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.
A Research grant to Dr Anne Marshall – University Liverpool
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
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.
A Research grant to Dr David Moore – Liverpool John Moores University.
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.
A Research grant to Dr. Javier Aguilera-Lizarraga -University of Cambridge.
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.
A Research grant to Prof John Dawes- University Of Oxford.
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.
A Research grant to Dr Sandrine Géranton – University College London
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.
A Research grant to Dr Helen Poole – Liverpool John Moores University
A feasibility study of a Behavioural Intervention for Opioid Reduction (BIOR) in primary care.
About 30-50% adults suffer from moderate or severe chronic pain not caused by cancer. Some are treated with opioids (e.g. morphine, codeine, tramadol). It is not unusual for this medication to be ineffective or to stop working over time, and produce unpleasant side effects (e.g. nausea, drowsiness and constipation). Stopping taking opioid drugs is not easy because doing this abruptly can cause unpleasant effects (withdrawal). Tapering the opioid drug in small steps is much easier, though some patients might struggle and need support. Experience from treating patients with substance dependence tells us that interventions offering education and psychosocial support can help.
This pilot study will investigate the effectiveness and feasibility of reducing inappropriate use of opioids through a tapering protocol, education and support in primary care. Working with Knowsley CCG we will identify eligible patients to be allocated to either the tapering group or the tapering with support group. Both groups will have their opioid dose reduced by 10% per
week. The taper with support group will have access to additional support during the process, including motivational counselling, realistic goal setting and a toolkit of resources to promote self-management. Some patients will successfully reduce their dose each week. For others, this may be more difficult, and the tapering reduction will be adjusted to 10% per
fortnight. We assess opioid use, pain and quality of life in both groups at the start and end of the study to determine what works best to support people with chronic pain who wish to stop taking opioids
A Research grant to Dr Vsevolod Telezhkin – Newcastle University
Development of novel in vitro human induced pluripotent stem cell (hiPSC)-derived sensory-like neuronal model of orofacial neuropathic pain.
Pain is usually triggered by injury. The aim of pain is to highlight the injured area, causing a change in its use to allow healing e.g. a sprained ankle is painful to walk on, this means we walk less,
allowing the ankle to recover. Neuropathic pain is pain which comes directly from nerves. Neuropathic pain commonly presents in nerves that have been injured previously, which despite
healing continue to send out pain messages when they should not. Neuropathic pain felt in the head, face or mouth is called orofacial neuropathic pain. Due to its location orofacial pain affects
essential social functions (e.g. eating and talking). Such social functions provide enjoyment of, and meaning to, life worsening the impact of this pain. Simple toothache is a good example
demonstrating how a relatively small injury (e.g. small hole) in a tooth can cause severe pain and lead to considerable distress.
There remain many unanswered questions as to what causes orofacial neuropathic pain and there is no specific treatment which is guaranteed to help this type of pain. This study would generate a
laboratory model of nerves which function as if they have orofacial neuropathic pain. There is no model of this type currently available. Generating this model will allow detailed exploration of how
and why the nerves are sending pain messages in this condition. This understanding offers potential in the future for the development of more targeted treatments which could reduce or
eliminate orofacial neuropathic pain for sufferers.
This research team is currently actively investigating Parkinson’s disease and neuropathic pain in similar models. Development of the specific orofacial neuropathic pain model by this study will allow more detailed exploration of the way nerves function. This offers potential benefit to any medical or pain condition which involves the incorrect functioning of nerves.
A Research grant to Dr Sizheng Steven Zhao – University of Liverpool
Identifying causal risk factors and health consequences of chronic widespread pain using genetic epidemiology
We aim to investigate risk factors that cause chronic widespread pain (CWP) and the consequences of CWP on other diseases using pre-collected survey, clinical and genetic data from approximately half a million people in the UK Biobank. CWP is a common affecting ~14% of the general population and is associated with reduced quality of life and social functioning. Studies demonstrate that people with CWP have higher risk of death from causes such as heart disease. It is not clear whether this association is causal or not. Current research lacks detail on whether interventions for risk factors can prevent CWP, or whether optimising pain management will reduce the risk of associated diseases.
We aim to investigate risk factors and the health consequences of CWP using a cuttingedge statistical technique called Mendelian randomisation, which leverages genetic information to strengthen traditional research designs. We will apply Mendelian randomisation to 1) data from existing genetic studies ranging from thousands to over a million individuals, and 2) over 380,000 individuals in the UK Biobank. Each approach will complement the other, to identify what causes CWP and whether CWP itself goes onto cause diseases that lead to death and further disability. Additionally, we will investigate the causal role of CWP on COVID19 risk and outcomes.
This study will be led by four clinicians/researchers with >360 publications and a wealth of experience in pain research and bioinformatics. Pilot data herein demonstrate the feasibility and utility of the proposed research. In the future, we will develop this research to identify potential treatments. The project will set foundations for longer-term research capacity building locally and nationally, in particular with Nuffield Department of Population Health, University of Oxford (Associate Prof Michael Holmes), with the development of
pilot data for future extramurally funded grants.
