The research into FMS is undergoing a quite fertile period. In this paper I take advantage of several recent papers to look at different theories regarding the origin of pain in this disease. The pain FMS patients suffer from could derive from two places in the body; the central nervous system/brain or in the muscles/tendons themselves. In this Part I, I focus on evidence suggesting that the pain in FMS is due to an oversensitized central nervous system.
There are several different types of pain disorders; some people have ‘hyperalgesia’- an increased sensitivity to painful stimuli, and some people have ‘allodynia’ – a painful responses to usually non-painful stimuli. FMS patients have both.
Where this pain derives from is still not clear but the type of pain found in FMS gives us some clues as to its origin. Researchers know, for instance, that people with allodynia usually exhibit either increased sensitization of their peripheral pain receptors (nociceptors) (peripheral sensitization) located outside of the brain, or increased excitability of neural circuits regulating pain in the brain (central sensitization).
The signal for muscle pain travels via two types of nerve fibers to the dorsal horn of the spinal cord, where it prompts them to release pro-pain substances such as substance P and calcitonin gene-related peptide (CGRP). Substance P is a sensitizer; when it is it released into the neurons of the spinal cord it makes their NMDA receptors hypersensitive to glutamate, when released into the tissues surrounding a wound it makes them more sensitive to stimuli.
NMDA receptor activation and the concomitant release of pro-pain substances such as substance P (SP), nerve growth factor (NGF), brain derived nerve factor (BDNF), and nitric oxide is believed to drive the process of central sensitization.
A recent text stated that the ‘recruitment of the NMDA receptor appears to be the pivotal event in increasing the sensitivity of the nociceptive (pain) spinal circuits to (painful stimuli)”. This is believed to occur when repetitive pain stimuli knock the magnesium block off the NMDA receptors (Staud 2004).
In order for a cell to respond to a substance it must have a receptor for that substance to bind to. Increased receptor activation occurs either when receptors are abnormally sensitive or when high numbers of a receptor are present.
High levels of the NMDA receptor on a cell indicate that that cell is hypersensitive to glutamate; i.e. only small levels of glutamate are necessary to prod it into action.
NMDA receptors form ion channels at the excitatory synapses of these nerves. Ordinarily these ion channels are a) closed and b) blocked by extracellular magnesium ions. Two things needed to happen for these ion channels to open, first adequate glutamate needs to be present to open the channel and the membrane of the cell needs to become depolarized in order to flush the magnesium out.
The negatively charged cell attracts magnesium ions which then close the NMDA ion channels. If the cell loses its negative charge, the magnesium ions will drift away. The loss of the magnesium ions allow sodium, potassium and most importantly calcium ions into the cell.
Once inside the nerve cell the calcium ions activate signaling pathways that call for the production of glutamate, substance P and other pro-pain factors. The neurons in the spinal cord then send a message to the part of the brain called the thalamus which processes it and amplifies the pain response.
Prolonged periods of NMDA ion channel activation and the high intracellular Ca2+ levels that accompany it can, by triggering the apoptotic process (cell suicide), result in nerve cell death.
Glutamate is the chief excitatory neurotransmitter in the brain. Ischemia (low blood flows).and low glucose concentrations can stimulate glutamate production. Ischemia is found in several neurodegenerative diseases does. Increased glutamate levels are associated with increased oxidative stress.
The controversy in the central sensitization theory in FMS comes from inability of brain imaging studies, in contrast to other pain diseases, to identify a lesion or wound in the CNS. The one other pain disease in which a CNS lesion is not found, trigeminal neuralgia, involves, interestingly, circulatory problems. In trigeminal neuralgia, increased pressure from a blood vessel applied to a cranial nerve supplying the face causes spasms of severe facial pain.
A recent study (Staud, R., Robinson, M. and D. Price. 2005. Isometric exercise has opposite effects on central pain mechanisms in fibromyalgia patients compared to normal controls. Pain 118, 176-184) that examined how FMS patients responded to exercise provided evidence that central sensitization is at work in FMS.
Many studies have shown that people usually display a decreased response to pain following exercise. The origin of this response is not known but could occur when receptors that monitor muscle movement and contraction (mechanoreceptors) activate anti-nociceptive (anti-pain) receptors.
