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 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
A research grant to Dr Francis O’Neil, University Liverpool
‘Corneal Confocal Microscopy in stratifying and tracking Small nerve fibre neuropathy in Burning Mouth Syndrome.
Burning mouth syndrome (BMS) is a painful burning sensation which can affect the tongue, palate or lining of the cheeks. It can be difficult to treat with sufferers being affected long term, causing significant distress.
BMS patients may be divided into subgroups based on their response to either lingual nerve block or blink reflex testing. These methods show patients can be sub-grouped into those that have a predominantly peripheral nerve involvement and those that have a predominantly central nervous system involvement. This is important because some BMS patients may respond better to peripherally acting drugs and others to those acting centrally.
We have shown recently that a new test called Corneal Confocal Microscopy (CCM), which looks
at the surface of the eye that is exclusively innervated by small fibre nerves, can detect small nerve fibre changes in some BMS patients. The numbers were small in our previous study but if we can show that CCM can differentiate subgroups of BMS patients then this rapid, non-invasive method would be useful in guiding personalized treatment options for patients. It would also be useful in research to track small nerve fibre changes in disease progression or response to treatment.
We propose to compare CCM data in healthy controls and BMS patients that have been subgrouped by their response to lingual nerve block and blink reflex testing. We will compare the CCM data to small nerve fibre counts in tongue biopsy samples from the same patients to ensure the findings are similar. Furthermore, we will look at changes in the density of a type of immune cell called Langerhans cells in these biopsies as an increase in Langerhans cell density was detected in our CCM study and this would help us confirm if these changes also occur in the oral mucosa.
A research grant to Dr Franzika Denk, Kings College, London
Cerebrospinal fluid – a window into how our central nervous system processes pain.
Current research suggests that chronic pain frequently results from miscommunication between our immune and nervous systems. However, evidence for this interaction in the central nervous system (CNS) comes mainly from experiments in models , since it is difficult to study with imaging. One way to overcome this challenge is to use the human cerebrospinal fluid (CSF). It contains number of immune cell, as well as the proteins they and the CNS release.
Together with collaborators at the Karolinska Institute, we have optimized the latest technologies to study CSF, which we now want to apply to study patients who are undergoing high frequency spinal cord stimulation as a treatment for chronic neuropathic pain.
CSF will be drawn when stimulators are implanted. We want to (1) isolate the different immune cells that are in CSF using a cell-sorting technology called ‘FACS’; (2)Check wihich genes they express; (3) study the proteins that are in the CSF solution. The nature of the pain the patients experience will be well- characterised and include measure of fatigue and quality of life.
We have personnel employed who could dedicate time to this project, but require consumables funding. We would like to answer the following questions.
(1) Is what is true in models also true in people: immune cells release substances that make CNS neurons hyper-sensitive and contribute to chronic pain?
(2) Can we use this information to group patients to identify those whose pain is entirely driven by the CNS compared to those whose pain is still driven by nerves out in the body.
(3) Can we use this information to predict outcomes in our clinical trials?Not all patients respond well to surgery and it would be useful to have a way to save those who are unlikely to benefit from a painful operation.
A research grant to Dr Bazbeck Daveltov, University of Sheffield
Novel long-acting analgesic for chronic pain.
Chronic pain is a major health problem affecting one in five adults. It has a substantial impact on patients’ quality of life and presents a huge socio-economic burden. Despite increased understanding of the biological mechanisms underlying chronic pain, there is still no reliable treatment. Current methods used to treat pain cause a significant number of side effects and they rarely work long-term. It has been recently discovered that botulinum neurotoxins are able to reduce for months certain pain conditions, alongside their paralytic effects on muscles. Our research demonstrated that we can remove the paralytic effects and also enhance the long-lasting analgesia. This provides a new and exciting therapeutic strategy for the treatment of chronic pain, especially neuropathic pain conditions unresponsive to standard treatments.
We have developed a process that is able to re-engineer the native botulinum molecule to target specifically neurons associated with pain signaling. By eliminating the effects at the neuromuscular junction, this results in a safer, non-paralytic molecule that can still silence pain neurons for months after a single application. Using this novel molecule we have shown that it is possible to reverse some aspects of the pain pathway in an animal model of cancer-drug induced neuropathy. Chemotherapy-induced peripheral neuropathy is a severe side effect often associated with several chemotherapeutic agents. Studies on cancer survivors have revealed significant difficulties with activities of daily living and impaired physical and psychological health due to chronic pain.
Our aim now is to elucidate biological mechanisms of long-lasting analgesia and test our novel molecule in additional models of neuropathic pain to determine its suitability as an alternative treatment for prevalent chronic painful conditions. The funding will allow us to complete characterization of the unique long-acting analgesic and prepare a high-quality publication in a peer-reviewed journal facilitating translation towards novel long-lasting pain relief.
Novel long-acting analgesic for chronic pain
Grant to Dr Bernhard Frank, Walton Centre NHS Foundation Trust
Additional funding for TMS operator.
Grant to Dr Andreas Goebel, University Liverpool
Additional Funding for Lab Technician.
A Research Grant to Emma Begley, Liverpool John Moores University
A qualitative study on opioids in the management of chronic pain
A research grant to Dr David Andersson, Kings College, London
Neuronal basis of pain produced by passive transfer of Fibromyalgia from patient to model.
Fibromyalgia is one of the most common causes of chronic pain worldwide. There is no diagnostic test available and patients are diagnosed on how severe and widespread their pain is and whether they have other symptoms, e.g. fatigue, sleep problems and depression. Treatment of fibromyalgia is focused on exercise and education, which help patients become more active and cope better with pain. Drugs that are used to treat pain in fibromyalgia are effective in some patients, but often cause problematic side effects and regularly become less effective with time. Fibromyalgia has a serious impact on quality of life, and the fact that patients look healthy, can make it difficult for them to convince their environment about how they feel and to qualify for benefits. The cause of fibromyalgia remains unknown, but an improved understanding of the condition will accelerate development of treatments and diagnostic tests.
Neuronal basis of pain produced by passive transfer of Fibromyalgia from patient to model During this project, we will identify how fibromyalgia antibodies cause pain and sensitivity by acting at pain-sensing nerves, and whether a subgroup or all patients have these antibodies. It is likely that our work will lead to improved treatment of fibromyalgia in the future.
A research grant to Dr Paul Strutton,Imperial College London
The effects of non-invasive brain stimulation on chronic pain & central sensitisation in patients with radicular low back pain(sciatica) randomised sham-controlled proof of principle.
The body has pain control systems in the brain which can alter the changes in the spine and many drugs used to treat chronic pain work in this way. However, they are associated with side effects and often do not work. There are now new, drug-free ways to treat chronic pain which involve activating the brain with a safe, easy to deliver electrical stimulus applied to the head. This approach has been used many times in patients with chronic pain, however we still do not know if the pain relief is due to changes in the spine.
In this study, we will investigate the effects of brain stimulation on the changes in the spine that lead to chronic pain in patients with sciatica. To do this, we will note patients’ chronic pain and will use a simple pain test on the leg. These assessments will be done before and after brain stimulation on 5 consecutive days. The patients will return 7 and 21 days later and will have the same assessments, this time without brain stimulation. This will be done to see if the daily treatment has any longer lasting effects on their chronic pain. A longer term follow-up at 2 months will also be carried out.The new knowledge that we will generate will help us understand how this new treatment works to reduce chronic pain.