On cytokines, inflammation, pain and fibromyalgia Cytokines are inter-cellular chemical messengers produced mostly by white blood cells. Some are generally pro-inflammatory (inflammatory cytokines turn inflammation ‘on’) while others are generally anti-inflammatory (they turn inflammation ‘off’). High levels of inflammatory cytokines indicate an ongoing inflammatory process. There might not be the appearance of ‘inflammation’ as we…
An increase in pro-inflammatory cytokines, especially IL-8, may be critical in the onset and progression of fibromyalgia. It has been observed that up to about two-thirds of those with fibromyalgia report its initial onset in connection with a highly stressful event or period in their lives. Is there a connection between stress and pro-inflammatory…
While the abstract referenced below is short, it makes mention of a number of key points, each suggesting that an inflammatory process may be at work in fibromyalgia: The cerebro-spinal fluid (CFS) of those with fibromyalgia has been shown to contain higher than normal levels of substance P and corticotropin releasing hormone (CRH). The blood…
Mild to moderate exercise is often recommended as a treatment for fibromyalgia. In the study summarized here, researchers followed changes in both pro- and anti-inflammatory cytokine levels over an eight month program of exercise. Give it time Results at the mid-point were not significant, but by the conclusion of eight months there was a…
Inflammatory cytokines impair memory and learning: Fibro fog. Cytokines are inter-cellular chemical messengers produced mostly by white blood cells. Some are generally pro-inflammatory (inflammatory cytokines turn inflammation ‘on’) while others are generally anti-inflammatory (they turn inflammation ‘off’.) Inflammatory cytokines, which are often elevated during sickness, are believed responsible for many of the common symptoms…
Growth hormone in fibromyalgia. Growth hormone is one of the numerous chemical mediators of the hypothalamic-pituitary-adrenal axis (HPAA,) a very complex system that governs many functions, including the immune response to stress. Various abnormalities of the HPAA have been implicated in fibromyalgia, including abnormalities in the production and release of growth hormone. Some research has…
It is hard to describe a possible cause for all of the diverse symptoms of fibromyalgia without making reference to cytokines, especially the pro-inflammatory cytokines IL-1, IL-6 and IL-8. Only pro-inflammatory cytokine excess offers a single, reasonable explanation for fatigue, sleep impairment, cognitive impairment (fibro-fog,) autonomic dysfunction (e.g.postural orthostatic tachycardia syndrome – POTS,) depression, anxiety,…
Central sensitization cannot be the cause of fibromyalgia Central sensitization is believed to start when persistent pain signaling causes cells in the spinal cord (dorsal horn neurons) to become over-activated. The cells (dorsal horn neurons) that transmit pain signals become much more sensitive as a result. Central sensitization causes stimuli that would normally be…
Determining the minimum significant change in the FIQ score. The data from three clinical trials of pregabalin (Lyrica) in the treatment of fibromyalgia were analyzed. These trials involved over 2,200 patients. Because these trials assessed each patient using multiple tests, analysis of the data allowed for the comparison of FIQ score changes with other…
Cymbalta modestly improves total FIQ scores. Just over 200 subjects were enrolled in a 12 week placebo-controlled trial of Cymbalta (duloxetine.) Just under 90% were female and 38% had a concurrent diagnosis of major depression. Approximately half the trial participants received a placebo, while the remaining half received duloxetine 60 mg twice a day….
