The Pain Relief Foundation has long supported the work of the Pain Research Institute and part funds both the post of Professor of Pain Science and Clinical Senior Lecturer in Pain Medicine at the University of Liverpool.
In addition funding in the form of annual grants is awarded to individuals working both within the Institute and elsewhere on chronic pain research. Grants are awarded each year based on the quality of applications.
Grants Awarded:
A research grant awarded to Dr Qasim Aziz – Queen Mary University of London
£29,969
Proof of concept assessment of the feasibility of artificial intelligence-driven transcutaneous Vagal Nerve Stimulation (tVNS) algorithm for somatic pain.
Abdominal pain is a common issue that can limit daily activities and lead to significant medical costs. While painkillers are often used to treat it, these medications can be ineffective and cause serious side effects, such as bleeding or addiction. Therefore, there is a need for safer, more effective treatments.
The autonomic nervous system, which controls the organs in our body, plays a key role in regulating pain. It consists of two parts: the sympathetic and parasympathetic nervous systems. The parasympathetic nervous system, in particular, is important for pain regulation and can serve as both an indicator and a target for treating abdominal pain.
One promising treatment for abdominal pain is transcutaneous vagal nerve stimulation (tVNS). tVNS stimulates the vagus nerve, a key part of the parasympathetic system, and can help reduce certain types of pain. While tVNS devices are available, patients must manually activate them, which may focus attention on the pain.
To improve this, we aim to combine tVNS with Artificial Intelligence (AI). AI can learn and adapt, and we plan to use it to automatically control tVNS. Previous studies show that parasympathetic nerve activity, which can be measured by an electrocardiogram (ECG), changes with pain. We have developed a prototype AI system that can detect these changes through a wearable device, predicting 80% of pain episodes before they occur.
In this project, we will enhance our AI to automatically turn tVNS on and off, creating an AI-driven system that treats pain autonomously. In the future, this technology could be applied to other treatment devices, enabling them to predict and treat pain automatically. This innovation will help patients receive treatment without focusing on their pain or manually operating the device, improving their overall quality of life.
A research grant awarded to Dr Andrew Marshall – University Liverpool
£16,625
Underpinning Mechanisms of Developing Neuropathic Versus Non-Neuropathic Pain After Stroke.
The proposed research will investigate why some people develop nerve pain after stroke and others do not. Central Post Stroke Pain (CPSP) is a chronic pain condition that develops in about 15% of stroke patients, but the reason for its cause is still mostly unknown. Recent research has identified some potential areas that become overactive after certain strokes, but this research is limited either by simple methods that cannot identify the cause or by small participant numbers.
This research intends to recruit participants with CPSP to identify which areas damaged by stroke are most likely to have resulted in chronic pain. To fully understand this, we will need to additionally recruit participants with stroke but (1) without any chronic pain, and (2) with nonneuropathic pain. The second group of participants suffer post-stroke chronic pain that is similar to CPSP but is not caused by nerve damage but by complications following stroke, such as reduced mobility. An example of this is Shoulder-Hand Syndrome, which is another condition that is poorly understood. By comparing people with CPSP to a non-neuropathic pain group, we will be able to understand why some people develop CPSP and others develop non-neuropathic pain. It will also provides us with a better understanding of mechanisms of non-neuropathic pain conditions such as Hand- Shoulder Syndrome. This knowledge could inform future treatments by (1) focusing our efforts on treating areas causing CPCP and SHS, and (2) developing a computer program that would flag new stroke patients that are at risk of developing CPSP so that they could start their treatment journey faster.
A Research grant to Dr Milena De Felice – University Sheffield.
£29,644
Inhibition of metalloproteinases: a novel approach for the treatment of post-stroke pain.
The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) highlights stroke as a significant cause of both death and disability worldwide, ranking it as the second-leading cause of death and the third-leading cause of death and disability combined. Following a stroke, approximately 30% of survivors endure pain, which commonly emerges shortly after the event but can also manifest months to years later. This pain detrimentally impacts survivors’ quality of life, often leading to depression, anxiety, and sleep disturbances, drastically limiting the effectiveness of or participation to rehabilitation. Unfortunately, post stroke pain is frequently underreported and overlooked, with limited effective treatment options available.