A Research grant to Andrew Marshall – University of Liverpool
Defining nociresponsive BA3a as a target to treat chronic pain
In the early 20th century the famous neurologist Henry Head, treating soldiers with traumatic brain injury, observed that pain was still present in many cases, even after extensive loss of cortical areas. In the mid-20th century another famous neurologist, Wilbur Penfield, mapped the cortical representation of the body in the primary somatosensory cortex (S1) leading to the discovery of the sensory homunculus. Further studies identified specific cellular areas within S1 that responded to different types of tactile or painful stimulation.
Surgical ablations of S1 (topectomies) were used in the 1940’/60’s to treat patients suffering from intractable chronic pain. Notwithstanding a lack of modern-day knowledge of the role of S1 in pain, topectomy resulted in permanent relief of pain in ~80% of patients. Despite this favourable long-term success rate, topectomy fell out of favour when opioid analgesia became prescribed widely.
In non-human primates, S1 contains a localised area, called pBA3c, which contains neurons that specifically respond to painful skin stimulation with properties resembling the type of burning, emotionally laden type of pain, termed ‘second pain’. Furthermore, based on what we know from animal research only procedures that specifically target pBA3c, but not other parts of S1, result in pain relief.
Using high-resolution MRI scanning we recently showed that pBA3c is also present in the human brain. Based on the rodent and non-human primate research we hypothesise that targeting pBA3c with established and novel neuromodulation techniques could be used to treat patients suffering with localised chronic pain.
Our current aim is to further develop non-invasive brain imaging methods that will enable precise localisation of pBA3c, as well as defining the role of the region in the generation of chronic pain in humans.
A research grant to Dr Stephanie Koch – University College London
Identifying spinal circuits in chronic widespread pain
Unrestricted widespread pain is a hallmark of chronic pain, and is a major therapeutic challenge for clinicians, in part due to the unpredictable nature of spreading pain across multiple body regions. The central nervous system learns to refine its response to pain over the course of early life: infants show whole body responses to painful stimuli, much as is seen in chronic widespread pain. These pain responses subsequently become refined over adulthood, leading to restricted pain responses seen in the healthy adult. Studying the development of pain circuits from the unrefined responses seen in the infant to refined pain responses seen in the adult therefore provides a novel framework to understanding how chronic pain leads to widespread pain responses. This programme will use the developmental maturation of sensory networks to investigate how circuits naturally adapt to control pain, and so how to correct these circuits when they are maladapted in the case of chronic widespread pain. Using cutting edge behavioural analyses, viral tracing, and state-of-the-art genetic technology, I will determine the neurochemical identity of these circuits thus providing potential new pharmacological targets for future chronic widespread pain therapies.
A Research grant to Dr Geoff Woods – Cambridge University
Novel long-acting analgesic for chronic pain’A Pilot project seeking genetic predispositions to fibromyalgia.
The aim of this project is to find out if a persons’ genes influences whether they develop fibromyalgia. Fibromyalgia is a cause of widespread pain and stiffness and fatigue, which usually disrupts sleep. The problems with fibromyalgia are that, it is common, we do not understand the cause, and medical treatments often do not work (and can cause
If we could understand why the condition occurs, then we may be able to,
- Diagnose it more quickly and accurately.
- Be able to tell who will recover quickly (and does not need treatment), and who will get the features long term.
- Know which medicines/therapies to try, and which to avoid.
We want to look for genetic changes that make a person more likely to get fibromyalgia. To do this,
- We have collected two groups of people with severe fibromyalgia (80 altogether),
- From each person we will use a blood sample to look at the DNA of all of their genes.
- Throughout all of our genes are changes that vary from person to person, and most are probably harmless (we ignore these), but some could alter the way a gene works.
- Looking at all 80 people’s results together for only changes that could alter the way genes work we can see if any of the gene changes are much more common than expected.
- If we find these, we will then use (mostly) internet tools to determine which changes are real and existing.
- (we have successfully used this approach twice before in pain conditions).
This is a first step. If it is successful, it will point us towards the genes and processes that cause fibromyalgia, and hopefully also to treatments.
A Research grant to Dr Nick Fallon – Liverpool University
Investigating the relationship between central& peripheral pathophysiology in fibromyalgia symdrome – pilot neuroimaging study.
Fibromyalgia syndrome is a chronic pain disorder which affects 1 in 20 people in the UK. It has a severe impact on quality of life of individuals, and represents a high cost to our NHS. The causes of fibromyalgia are not fully understood and current treatments are often deemed unsatisfactory. Our previous research using brain imaging revealed differences in brain structure and function which contribute to pain in fibromyalgia . However, evidence from our team and others indicates that nerves located throughout the body (peripheral nerves) also play an important role. We believe that both of these mechanisms work together to shape patient experience, This project aims to investigate whether brain and peripheral mechanisms are related to each other. As a pilot study, this represents the first research to measure relevant brain and peripheral nerve activity in the same group.