Non-pharmacologic treatments are needed Fibromyalgia is a common and poorly understood pain disorder that afflicts an estimated 200 million or more people worldwide. Pharmacological treatments for fibromyalgia are not available to the vast majority of these individuals. Even when available, prescription treatments for fibromyalgia are often marginally effective or entirely ineffective. Standard drug treatments…
Sodium oxybate (Xyrem) appears superior to current FDA approved medications. An 8 week trial of sodium oxybate in the treatment of fibromyalgia resulted in a significant decrease in fibromyalgia impairment as measured by the Fibromyalgia Impact Questionnaire (FIQ.) Among those receiving sodium oxybate, the 4.5 gm dose resulted in a 20.4 point reduction in…
Growth hormone deficiency in fibromyalgia. Growth hormone is one of the many chemical mediators of the hypothalamic-pituitary-adrenal axis (HPAA,) a very complex regulatory system affecting nearly every bodily function but especially critical in homeostatic regulation of the stress response. Is growth hormone low in fibromyalgia? Some studies (including the second study referenced below) have shown…
A 12 week trial of Savella in the treatment of fibromyalgia. Approximately 500 patients received Savella, 50 mg twice a day, for 12 weeks. Prior to the 12 week period, patients had their dose of Savella gradually increased over 4 to 6 weeks in preparation for the 12 week stable dose phase of the…
The term ‘sickness syndrome’ refers to a constellation of non-specific symptoms that develop in connection with many ailments, especially infections. Simply stated, when you get an infection you feel lethargic, fatigued, sleepy, and somewhat depressed. You feel sick.
Fibromyalgia results in those same symptoms, not (of course) because it’s caused by a ‘bug’, but fibromyalgia might trick your brain into thinking you’ve got one doozy of an infection – an infection that never seems to go away.
To see how fibromyalgia does that, and the expected results of such trickery – read on.
One of the more unusual symptoms of fibromyalgia is a skin rash. It’s unusual in terms of frequency (perhaps 10% of those with fibromyalgia report a skin rash?) But it’s more unusual in that it’s hard to explain why fibromyalgia should cause a skin rash. At least it’s hard to explain if you accept the…
Fibromyalgia results from a dysfunction of the immune system.
The authors of the study briefly summarized below (full text version here) begin by mentioning the theory of central sensitization. Immediately thereafter they note its inability to account for many of the common symptoms of fibromyalgia. Specifically, “mood disorders, fatigue, specific sleep disturbances, stiffness and post-exertional pain cannot be fully explained by the abnormalities of central pain processing.”
They note the similarity of fibromyalgia to those seen in ‘sickness syndrome’ – lethargy, fatigue, somnolence, and mood disorders (primarily depression) that results from the activation of the immune system, especially the production of pro-inflammatory cytokines, and perhaps the activation of glial cells by those cytokines.
There is substantial evidence that central sensitization plays a significant role in the pathophysiology of fibromyalgia, but several questions remain unanswered. How does central sensitization originate? How to account for the diversity of symptoms, common among those with fibromyalgia that cannot be explained by means of central sensitization?
Cytokine abnormalities may provide some basis for answering both questions. As noted in the publication briefly summarized below, cytokine abnormalities are associated with fatigue, sleep impairment, pain, stress, and aching. Cytokine abnormalities may also contribute to (or determine) the initial onset of central sensitization.
Fibromyalgia is a chronic pain condition that affects approximately 5 million individuals in the United States. These individuals comprise an estimated 5%–6% of all patients in primary care clinics and 10%–20% of all rheumatology outpatients. Those with fibromyalgia experience significant impairment in quality of life, disability, and incur total health care costs that are three…
Elevation of cytokines in fibromyalgia, including IL-8, provides evidence in support of an inflammatory hypothesis. With exercise, the level of circulating markers of inflammation, including IL-8, are shown to decrease in fibromyalgia. It is well established that exercise reduces inflammation generally. Fibromyalgia symptom response to exercise is consistent with, and supports, the inflammatory hypothesis in…
Substantial evidence has accumulated that cytokines, especially IL-8, may play an important role in the initiation and progression of fibromyalgia.
Cytokines are small molecules that serve as inter-cellular messengers. There are many different types, each with multiple, diverse and sometimes overlapping functions. Understanding of cytokine function is limited, but cytokines are known to play an important role in regulating the immune system.
Alterations in cytokine levels (cytokine dysregulation) has been linked to sleep disorders, hyperalgesia (excess sensitivity to pain signals), stress, ‘aching’, anxiety and cognitive difficulties (e.g. such as with “fibro fog”.)
