Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS
Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies.
Materials and Methods
Various studies showed generalised hyperalgesia in CFS for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia in CFS is augmented, rather than decreased, following various types of stressors like exercise and noxious heat pain. Endogenous inhibition is not activated in response to exercise and activation of diffuse noxious inhibitory controls following noxious heat application to the skin is delayed.
The observation of central sensitisation in CFS is in line with our current understanding of CFS. The presence of central sensitisation in CFS corroborates with the presence of several psychological influences on the illness, the presence of infectious agents and immune dysfunctions and the dysfunctional hypothalamus-pituitary-adrenal axis as seen in these severely debilitated patients.
Comment by ME Research UK
Widespread and persistent pain is common in people with ME/CFS. In surveys, around 80% of patients say that they have severe pain sometimes, much or all of the time, while 84 to 94% of patients in formal research studies report some degree of muscle or joint pain. Also, around one-third of patients say that chronic pain limits or restricts their everyday activities, and that pain is a more disabling day-to-day symptom than fatigue.
Despite this, there has been very little scientific investigation of the pain characteristics of ME/CFS patients. One of the very few studies done – part of a PhD studentship at Glasgow Caledonian University – was funded by ME Research UK and published in the Journal of Musculoskeletal Pain. As the results of this investigation showed, the patients used words such as ‘throbbing’, ‘aching’, ‘tender’, ‘gnawing’ and ‘burning’ to describe their pain experience, while those with more severe illness also used ‘exhausting’ and ‘nagging’.
These descriptions may give clues as to the mechanisms causing pain in ME/CFS; in particular, ‘burning’ pain is often associated with neuropathic conditions in which the nerves have been damaged. Significantly, ME/CFS patients reported more pain than did patients with rheumatoid arthritis or multiple sclerosis in previous studies, both conditions in which pain is recognised as a major symptom.
Fibromyalgia is an illness with overlapping symptoms to ME/CFS, and one concept which has been extensively explored in fibromyalgia research in recent years concerns central sensitization – an increased sensitivity of cells in the spinal cord and the brain to various stimuli, including touch, heat, cold and chemicals. Central sensitization is believed to underlie many chronic pain conditions (see below), leading to an increased sensitivity to pain, but could it also be a factor in the pain felt by ME/CFS patients?
What is central sensitization?
- Nerve impulses can be thought of as messages fired along nerve fibres at great speed. Central sensitization involves an abnormal increase in the firing of nerve cells lying deep within the central nervous system (i.e., the brain and the spinal cord). This leads to an increase in the pain experienced by the person.
- The increased firing (excitability) is typically triggered by a burst of activity in nociceptors (pain receptors) which send nerve signals to the spinal cord and brain.
- The mechanisms involved in central sensitization are complicated. Some are topdown (from brain to the periphery), such as when sensory processing is altered in the brain. Others are bottom-up (from periphery to brain), such as when local infections trigger the release of the inflammatory molecules which activate cells in the spinal cord.
- An example of central sensitization is when a very light touch of the skin (from low-threshold sensory fibres) activates nerve cells in the spinal cord or brainstem that normally only respond to harmful stimuli. In this case, the light touch produces pain inappropriately – to the person, the pain feels like it comes from the skin or limb, whereas actually it is a manifestation of abnormal sensory processing in the central nervous system.
- Central sensitization is known to be responsible for tactile allodynia (pain in response to light brushing of the skin) and for the spread of pain hypersensitivity beyond an area of tissue damage so that adjacent non-damaged tissue is tender. The phenomenon can also occur after surgery, contributing to pain on movement or touch; during migraine attacks where brushing hair is often painful; and in some patients with nerve damage where even blowing on the skin produces excruciating burning pain.
One of the most active ME/CFS and fibromyalgia research groups in the world is headed by Prof. Jo Nijs at Vrije Universiteit and Artesis University College Antwerp in Belgium. With funding from ME Research UK, he and his colleagues have been investigating immunological responses to exercise, and have been undertaking a comparison of the different criteria for myalgic encephalomyelitis and CFS currently in use. The group also has a long-standing interest in central sensitization, and has just published this narrative review of its potential relevance in ME/CFS.
After searching the scientific literature, they found a range of experimental studies that had tested patients’ responses to stimuli including mechanical pressure, heat, aerosol inhalation of histamine, and electrical stimulation. Taking the studies as a whole, there was good evidence that ME/CFS patients had a generalised hyperalgesia (an increased sensitivity to pain throughout the body). Furthermore, patients’ pain sensitivity increased after stressors, such as harmful heat pain, and following exercise – an unusual observation since sensitivity to pain normally decreases in people during physical activity.
These findings came as no surprise to the researchers, who say that the presence of central sensitization accords with many of the symptoms of ME/CFS, as well as simply increasing sensitivity to pain. For example, infections are associated with the illness, and immune dysfunctions are characteristic features. Infection is known to trigger the release of the substances promoting inflammation, such as interleukin-1b, which play a role in sensitising peripheral nerves, and infections themselves can activate cells in the spinal cord which enhance the pain response.
Also, the activity of the hypothalamus–pituitary–adrenal (HPA) axis – a major player in the neuroendocrine system that controls reactions to stress and regulates many body processes – is known to be blunted in ME/CFS, and some crucial factors in the HPA axis are involved in pain sensitivity. In particular, low cortisol levels might contribute to (pain) hypersensitivity since cortisol levels are involved in pain inhibition. Finally, the neurocognitive symptoms seen in patients – principally memory and attention span and associated emotional processes – could inhibit central nervous system pathways from the brain downwards, resulting in sensitization of nerve cells in the spinal cord. Indeed, this could explain why psychological therapies designed to help patients manage symptoms and cope better with illness can be helpful in a minority of cases, as some patient surveys and clinical trials have shown.
The fact that central sensitization can be found in ME/CFS patients raises the question of treatment strategies to desensitize the central nervous system, making it less sensitive to painful stimuli. Fortunately, over the past few years there has been ongoing scientific work to develop targets specifically designed to block or reduce central sensitization. Various centrally acting drugs that have shown promise in animal models include analgesics, serotonin reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, and NMDA receptor antagonists (a class of anaesthetic). However, some of these agents may not be appropriate for ME/CFS patients. Likewise, various non-invasive treatment options have been proposed, based on the premise that nerve pathways from the brain downwards could be activated to help inhibit pain. These therapies include transcranial magnetic stimulation and transcutaneous electric nerve stimulation, and may also include cognitive techniques or biofeedback to address the emotional aspects of increased pain.
Of course, it is widely recognised that the ‘black box’ diagnosis of ME/CFS probably contains a variety of different types of patients, and it will be important to identify patients with a clinical picture dominated by central sensitization. The researchers say that these patients could be identified clinically by questioning them regarding hypersensitivity to bright light, sound, smell, hot or cold sensations, pressure, touch, and mechanical loading, whereas widespread sensitivity to pain can be recognised by testing muscle tone at various anatomical locations. Interestingly, the new International Consensus Criteria for ME (Journal of Internal Medicine, 2011) includes several characteristics related to central sensitization.
Since its first description, central sensitization has become an increasingly important concept in pain research. It is known to underlie many pain conditions (from allodynia caused by nerve injury, to headache), and now this review from the Brussels team has shown that it could be involved in ME/CFS as well. In their view, a change in thinking towards studying and treating ME/CFS as a central sensitization disorder appears warranted, particularly as therapeutic interventions become available.
This essay is an extract from our article (pdf 1.4 MB) in the Autumn 2012 issue of Breakthrough.