Both FMS (and some CFS patients) appear to have an anomalous response to exercise – following it they report an increased not decreased sensitivity to pain.
FMS patients have long reported that the pain they experience is not located in one place but often occurs body-wide. (Staud indicates it is more intense and widespread in the upper half of the body.) This is the first study to verify this anomaly; it found that the pain thresholds in both exercising and non-exercising muscles were increased after exercise in FMS patients. The pain intensity in the FMS patients did not appear to be particularly high – what was notable is that it increased at all.
Since trauma in the muscles results in local not systemic increases in pro-pain substances it is difficult to imagine how a peripheral process (one located in the muscles) could be at work here. This reaction, therefore, is another indication that a central pain mechanism is at work in CFS. It illustrates that a stimulus centered on one part of the body can, possibly by inducing a hyperexcitable response in the brain, can cause an aberrant response to normal stimuli across the body.
Just what is causing this hyperexcitability is unclear but there is evidence of increased levels of pro-pain substances in the brains of FMS patients.
FMS is due to increased levels of pro-pain substances in the brain
Increased levels of at least three pro-pain compounds associated with NMDA activation (substance P, nerve growth factor (NGF), brain derived growth factor (BDNF)) have been found in FMS. Substance P, the most well-studied pro-pain substance in FMS, is a neurotransmitter and neuromodulator that, besides pain, has been associated with anxiety, stress, neurotoxicity and nausea.
Substance P is also involved in the transmission of pain impulses from peripheral receptors to the central nervous system. Releases of substance P cause the area surrounding a wound to become more sensitive to pain. Several studies have found increased levels of substance P in the cerebral spinal fluid of FMS patients.
NGF and BDNF are two neurotrophins that are increased in the cerebral spinal fluid (CSF) of chronic headache patients.Neurotrophins enhance the survival of neurons by blocking the apoptotic process (suicide). They also regulate neuronal plasticity.
Alterations in the neural network (neural plasticity) could result in a chronically increased pain state. In vivo studies have indicated that nerve growth factor (NGF) increases the level of the pro-inflammatory neuropeptides CGRP and substance P as well as the growth factor BDNF. One study has found increased levels of nerve growth factor in the CSF of FMS patients.
Like substance P, BDNF appears to be both a neuromodulator and neurotransmitter. BDNF appears to enhance NMDA activity in two ways; first it enhances the production of glutamate and secondly it is able to increase NMDA receptor activity.
BDNF is particularly interesting in its ability to induce a long term increase of sensitization in some parts of the brain. Unfortunately, no studies have addressed levels of this important compound in the cerebral spinal fluid of FMS patients. BDNF levels have been assessed in the peripheral blood, however/
The pain in FMS is may not simply be due to increased levels of pro-pain substances. The central nervous system also employs a battery of anti-pain substances designed to turn off or limit the pain response. These may be low in as well.
FMS is due to decreased levels of anti-pain substances in the brain
Sarchielli, P., Alberti, A., Candeliere, A., Floridi, A., Capocchi, G. and P. Calabresi. 2005. Glial cell ine-derived neurotrophic factor and somatostatin levels in ccerebrospinal fluid of patients affected by chronic migraine and fibromyalgia. Cephalalagia 26, 409-415.
In addition to having high levels of ‘pro-pain’ factors, FMS patients could also have low levels of ‘anti-pain’ factors. These are compounds that inhibit the pain response in the spinal cord. One anti-pain factor called ‘glial cell line derived neurotrophic factor (GDNF), which works specifically on the sensory neurons, was recently studied in relation to FMS.
GDNF is intriguing in several ways; first it belongs to the transforming growth factor family, one of whose members (TGF-B) is often increased in CFS, and it interacts with the sodium channels in cells. There is some indirect evidence of altered sodium channel activity in CFS (See A Channelopathy in CFS?)
GDNF plays an important role in the regulation of pain in the body. Since GDNF appears able to modify the expression of two NGF regulated pro-pain factors; substance P and the capsaican receptor, low GDNF levels could be at the heart of the sensitization seen in FMS.
GDNF also appears to modulate the release of another anti-pain factor called somatostatin. Somatostatin is a key regulatory and anti-inflammatory peptide produced throughout the central nervous system and in most of the peripheral organs.