On investigation, the level of IL-8 in fibromyalgia patients was 300% of that found in healthy controls. Furthermore, only IL-8 levels were shown to increase over time.
Fibromyalgia and irritable bowel syndrome frequently occur together (they are frequently “co-morbid”.) Up to around 40% of those with fibromyalgia have irritable bowel syndrome (reported figures vary from around 30% to around 60% or even higher.) And up to around 30% of those with irritable bowel syndrome have fibromyalgia.
What might account for this frequent association?
The novel theory of fibromyalgia advanced on this site includes that an increase in pro-inflammatory cytokines, especially IL-8, may be critical in the onset and progression of fibromyalgia.
If that theory is correct, or to the extent that it is correct, it should explain most of the symptoms, associated conditions and observations common to fibromyalgia.
It has been observed that up to about two-thirds of those with fibromyalgia report its initial onset in connection with a highly stressful event or period in their lives. Can the novel theory advanced on this site account for that observation?
Increased IL-8 production in response to stress increases the risk of disease.
The novel theory advanced on this site suggests that dysregulation of the inflammatory response system with an elevation in pro-inflammatory cytokines, especially IL-8, is critical to the onset of fibromyalgia.
To the extent that theory is correct, it should account for all the various symptoms and associations of fibromyalgia.
This site presents a novel theory. It is proposed that fibromyalgia results from a form of ‘inflammation’ – specifically a dysfunction in the inflammatory response system leading to cytokine imbalance, including a persistent elevation in pro-inflammatory cytokines, especially IL-8.
Cytokine abnormalities, including elevations in IL-8 and other pro-inflammatory cytokines, are well-documented in fibromyalgia. Of special interest, pain intensity has been shown to correlate with IL-8 elevation. When IL-8 levels decrease – so does pain.
IL-8 is a potent activator of NF-kappaB (a central mediator of inflammation.) Once activated (by IL-8 or any one of many other agents,) NF-kappaB triggers the production of more pro-inflammatory cytokines, including more IL-8. This positive feedback loop (IL-8 acts via NF-kappaB to increase the production of IL-8) could easily become a vicious cycle. It seems that might be what happens in those with fibromyalgia, as suggested by the observation that such individuals have excess IL-8 as well as excess NF-kappaB activation.
Recently heard about a geneticist who, several years after having first diagnosed a patient with Ehlers-Danlos syndrome, was then asked by that patient about a more recent diagnosis of fibromyalgia.
“Oh, fibromyalgia is just a symptom of EDS,” the geneticist is said to have replied.
So the question is, in the case of a patient with EDS, is it possible to make the distinct diagnosis of fibromyalgia?
The answer is simple. A lot of men actually do have fibromyalgia – but technically, officially, many don’t. At least not according to the most widely recognized diagnostic criteria, which defines fibromyalgia in such a way that few men qualify (official diagnosis) but a lot of men almost qualify (they have the same condition, but…
In a nutshell 
those suffering with fibromyalgia or rheumatoid arthritis experienced a substantial improvement in their conditions when they switched to a raw, vegan diet. Specifically, they experienced a decrease in pain and stiffness and self-perception of their health was improved.
The problem, of course, is that this diet represents a substantial and some would say extreme departure from our ‘normal’ diet. A vegan diet includes no animal products whatsoever – no milk, eggs, butter. The “living food” diet studied here included only raw foods – no cooking whatsoever.
The obvious reality is that very few people will ever attempt such an extreme dietary modification, and fewer still will adhere to it. Nonetheless, it is one option, and might result in general improvement in conditions related to inflammation other than those specifically studied.
As an alternative, one might want to add more fruits and vegetables to the diet, especially fresh, raw fruits and vegetables. Supplements might be considered as well.
IL-8 may be significant in the pathology of fibromyalgia as a mediator of sympathetic pain.
The hyperalgesic effect of IL-8 was measured, and was shown to result in a dose-dependent hyperalgesia that was not reduced by the COX inhibitor indomethacin.
