Please could you give a brief introduction to chronic nerve pain?
Chronic nerve pain results from pathological changes within a nerve that appear to be self-sustaining and thus the pain continues for a long time. The pathological changes can result from partial damage to a nerve and/or inflammation within the nerve. It is this we have studied. They can also result from diseases involving the nerve.
What can cause partial nerve injury that leads to chronic nerve pain?
Partial nerve damage leads to death of some nerve fibres within a nerve, and survival of other fibres. Partial damage can result from crush or stretch of a nerve during an accident, or during surgery sometimes leading to long term postoperative pain. Some lower back pain results from a nerve being compressed or partially crushed, or from a prolapsed disc causing pressure on the nerve and also local inflammation.
Death of some nerve fibres within a nerve also occurs in some diseases, including diabetic neuropathy in patients with advanced diabetes, and also in HIV. Other autoimmune diseases have immune responses within the nerve that cause nerve damage and neuroinflammation. Several chemotherapeutic drugs for cancer cause toxic damage to peripheral nerves. All the above can result in chronic nerve pain.
Do the damaged or surviving nerve fibres cause the pain?
There is growing evidence that degeneration of damaged nerve fibres and particularly of their myelin sheaths, cause neuroinflammation and/or immune system activity, and that this causes greater excitability and firing of the surviving fibres, which contributes to, or results in, chronic pain. Simply, the degeneration of damaged fibres may cause an environment that triggers activity in the surviving fibres.
By showing changes in subgroups of these surviving neurons that could lead to the different qualities of chronic nerve pain, our study adds support to the view that the surviving fibres are very important in causing chronic nerve pain.
What are the different qualities or types of chronic nerve pain?
Patients experiencing chronic nerve pain describe a combination of different types of pain. The pain may be evoked pain (a stimulus is needed to cause the pain) as in allodynia: intense pain from gentle stimulation such as skin touch (e.g. moving cotton wool across the skin) or hyperalgesia: more pain caused by a normally painful stimulus.
Patients also report spontaneous pain unrelated to any stimulus: either ongoing burning pain or sharp, shooting, stabbing pain. This spontaneous pain is hard to live with as it is unrelenting, sometimes called “unbearable” and makes people feel very unwell and very miserable. People with this type of pain may find they are unable to be comfortable even in bed, which can cause insomnia. Some patients report strange sensations, called paresthesias.
What causes these different qualities of chronic nerve pain?
The reason for these different types of pain has never been fully explained. Key questions are whether the central or peripheral (sensory) nervous systems are responsible and whether the dying or surviving nerve cells in a partially injured nerve are more responsible. Our hypothesis was that it was due to the surviving sensory fibres becoming more excitable due to the pathological changes in the nerve; our findings support this hypothesis.
What did your research show?
We found changes in several different groups of the surviving sensory nerve cells that could account for the different types of chronic nerve pain. We found:
- spontaneous ongoing firing in C-fibre nociceptors: we have shown previously that spontaneous pain (probably the burning type pain) is linked to the rate of this firing (Djouhri et al., 2006).
- spontaneous firing in fast conducting A-fibre nociceptors: this would be likely to cause the spontaneous sharp shooting pain complained of by patients.
- that A-fibre nociceptors became more excitable; this could contribute to the greater sensitivity to stimuli; if these nociceptors are more easily stimulated, gentle (normally not painful) stimulation could cause pain.
- finally we found spontaneous firing in subgroups of surviving sensory neurons that normally contribute to the sense of touch. This could cause the strange sensations or paresthesias.
Thus there are changes in different groups of surviving sensory neurons that could account for the main types of pain and paresthesia reported by patients with chronic nerve pain.
Why has neuropathic pain traditionally been hard to treat clinically?
There are many different views on this. A lack of knowledge about which types of sensory nerve cells contribute to the different aspects of neuropathic pain, may have contributed. For example, many studies in the past focussed on neurons with injured fibres, not those with surviving fibres that we describe here. We hope that our study will help to shift the focus towards the uninjured nerve cells and their contributions to different types of nerve pain.