Recognizing the urgent need for research in this area, we aim to investigate the mechanisms underlying post stroke pain using an innovative model. By integrating cellular and behavioural approaches, we seek to uncover how the inhibition of matrix metalloprotease MMP-9 and -12 contributes to the onset and persistence of post stroke pain. Our study will explore the correlation between changes in nervous system function resulting from stroke and the development of post stroke pain, focusing specifically on the MMP pathways. To achieve our objectives, we will utilize a clinically-ready MMPs inhibitor to gain insights into the mechanisms driving post stroke pain.
This research will not only enhance our understanding of the safety and efficacy of MMP inhibition in alleviating post stroke pain but will also lay the groundwork for the development of novel and safe treatments in this critical area. Ultimately, our work aims to address the significant public health challenge posed by post stroke pain, both on a national and global scale.
(2024-2026)
A Research grant to Dr Maria Maiarú – University Reading.
£29,769
Novel botulinum-based construct for the treatment of chronic pain.
Pain is a protective mechanism necessary for survival that inform us of tissue damage that will require time to heal. While normally of biological benefit, pain can sometimes persist after healing or because of on-going disease and become chronic, a condition that is particularly difficult to manage with currently available treatments. In the UK alone, chronic pain affects 15 million people and remains a major clinical challenge.
Botulinum neurotoxin/A (BoNT/A) injections are widely used in clinical practise to manage chronic pain states such as migraine and peripheral neuropathic pain. However, the degree of pain achieved is often modest and the use of BoNT/A is associated with high risk of muscle paralysis. We have therefore developed a non-paralytic version of the construct (el-iBoNT) to achieve pain relief without toxic effect. Nevertheless, the mechanism through which this pain relief is attained remains unclear.
Our aim is to use models and laboratory techniques to provide a better understanding of the molecular mechanism responsible for the analgesic effect of el-iBoNT and therefore to further promote el-iBoNT as a novel approach for pain relief.
(2024-2025)
A Research grant to Dr Olivia Grech – University of Birmingham.
£29,975
The role of glucagon-like peptide 1 in migraine.
Migraine affects a billion people worldwide and is one of the leading causes of disability. It is a multi-system disorder that significantly reduces quality of life and disrupts daily life. Despite recent progress, 52% of migraine patients have not yet found an effective treatment. Our study focuses on investigating the glucagon-like peptide 1 (GLP-1) and its potential role in migraine. GLP-1, a hormone known for regulating blood sugar, has shown promise in influencing headache-related mechanisms and is already clinically licensed for use in diabetes and obesity.
This study aims to explore how GLP-1 interacts with another important molecule involved in migraine called calcitonin gene-related peptide (CGRP). While treatments targeting CGRP have shown promise, they don’t work for everyone, necessitating the identification of alternative approaches. Building on our previous research with exenatide, a GLP-1 receptor agonist, we aim to understand how CGRP and GLP-1 interact in areas of the brain responsible for head pain and how the modulation of GLP-1 signalling might help treat migraines.
In our experiments we plan to study how GLP-1 receptor activation affects migraine symptoms including allodynia, a feeling of pain or discomfort from stimuli that are normally painless. We will further investigate the direct impact of exenatide on the activity of nerve cells in the brain responsible for migraine-related pain. Our goal is to determine if GLP-1 receptor agonists represent a novel target to treat migraines. The results have the potential to uncover new targets for not only treatment for migraines, but also other pain conditions. This project will generate new data to facilitate our understanding of how GLP-1 can be leveraged for the treatment of migraines. This research is in line with the goals of the pain foundation, working towards reducing the impact of pain on people’s lives, especially those dealing with migraines.
(2024-2025)
A Research grant to Dr Charlotte Krahé – Liverpool John Moores University.
£10,097
Perceived social threat in chronic pain.
In addition to physical distress, such as pain and fatigue, chronic pain is linked with experiencing social distress. Chronic pain patients often report feeling socially isolated and disconnected from others. We currently do not fully understand the processes that cause this heightened social distress and keep it going. In this grant, we want to test whether being sensitive to social threat plays a key role. Social threat includes worrying about threats to our body (e.g., someone harming us or worsening our pain directly) or threats to how socially connected and safe we feel around others. People with chronic pain are generally more aware of threats around them, but we do not know if this also applies to social threats.