Therefore a new activity of IL-8 is described which is the ability of IL-8 to generate hyperalgesia through a prostaglandin-independent pathway. IL-8 is therefore shown to cause hyperalgesia that involves the sympathetic nervous system. IL-8 may be the link between tissue injury and sympathetic hyperalgesia.
Levels of IL-8 are high, and correlate with pain intensity, in those with fibromyalgia.
The study referenced below looked at cytokine levels in the blood of 32 healthy volunteers and compared findings with those from 81 fibromyalgia patients.
The most noteworthy finding was that IL-8 levels were found to be elevated in those with fibromyalgia. Furthermore, there was a direct correlation between IL-8 level and pain intensity, suggesting that IL-8 may play a key role in the pathology of fibromyalgia, and especially in the pain of fibromyalgia.
IL-8, as well as other cytokines, are noted to be elevated in fibromyalgia.
The observation that certain pro-inflammatory cytokines are elevated in fibromyalgia suggests an inflammatory response. The correlation between cytokine levels and clinical outcome suggests a cause and effect relationship.
There’s substantial research suggesting that it might be – and substantial research suggesting it isn’t.
Approximately 95% of those with chronic fatigue syndrome have diffuse pain in addition to chronic fatigue.
Over 75% of those with fibromyalgia report extreme, often debilitating fatigue.
Approximately half of those with either diagnosis meet the formal diagnostic criteria for the other.
Both conditions have been associated with excess activation of NF-kB, pro-inflammatory cytokine elevation and certain other dysfunctions in the inflammatory response system.
All of the above suggests that we may be dealing with two variations of a single underlying problem.
One notable difference between the two is that a far higher percentage of men comprise those with chronic fatigue syndrome vs. the percentage of men found among those with fibromyalgia. However…
Fibromyalgia may affect up to 7% of all adult women, given that its incidence in the general population is estimated to range between 2-4% and that up to 90% of those with fibromyalgia are female.
In the study summarized below, 13% of all women with psoriasis were fount to have fibromyalgia, and another 14% had fibromyalgia-like symptoms. Clearly this represents a substantial increase in the rate of fibromyalgia among those with psoriasis vs. the incidence of fibromyalgia in the general population.
The higher incidence of fibromyalgia among those with psoriasis may be attributed to the fact that psoriasis is associated with elevated levels of IL-8, a pro-inflammatory cytokine that appears to be a risk factor for developing fibromyalgia.
Increased IL-8 production in response to stress increases the risk of disease My theory of fibromyalgia proposes that an elevation in pro-inflammatory cytokines, especially IL-8, is critical to the onset and progression fibromyalgia and the various symptoms of fibromyalgia. The study briefly summarized below is of interest because: They identify a problem in the “innate…
It appears that somewhere between two-thirds and three-fourths of those with fibromyalgia first developed the condition during or immediately following a period of great stress. Sometimes that’s a physical stress (such as an auto accident or even what seems at the time like a relatively mild injury) – but most often the stress is psychological…
Neuropathic pain represents an often substantial component of the overall pain in fibromyalgia, and may result from NF-kappaB activation by cytokines, especially IL-8.
It is likely that pain in fibromyalgia syndrome is of several different types. Fibromyalgia patients not infrequently report burning, tingling or sometimes stabbing pain that is unique from the diffuse pain (“aching”) of fibromyalgia. Those unpleasant sensations are most often identified as neuropathic pain. Neuropathic pain is commonly thought to result from nerve damage, but the actual cause of neuropathic pain remains unknown.
How might neuropathic pain arise in fibromyalgia syndrome?
IL-10 is an important anti-inflammatory messenger in the body. It helps turn inflammation off.
In the study summarized below it was found in lower than normal levels in fibromyalgia patients.
This is an essential publication because it:
* Demonstrates excess NF-kB activation in muscles of fibromyalgia patients;
* Provides a possible explanation for connective tissue changes in fibromyalgia; and,
* Suggests one means by which local pain and inflammation might become self-perpetuating in fibromyalgia.