Our team is made up of experts in brain and peripheral nerve imaging. We have unique access to a suitable group of 77 people with fibromyalgia who are participating in a project to investigate their peripheral nerve function. We propose to utilise a sub-group of these patients who will volunteer for an additional brain scan at the University of Liverpool. We will consider whether patients find this research to be acceptable and perform a preliminary analysis of the relationship between brain and peripheral nerve function. We anticipate that our study will highlight, for the first time, the existence of a positive relationship between these two mechanisms. This will directly contribute to the development of research which investigates the balance of this mechanisms in relation to patient symptoms or treatment response. Our overarching aim is to eventually develop clinical approaches which can categorise individuals to improve diagnosis for fibromyalgia, or to target individualised treatment plans which improve the lives of patients.
A Research grant to Dr Andrew Marshall – The Walton Centre NHSFT, Liverpool
Reversal of EEG theta band rhythm as an objective measure of efficacy of spinal cord stimulation in chronic neuropathic pain – a pilot study.
Chronic neuropathic pain is a very common condition. Some patients suffering this condition are refractory to medical management and are therefore considered for implantation of spinal cord stimulator. Unfortunately, spinal cord stimulation only works for 60-70% patients. Currently, these patients are identified by a trial of spinal cord stimulation and subjective pain relief is used for decision making. This is no always accurate.
Recent studies have shown that brain activity mapping in the form of electroencephalography shows dominance of slow (theta) waves in patients with chronic neuropathic pain. Reversal of this pattern to normal is seen with effective spinal cord stimulation.
In this study we aim to see if the reversal of theta activity could be used as an objective marker of effective spinal cord stimulation. To do this, we aim to record EEG before and during trial and after 6 months of implantation of SCS. The obtained results shall be compared against subjective pain relief to assess the validity of EEG as an objective test. Also there are three main forms of SCS and each is known to affect EEG in specific manner. As a secondary aim of this study we seek to assess if EEG can be used to identify which stimulation type is best suited to a given patient. This shall be achieved by comparing the patient’s baseline EEG with EEG obtained during stimulation with each type of SCS during trial period and comparison will be made to respective subjective scores.
A Research grant to Dr Andreas Goebel – Liverpool University
Autoimmunity informed phenotyping in chronic non specific low back pain sufferers.
Non-specific low back pain (NsLBP) is a common painful condition and refers to the experience of back pain without an identified injury causing it. Despite its common occurrence, we do not fully understand the causes and risk factors and many people suffer from severe, disabling symptoms without effective management.
Recent research from our group has identified the importance of immune factors in the chronic painful conditions complex regional pain syndrome (CRPS) and fibromyalgia. These conditions are associated with severe pain on light touch pressure and local skin signs such as increased sweating, or with widespread pain, respectively.
Some patients with severe NsLBP present with similar skin signs to CRPS, and NsLBP is a risk factor for the development of fibromyalgia. We wish to find out whether sub-groups of NsLBP sufferers may have similar skin immune factors as CRPS and if sufferers can be identified early as being at particularly high risk for the development of fibromyalgia this study will also provide blood samples for later analysis into immune factors,
We will identify 100 patients through back pain physiotherapy clinics at the NHS Walton Medical Centre and Aintree University Hospital and invite them for a single visit for clinical assessment and blood donation. Participants with severe skin symptoms will be asked to return for a re-assessment scheduled at a time of maximal pain flare. In a one-year follow-up telephone consultation we will then assess all patients for the development of widespread pain and will invite those that have developed widespread pain and will invite those that have developed widespread pain (about 1/5) for a repeat assessment visit.
We expect that this study will allow us for the first time to identify subgroups of NsLBP with similarities to CRPS or fibromyalgia, opening new avenues for their future treatment.
A Research Grant to Dr Nick Fallon – University Liverpool
Impact of COVID-19 related lockdown and isolation on chronic pain experience.
Myself and local colleagues (Dr Christopher Brown, Dr Andrej Stancak, Dr Charlotte Krahe, Miss Eleanor Brian, Dr Hannah Twiddy, Dr Bernhard Frank & Prof. Turo Nurmikko) have initiated some online research to consider the impact of UK responses to the COVID-19 on people living with chronic pain. We believe that the implementation of lockdown measures, social distancing and isolation could exacerbate pain and other symptoms and adversely affect the lives of those living with chronic pain. We hope to capture and understand this using a longitudinal online study that will follow patients from lockdown for at least the next 3 months with an option to follow-up for a longer period.
We are now approaching our study capacity (total 300) for the funding we have available. However, we would really like to continue and collect more patients during this critical period. The data we have accumulated so far is very encouraging (see attached preliminary analysis document). However, greater numbers would allow us to perform more complex analyses in future, e.g., to consider whether particular types of chronic pain patients are more affected than others and require more help and support at this time. This would help us to turn the findings into something that we can utilise to improve the care provision for UK chronic pain patients.
MSc Health Psychology Student Liverpool John Moores University.
A qualitative study on opioids in the management of chronic pain