In Study 1, we will investigate social threat related to physical safety. We focus on personal space, specifically the point at which footsteps approaching are felt as uncomfortably close. We expect that people with chronic pain will feel uncomfortable at an earlier point than people without pain, especially when footsteps belong to a stranger.
In Study 2, we investigate threats to social connectedness. We will briefly make people feel socially excluded through using a virtual ball tossing game. People with and without chronic pain will play this game with virtual players. First, they are included in the game, but then virtual players pass the ball less and less. We study whether this brief exclusion leads to greater social threat in chronic-pain than pain-free participants, and whether it worsens in-the-moment pain.
Together, the two studies can help us understand processes involved in social distress in chronic pain and allow us to develop ways to help people with chronic pain feel safer in their social interactions. Ultimately, the findings may help create safer, more supportive environments for people with chronic pain.
(2024-2025)
A Research grant to Dr Anne Marshall – University Liverpool
£25,764
REliability of HRDD as a biomarker in Painful diabetic nEuropathy – a vaLidation study (REPEL)
Damage to the nerves caused by diabetes, diabetic neuropathy, is the most common complication of diabetes, affecting up to half of all patients. It primarily affects the feet and can cause severe
pain and distressing sensations which are difficult to treat. Gaps in our understanding of the mechanisms involved in the development of pain in diabetic neuropathy have led to inadequate
treatment.
Damage to the ends of the nerve fibres in diabetes is thought to lead to an increase of pain signals to the spinal cord. Normally the nerve circuits in the spinal cord would attempt to suppress these
pain signals. However, in animal studies of diabetes, it has been shown that changes within the spinal cord inappropriately amplify these pain signals rather than suppressing them – a process
called spinal disinhibition.
A biomarker (measure) of spinal disinhibition is H-reflex rate dependent depression (HRDD), which can be tested non-invasively in humans. We have demonstrated that HRDD is impaired in people with painful diabetic neuropathy and believe that HRDD could be used to identify patients who may benefit from targeted therapies that reverse spinal disinhibition. However, before we can test this in large numbers of patients in clinical trials, we need to know whether HRDD readings are reliable when tested on multiple occasions (repeatability) and when tested by different individuals (reproducibility).
In this prospective study we will determine the reliability of HRDD in the target clinical population by testing whether the measurements are repeatable and reproducible. We will also generate
preliminary data to determine if HRDD may predict pain relief in patients with painful diabetic neuropathy in response to treatment with an anti-neuropathic pain drug that is thought to target
spinal cord circuits involved in spinal disinhibition.
(2023-2024)
A Research grant to Dr David Moore – Liverpool John Moores University.
£12,792
Experience of autistic adults of pain and pain management: Barriers to effective treatment.
Autistic people are at greater risk of a range of painful conditions. In addition to the greater risk of pain there is a lack of understanding and poor pain management for autistic people. It is
perhaps therefore unsurprising that autistic people are more likely to develop chronic pain which requires complex management within tertiary services. What is currently unknown about
pain management for autistic people is how individuals respond to and experience these services. Within wider health services there is evidence that autistic people might respond to
speaking therapies such as Cognitive Behavioural Therapy. It also appears however that autistic people might experience challenges with engaging with such treatment and that therapy
between autistic patients and non-autistic healthcare providers might present a particular challenge. There is some evidence that there are modifications to these treatments that might
be more suitable for autistic people, however this work is limited and has only so far focused on depression or anxiety and has not been examined in pain management. In the present study we
propose to interview approximately 12 autistic people who have co-occurring chronic pain and have either undertaken or are presently undertaking the pain management program at Walton
Centre NHS Foundation Trust (WCFT). We will ask about the persons experiences of pain prior to referral, what support was offered and how this was experienced and how they sought help. We
will also interview participants about their experiences of the chronic pain management program to consider where they might have gained benefit from this process but also the barriers experienced to successful pain management.
(2023-2024)
A Research grant to Dr. Javier Aguilera-Lizarraga -University of Cambridge.
£20,556
Mechanisms of inflammatory joint pain: The role of TRPM3 in knee nociceptors and its interaction with fibroblast-like synoviocytes.
