How is severe arthritis pain defined?
Pain is defined by the sufferer’s experience. Pain may be severe because it is intense, frequent or sustained, and because it is distressing.
What is currently known about the causes of severe arthritis pain?
The severity of pain is not simply due to what is going on in the joint, but is also affected by how the body processes the pain signals, and the context in which it is experienced.
Arthritis pain is more commonly severe when the joint is inflamed, when the normal protective cushioning in the joint (the cartilage) has been damaged, and when the bone underneath the joint is exposed to abnormal mechanical stresses.
Movement and weight bearing on an arthritic joint can often cause severe pain, and our programme of research will try to find ways of blocking the molecules that convert these mechanical stimuli to pain.
Please can you outline the treatments that are currently available for severe arthritis pain? How do these work?
Treatments for arthritis pain include drugs and non-drug treatments. The commonest pain relieving drugs used in arthritis are paracetamol, non-steroidal anti-inflammatory drugs (such as ibuprofen or naproxen), and opioids (such as codeine or tramadol).
Exercises may help reduce arthritis pain, and slimming can be helpful for people who are overweight, particularly those with knee pain. All these work in different ways and so are often used together.
Unfortunately they often do not adequately relieve arthritis pain, so there is a great need to develop new treatments. People with severe, unremitting pain may sometimes be able to get relief from joint replacement surgery.
Why are these drugs not always effective for people experiencing severe pain?
Current drugs are often limited by their side effects. Paracetamol is dangerous in high doses because it damages the liver. Non-steroidal anti-inflammatory drugs can cause stomach ulcers and heart disease.
Opioids commonly cause constipation, confusion (or a spaced out feeling and inability to concentrate), and nausea. Opioids also often stop working after prolonged use as the body gets used to them.
Arthritis pain is not always caused by inflammation, so it is not surprising that anti-inflammatory drugs do not always work.
You have recently received a grant of £800,000 from medical research charity Arthritis Research UK to develop new treatments for severe arthritis pain. How do you plan to use the funds?
The plan is to identify molecular events associated with the development of pain in models of arthritis. We believe that pressure sensors in nerve cells that are found in arthritic joints are very important for initiating pain. They seem to be sensitised in arthritis and if we can identify them, we should be able to devise drug screens to find small molecules that may be useful pain killers.
Importantly, we have biopsy material from people with severe arthritis pain that will enable us to make sure that the events we identify in the models are identical to those that occur in people. In other diseases, models have proved faithful to the human pathologies they mimic.
How will pain be measured in this study?
In the models, the threshold for detection of pliable bristles (von Frey hairs) combined with weight bearing ability is used as a measure of the arthritis pain. These measures are a little distant from the on-going pain that may occur in people with arthritis, but they are feasible, have been shown to be linked to on-going pain in other pain states, and importantly are not too stressful.
We are convinced that the relief of human suffering justifies these kind of experiments.
How will your research build on what is already known about severe arthritis pain?
Our work uses state of the art novel approaches to exploit genetics that will give us new insights in into arthritis pain - so this is a new departure.
How long will this research take and what do you hope to achieve in this time?
The fundamental mechanisms of arthritis pain involving pressure should be clarified over the 4 year period of the grant.
Drug development is a much harder process, because of the need to make sure that new drugs are safe, which is ensured by a very complex regulatory structure for drug approval.
Realistically, any new drug that derives from our studies is at least a decade away from regular use in the clinic.
What hurdles do you expect to have to overcome in order to achieve these goals?
There are three main hurdles; Can we identify the Mechano-sensors in nerves from our models and people with arthritis pain? The human biopsy material is key to this work.
Can we then identify drug leads that are useful analgesics, and can we translate these studies into effective non-toxic drugs? Very excitingly, in preliminary experiments, we have identified the population of neurons that are required for osteoarthritis pain in mice, and found two proteins that are known pressure sensors that seem to be needed for the development of osteoarthritic pain. So we are off to a good start!
Where can readers find more information?
About Professor Walsh and Professor Wood
David Walsh is Professor of Rheumatology at the University of Nottingham and Consultant Rheumatologist at Sherwood Forest Hospitals NHS Foundation Trust, where he directs the Back Pain Unit which provides diagnostic assessment and multidisciplinary Pain Management Programmes for people with chronic low back pain.
In 2010 he established the Arthritis Research UK Pain Centre in Nottingham, together with a multidisciplinary research team including preclinical neurosciences, psychology, neuroimaging, orthopaedics and evidence synthesis.
The Centre aims to develop new and improved treatments through a translational research programme into the mechanisms by which changes within the joint and in the nervous system interact with psychosocial factors to produce arthritis pain.
His preclinical research has focused on structural changes that contribute to joint pain, in particular angiogenesis, nerve growth and inflammation in the synovium and subchondral bone.
His clinical research is defining the spectrum of pain phenotypes in people with arthritis based on underlying pain mechanisms, in order to better target treatments to those most likely to benefit.
John Wood spent 12 years in the Pharmaceutical Industry before setting up a pain research group at University College London. He is a fellow of the Royal Society and won the Grand Prix Scientifique of the French Academy for his pain research in 2009.
His group focusses on the events that cause peripheral neurons to drive pain pathways in the Brain. They have identified many potentially important analgesic drug targets using genetically modified mice and human genetic studies.
About Arthritis Research UK
Arthritis Research UK is the leading authority on arthritis in the UK, conducting scientific and medical research into all types of arthritis and related musculoskeletal conditions. It is the UK’s fourth largest medical research charity and the only charity solely committed to funding high quality research into the cause, treatment and cure of arthritis.
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