duplication of effort (and therefore potential waste of NHS resources) in recording the same information in several different systems for different purposes. Reducing the burden of data collection and making better use of data and technology are national priorities. More efficient and appropriate use of patient data could improve care for current patients and support more cost- and time-efficient research to benefit future patients.

We intend to link patient data from hospitals and GPs in England to create a more complete picture of the journey undertaken by patients undergoing major surgery. Hospital Episode Statistics (HES) is a database of all hospital admissions containing information about operations and diagnoses. The Clinical Practice Research Datalink (CPRD) is a database of anonymised GP medical records containing the information entered onto computer by a GP every time they see a patient. Linking these data sources together, we will look at patients who have had a major surgical operation and attempt to identify if and when patients experience complications, and determine whether this affects where and how often they access healthcare. Rigorous processes will be followed to ensure confidentiality of patient data, records are stored securely, and analysed in accordance with current legal and ethical guidance.

At the end of the study we hope to have developed methods for using linked GP and hospital data to improve our understanding of the scale and type of complications occurring after surgery, and the implications for patients and the NHS. We will develop a better understanding of who is more at risk of complications after surgery, which should help patients and healthcare professionals make better plans together to reduce these risks. Finally, we hope to enhance the quality of data collected by national clinical audits, and reduce the burden of data collection on local hospitals, so contributing to improved patient care and saving NHS resources.

Background
Chronic pain is one of the significant medical challenges and causes of disability worldwide. Half of the reported chronic pain conditions is related to chronic musculoskeletal pain, and the most common diseases related to musculoskeletal pain are osteoarthritis (OA) and fibromyalgia. The main symptom of OA is a localised joint pain, while fibromyalgia is described as widespread pain and multiple muscle tender points associated with fatigue, poor sleep and cognitive dysfunction. Although first localised, and second widespread, the common to both is an imbalance between severity of changes on the painful site and reported pain. The explanation for this imbalance is possibly due to modulation of pain perception by the nervous system. However, to improve understanding of this modulation and possibility to use it to improve treatment, we need to identify molecules that play critical roles in this process. These molecules are often called biomarkers and can help in diagnosing the disease, inform on its severity as well as for the development of new medications.

Aims
In this study, we want to look into the fluid of central nervous system called cerebrospinal fluid (CSF) to search for biomarkers that can tell us about the process of modulation of the pain perception. These molecules can inform us about the specificities of localised and widespread pain, as well as their commonalities.

Methodology
We will use already collected and stored CSF samples: 103 of patients with fibromyalgia, 98 OA patients and 70 healthy participants. The samples were collected systemically and consistently ensuring a high quality, and so far, it is the most extensive collection of this type in the chronic pain field. We will use a state-of-the-art approach called proteomics in these samples that substantially increases novel biomarker discovery. Further, we will use advanced statistical methods to find candidates associated with musculoskeletal pain intensity as well as those to describe localised and widespread pain groups.

Expected outcomes
As a result of this study, we expect to identify protein biomarkers of musculoskeletal pain that we can further explore in blood samples and extensive cohort studies. These biomarkers will inform us about the fingerprints of localised and widespread musculoskeletal pain as well as shared pain modulation.

Implications
Results from this study will provide additional knowledge about chronic musculoskeletal pain and can have an impact on drug development, drug utilisation, diagnosis and potentially prognosis of fibromyalgia and OA. Thus, these can help in establishing the grounds for personalised medicine of two most common rheumatic conditions. Primary, we expect the candidates we identify can inform us on potential targets for future drug development, and with this help in reducing the opioid crisis and provide pain relief even to those patients that do not respond to currently available medications.

Background
In many critically ill patients treated in intensive care units oedema formation is a major problem. Oedema is where fluid leaks out of the blood vessels and into the organs and causes them to malfunction. This is particularly damaging in the lung as oxygen is essential for the body to survive. Oedema occurs due to the lining of the blood vessels becoming leaky. The reason for this leak is not completely understood but may be because the viscosity of the blood is reduced. Viscosity is the term used to describe how "pourable" a fluid is. For example honey is much harder to pour than water, and therefore has higher viscosity. Recent evidence published from our laboratory demonstrates that reduced viscosity of fluid in blood vessels causes them to become leaky and that if viscosity is increased it protects against oedema.

Aims
Given the previous demonstration that increasing viscosity helps to prevent oedema, first we will identify the optimum value for viscosity. Next we will examine how it produces its protective effect. In particular we will examine how viscosity improves the function of the cells lining the blood vessels and prevents fluid from leaking out. We will also test, in a lung that has already been injured in a manner seen in critically ill patients, how changes in viscosity affects the leak of fluid into the lungs.

Methodology
This will be a laboratory study using mouse lungs that have been isolated. This experimental model is a validated method that allows us to examine interventions (such as manipulation of viscosity) that would not be possible in humans. Building on our previous demonstration that increased viscosity of the blood substitute pumped through these lungs, we will now identify the optimum viscosity. We will then determine how this fluid protects against oedema formation. Finally we will examine the ability of optimum viscosity to reduce oedema formation in injured mouse lungs typical of the damage found in critically ill patients.

Expected Outcome
We anticipate that the identified optimum viscosity fluid will reduce, or delay, the rate at which fluid will leak from the blood vessels in the lung by protecting the lining of these vessels. This will also further our understanding of how viscosity works in the body by identifying the sensors with which it may be interacting.

Implications
By developing our understanding of how viscosity benefits the cells lining our blood vessels we could potentially design improved intravenous replacement fluids that limit the leak from vessels in critical illness. This would benefit patients suffering from diseases that result in the life threatening accumulation of fluid in their lungs. A second potential use of an optimal viscosity perfusion is in the field of organ transplantation. A recent development has been the perfusion and ventilation of donor lungs after explantation using a technique identical to that of the isolated mouse lung preparation (as above). This allows improvement of the condition of the donor organs and thus increases the number of organs available for transplant.