This study, which appears to be the most complete survey yet of anti-nociceptive factors in FMS, found that levels of both GDNF and somatostatin were markedly reduced in both FMS and chronic migraine patients. That somatostatin and GDNF levels were correlated with each other suggests that GDNF, in particular, plays a key regulatory role in these diseases.
This study suggests drugs developed to increase GDNF and somatostatin could be effective in FMS.
A shocking 2006 study provides more evidence of central nervous system dysregulation in FM
Usui, C., Doi, N., Nashioka, M., Komatsu, H., Yamamoto, R., Ohkubo, T., Ishizuka, T., Shibata, N., Hatta, K., Miyasaki, H., Nishioka, K. and H. Arai. 2006. Electroconvulsive therapy improves severe pain associated with fibromyalgia. Pain 121, 276-280.
A recent trial involving electroconvulsive therapy (ECT, i.e. electroshock) also suggests that the hyperexcitability seen in FMS is due to lack of anti-nociceptive activity. ECT was found to significantly improve the pain scores in FMS patients with severe pain. Their scores, promisingly, remained low three months after the treatment.
An examination of regional cerebral blood flows after ECT found that it significantly improved blood flows to the thalamus, a part of the brain involved, among other things, in the interpretation of sensory inputs. Chaudhuri and Behan suggested thalamic inhibition may also cause central fatigue in CFS.
It is believed that the ECT activated anti-pain nervous system pathways involving serotonin, norepinephrine or dopamine. Prior studies have found reduced serotonin levels in FMS. The recent pharmacogenomics studies suggest these same pathways may be involved in CFS. Once again we see evidence suggesting that circulatory problems may play a role in FMS pathophysiology.
More evidence that the brain is involved in FMS comes from a 2005 study that found it may be allied with a disease of exquisite CNS sensitization: migraine.
Migraine and FMS – two sister diseases?
Marcus, D., Bernstein, C., and T. Rudy. 2005. Fibroymalgia and headache: an epidemiological study supporting migraine as part of the fibromyalgia syndrome. Clin. Rheum. 24, 595-601
There are a number of similarities between migraine and FMS; both disease appear to involve an exquisite sensitization to stimuli, both are pain syndromes, and depression and anxiety are common in both. Although migraine is chiefly thought of as headache, recent reports indicate that increased sensitization in the periphery is common as well – almost half of migraine sufferers suffer from allodynia (a painful response to normal stimuli) and about 40% display widespread tender points. A recent study found that about 15% of migraine sufferers fit the criteria for FMS.
Chaudhuri and Behan state there are numerous similarities between CFS and migraine as well. CFS patients share with migraine sufferers such symptoms as headache, confusion, increased sensitivity to light, sounds and smells as well as exacerbated responses to serotonin.
Symptom exacerbation during menstruation and muscle pain, disequilibrium and unusual sweating are also often seen in both diseases as are white brain matter abnormalities and reduced cerebral blood flows. Stress, alcohol and caffeine can exacerbate symptoms in both and transient or chronic fatigue is also common in migraine (see A Neurological Channelopathy in Chronic Fatigue Syndrome (ME/CFS?))
This study found that almost half of FMS patients suffered from migraine and 80% suffered from severe headaches. Most intriguingly a finding that headache preceded FMS symptoms in almost half of the FMS patients suggests that sensitization began in the brain and later spread to periphery.
Other studies have found an increased incidence of another pain disease possibly allied with FMS, irritable bowel syndrome (IBS), in migraine patients. We just saw that both migraine and FMS patients have low levels of the anti-pain factor BDNF in their spinal cords.
Is FMS a disease in which the central pain producing pathways in the brain and spinal cord are overactive? Several studies have suggested it is; not only have high levels of several pain producing substances (substance P, nerve growth factor) been found in the CSF of FMS patients but reduced levels of an important anti-pain factor, GNDF, have as well.
A successful electroshock therapy study suggested that reduced blood flows in the thalamus of the brain may be implicated as well. A possible connection with a disease of exquisite central nervous system sensitization, migraine, further implicates the brain in FMS.
But is central sensitization the answer in FMS? Recent studies that provide evidence of peripheral sensitization suggest that FMS patients may get hit from both sides – the body and the brain. See the next paper in this series for evidence that FMS is disease of the periphery, not the central nervous system.