Fibromyalgia is associated with increased levels of corticotropin-releasing hormone – corticotropin-releasing hormone has been shown to activate NF-kB.
Fibromyalgia is associated with increased levels of substance P, which is also known to activate NF-kB.
Fibromyalgia is associated with inflammation, as evidenced both by the frequent occurrence of other inflammatory conditions in those with fibromyalgia, and by the observation that pro-inflammatory cytokines are found at higher levels in the blood and cerebro-spinal fluid (CSF) of fibromyalgia patients.
The author of the study briefly summarized below suggests the use of anti-inflammatory supplements in the treatment of fibromyalgia and notes that these may be safely combined with other treatments.
Fibromyalgia is associated with increased levels of “substance P” – a neurotransmitter and neuromodulator that is found in the brain and spinal cord and that is associated with inflammatory processes and especially pain processes.
Pregabalin is used in the treatment of seizure, neuropathic pain and fibromyalgia. It is thought to act by binding to a specific receptor on nerve cells and reducing or slowing nerve transmissions in the central nervous system.
In this study it was shown to reduce the ability of substance P to activate NF-kB.
Inflammation in white blood cells contributes to the cause of chronic fatigue syndrome
Summary of key findings:
* Chronic fatigue syndrome is an inflammation related disease.
* NF-kB recogniged as the Master switch controlling inflammation in chronic fatigue
* Those with chronic fatigue show higher levels of activated NF-kB
* More activated NF-kB results in (correlates with) more severe disease symptoms
* Inflammation in the white blood cells plays an important role in chronic fatigue syndrome
* Chronic fatigue syndrome should be treated with agents that reduce NF-kB activation, such as anti-oxidants like turmeric (curcumin)
Some fibromyalgia patients seem to respond relatively well to non-steroidal anti-inflammatory drugs (NSAIDs.)
Some fibromyalgia patients (about 30% in the study below) have evidence of neurogenic inflammation on skin biopsy. This might explain, at least in part, why some patients respond better than others to NSAIDs.
Some pro-inflammatory cytokines elevated in fibromyalgia; correlation with pain intensity This is an important publication because it clearly demonstrates that fibromyalgia is a disease of inflammation and that symptomatic relief can be achieved through the reduction of inflammation. Higher than normal levels of pro-inflammatory cytokines in the blood indicate ongoing inflammation. When inflammation is relieved,…
Elevated cytokine levels were observed in fibromyalgia patients. The extent to which these were elevated was found to correlate with symptom severity. These findings suggest that fibromyalgia is related to an inflammatory process, and that effective reduction in inflammation might be of value in relieving symptoms.
Inflammation initiated by nerve endings (neurogenic inflammation) can be observed on skin biopsy of those with fibromyalgia. It is now apparent that the role of peripheral nerve endings in fibromyalgia is much greater than previously thought.
Common musculoskeletal conditions among those with inflammatory bowel disease – arthritis and fibromyalgia.
Three observations suggest that we might be looking at a single underlying mechanism of disease.
Blocking NF-kB in this model of neuropathic pain eliminated the pain stimulus.
Mugwort is an inhibitor of NF-kB, which accounts for its frequent historic use in herbal medicine in many countries.
In a process known as “moxibustion,” mugwort is burned – generally in a rolled up shape resembling a cigar. This burning ‘mugwort cigar’ is held near the patient’s skin at acupuncture points until it either warms or sometimes burns the skin.
It may be that the patient benefits from the inhalation of mugwort fumes/smoke or that in the warming process, when the mugwort is in direct contact with the skin, that some absorption of herbal actives takes place.
There is no good explanation of why this might work, and scant evidence – save the publication referenced below – that it does work.
Nonetheless, it is reported that 93% of fibromyalgia patients improved when moxibustion was combined with standard therapy, whereas only 57% improved with standard therapy alone.