Rheumatoid arthritis is a debilitating inflammatory condition affecting over 400,000 people in the UK. In rheumatoid arthritis, joint damage and swelling occur that produce chronic pain, which in turn decrease an individual’s quality of life. Rheumatoid arthritis is a complex condition, but it is becoming increasingly clear that fibroblast-like synoviocytes, a type of cell that lines synovial
joints, such as the knee, play an important role in disease progression. Recent research in our laboratory showed that molecules produced by these cells during inflammation can increase the
sensitivity of sensory neurons that transmit pain signals. This process results in stronger and/or longer-lasting neuronal signals and can lead to the development of chronic pain. Therefore, the
interaction between fibroblast-like synoviocytes and sensory neurons might be a crucial factor in the development of inflammatory joint pain.
We previously showed that TRPV1, an important receptor for the transmission of pain signals in sensory neurons, plays a key role in inflammatory joint pain and that its function is modulated by
fibroblast-like synoviocytes. However, clinical trials have shown that drugs targeting this receptor may cause undesired adverse effects. In this study, we aim to establish new mechanisms in
inflammatory joint pain. Thus, we will investigate the role of TRPM3, another receptor involved in transmitting pain signals. To this end, we will use pharmacological tools to assess if the
TRPM3 receptor is involved in inflammatory joint pain using a mouse model of knee joint inflammation. Furthermore, we will study the impact of molecules produced by fibroblast-like
synoviocytes on the function of this receptor. For this purpose, we will use cell cultures, live-cell imaging techniques and electrophysiology to characterise the role of TRPM3 in sensory neuron
function in joint pain. Ultimately, this project will provide new insights into the mechanisms underlying inflammatory joint pain.
(2023-2024)
A Research grant to Prof John Dawes- University Of Oxford.
£30,000
Using live sensory neurons to assess the pathogenicity of autoantibodies from pain patients.
Chronic pain affects around 1 in 5 adults despite the use of current analgesics. Therefore, there is a need to better understand the underlying mechanisms in an effort to develop more effective and
targeted therapies. The immune system has a role in chronic pain and it is increasingly recognised that this includes autoimmune mechanisms and the action of autoantibodies which target proteins within the nervous system. Excessive activity of pain sensing neurons is a key driver of many chronic pain conditions. Recent work has shown that autoantibodies can cause pain by targeting these neurons, disrupting ion channel function and causing them to become overactive.
These studies support the idea that autoantibodies are a mechanism to cause pain and preclinical work inconditions such as FMS, suggest that this mechanism may be represented more widely among pain conditions. The aim of this study is to use samples from a range of pain patients (FMS, CRPS, diabetic neuropathy and sciatica) and assess autoantibody binding using both mouse
(primary) and human (IPSC-derived) sensory neurons as an indication of their pathogenicity. Pathogenic autoantibodies have been established in FMS and CRPS, but only a small number of
samples have been tested and the exact cellular targets remain unclear. Here we will use larger sample cohorts, compared to age and sex matched healthy controls, and quantify antibody binding
in model and human sensory neurons.
In addition, we will use this platform to screen for pathogenic autoantibodies in pain conditions where this mechanism has not previously been implicated (e.g., diabetic neuropathy, sciatica). The work conducted in this study will give insight into the prevalence of autoantibodies as a mechanism to cause pain, help to facilitate the identification of target proteins and ultimately help steer future treatment strategies for chronic pain patients.
(2022-2023)
A Research grant to Dr Sandrine Géranton – University College London
£29,884
A novel approach for the treatment of migraine
Chronic migraine is a complex neurological disorder characterised by recurrent unilateral headaches and sensory deficits. One third of migraineurs also suffer from migraine aura, which often precedes the headache and presents as further sensory disturbances such as dizziness, numbness and blindness. Chronic migraine is a significant burden to society. In the UK alone, it affects 6 million people and remains a major clinical challenge.
Stress is the major trigger of migraine attacks and we have evidence that inhibiting the stress regulator FKBP51 would be a suitable approach for the treatment of migraine. However, we still do not know why blocking the protein FKBP1 reduces the symptoms of migraine and whether it also reduces symptoms particularly associated with the migraine aura.
Our aim is to use animal models to provide a better understanding of the impact of blocking FKBP51 on migraine and therefore to further promote FKBP51 as a novel target for migraine relief. Reducing high attrition rates in drug development continues to be a key challenge for the pharmaceutical industry which can only be overcome by a better understanding of the treatment targets. Ultimately, this project will provide evidence that blocking FKBP51 can result in the clinical management of migraine.
(2022-2023)