Fibromyalgia is a chronic and often disabling condition characterized by widespread pain, fatigue and multiple tender points; often accompanied by non-restorative sleep, anxiety, depression, cognitive difficulties and a host of additional symptoms.
A great deal of fibromyalgia research has recently focused on abnormalities in pain processing. Such abnormalities (collectively referred to as “central sensitivity”) have been suggested as a principal cause of fibromyalgia pain. Indeed, certain medications now approved for the treatment of fibromyalgia are believed to reduce pain by altering or slowing the transmission of pain signals.
Unfortunately, such medications have significant side effects, are often ineffective against pain, and generally fail to provide meaningful relief for symptoms other than pain. Furthermore, central sensitivity cannot account for many symptoms of fibromyalgia.(1) Neither can it explain much of what is known about the pathophysiology of fibromyalgia, the onset of fibromyalgia, or why fibromyalgia is so frequently associated with seemingly unrelated inflammatory conditions.
It is proposed that fibromyalgia results not from central sensitization, but from a dysfunction in the inflammatory response system, resulting in persistent elevation of pro-inflammatory cytokines, especially IL-8.
Cytokine abnormalities, including elevations in IL-8 and other pro-inflammatory cytokines, have been frequently observed in those with fibromyalgia.(2) Pain intensity in fibromyalgia has been shown to correlate with IL-8 elevation.(3, 4)
IL-8 is a potent activator of NF-kappaB(5) – a central mediator of inflammation. Once activated (by IL-8 or by any other means,) NF-kappaB acts to increase the production of pro-inflammatory cytokines, including IL-8. What is normally a well-regulated positive feedback loop might, as a result of some unknown defect, become instead a vicious cycle. That possibility is suggested by the observation that fibromyalgia patients have both an elevation in IL-8 and excess NF-kappaB activation.(6)
IL-8 is believed to increase neuropathic pain(7) and, along with other pro-inflammatory cytokines, is likely to sensitize pain receptors generally. So it is reasonable to speculate that a vicious cycle of IL-8 elevation could lead to a vicious cycle of pain, in which case a reduction in IL-8 might provide an effective means of pain relief.
Persistent elevation of IL-8, and associated NF-kappaB activation, may result in chronic over-production of inflammatory cytokines other than IL-8, including those associated with fatigue and impaired sleep. Indeed, it appears that inflammatory cytokine excess may offer the single best explanation for a wide variety of fibromyalgia symptoms. In addition, cytokines such as IL-8 are elevated in those subject to prolonged psychological stress.(8, 9) That might explain why the initial onset (or worsening) of fibromyalgia often occurs in connection with highly stressful events.
Pro-inflammatory cytokine excess might also best explain the frequent association of fibromyalgia with seemingly unrelated conditions. An excess in pro-inflammatory cytokines, especially IL-8, has been observed in rheumatoid arthritis,(10) inflammatory bowel disease,(11) psoriasis,(12) irritable bowel syndrome,(13) chronic fatigue syndrome,(14) and lupus.(15) Each of these ‘unrelated’ conditions is, like fibromyalgia, characterized by sleep disturbance, fatigue and heightened pain perception.
Furthermore, pro-inflammatory cytokine excess may be responsible for the onset of central sensitization via chronic activation of spinal cord glia and dorsal horn neurons.(16)
As can therefore be seen, pro-inflammatory cytokine excess provides the best explanation for both the painful and non-painful symptoms of fibromyalgia. Pro-inflammatory cytokine excess reasonably explains the frequent association of fibromyalgia with other ailments, its frequent onset in connection with stressful life events, and the resulting central sensitization of fibromyalgia.