In addition, the study of spontaneous pain and the underlying spontaneous firing in the surviving nociceptors has been under-researched. Now more research groups are examining spontaneous pain and its causes and clinical trials of potential novel pharmaceutical treatments are beginning to include evaluation of spontaneous pain.
What methods of pain relief do patients with chronic pain currently use?
Many people find pain relief with drugs available over the counter, including the non-steroidal anti-inflammatory drugs (NSAIDS) such as paracetamol/acetaminophen, aspirin, and ibuprofen. If these do not provide adequate relief, it is important to consult a physician who prescribe a variety of drugs including: the NSAID diclofenac/volterol, gabapentin or pregabalin, lidocaine patches, opioids, tramadol or tricyclic antidepressants.
These have all been shown to be effective but their efficacy varies between patient and the use of some is limited by adverse side effects. There are other treatment options, but treatment is often not fully effective, leaving an urgent need for development of more effective neuropathic pain therapeutics.
How will your recent research allow for more effective pain killers to be developed?
A greater focus on the uninjured sensory nerve that may cause the different types of nerve pain could contribute to novel approaches tp cpntrolling different aspects of this pain.
How do you think the understanding of chronic nerve pain will develop?
In animal experiments there has been much excellent research on particular protein receptors on nerve fibres that respond to different types of stimulation (i.e. to different thermal, chemical or mechanical stimulation). A combination of these receptors may need to be targeted by drugs to combat effectively the different aspects of chronic nerve pain.
There are other approaches that involve tackling the inflammation or the immune system in the periphery (the last approach is still in its infancy), or targeting the central nervous system (CNS) because it becomes hyperexcitable during this chronic pathological pain, or using the body’s own inhibitory CNS pathways to limit the pain. In small numbers of patients, neuropathic pain results from a mutation in a specific protein channel. The discovery of such mutations may lead to very specific therapies for these patients.
In the sensory neurons it is clear that there are two main types of ion channels that control nerve fibres excitability. Simply put the Na+ channels are the main excitatory machinery of a nerve fibre while the K+ channels tend to be inhibitory or stabilising. It is becoming clear that some of these K+ channels limit the amount of pain that we feel. Perhaps these internal control mechanisms could be increased to limit chronic nerve pain.
The more we understand about the specific mechanisms in different types of sensory nerve cells contributing to, and controlling, their excitability and thus this pain, the more likely it is that these mechanisms can be utilised or modulated therapeutically to limit or block the neuropathic pain.
What plans do you have for further research into this field?
My colleagues Dr. Cristian Acosta, Roger Watkins and I are currently engaged in seeking answers to the following questions:
- What causes the undamaged C-fibre nociceptors to fire spontaneously and cause ongoing spontaneous pain?
- Which subdivisions of these neurons are able to fire spontaneously?
- What controls whether they fire spontaneously and how rapidly they fire? This is important as the level of pain is related to the rate of the firing.
- What natural mechanisms (such as K+ channel subtypes) do we have that limit this spontaneous firing? Can these perhaps be enhanced?
Dr. Laiche Djouhri, the lead author on our recent paper, now at University of Liverpool, is pursuing different questions related to the types of K+ channels involved in spontaneous firing in subtypes of sensory neuron in pathological pain.
Where can readers find more information?
About Professor Sally Lawson
Professor Sally Lawson is Emeritus Professor in the School of Physiology and Pharmacology, Medical Sciences Building, University of Bristol.
After a Physiology degree and Neuroscience PhD at Bristol University, she was on the staff from 1977. She has been running a group researching primary sensory neurons and their contributions to chronic pain since 1980, with continuous funding from sources including the BBSRC, the MRC and for the last 20 years, the Wellcome Trust.
Her research group has examined electrophysiological and chemical properties of primary sensory neurons with different sensory properties. This led to studies of how subgroups of sensory neurons change their properties to become spontaneously active, more excitable, and contribute to chronic pathological pain of peripheral origin.
Her group are currently examining the role of K+ leak channels in sensory neurons in chronic pathological pain, and the factors contributing to the spontaneous firing in nociceptors that results in spontaneous pain.