Peripheral Sensitization in Fibromyalgia

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Neurogenic inflammation[edit]

According to Littlejohn et al., in fibromyalgia research evidence is mounting that there are “neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain…” These are known to involve various “neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems.” They say these features are clinically relevant to “swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition.” They believe that “emotional and stress-related physiological mechanisms are” what they referred to as “upstream drivers of neurogenic inflammation in fibromyalgia.” (Neurogenic inflammation in fibromyalgia, Geoffrey Littlejohn & Emma Guymer, Seminars in Immunopathology volume 40, pages291–300 (2018), abstract available at:

Receptor sensitization[edit]

Staud et al. note that in fibromyalgia changes “include sensitization of vanilloid receptor, acid-sensing ion channel receptors, and purino-receptors. Tissue mediators of inflammation and nerve growth factors can excite these receptors and cause extensive changes in pain sensitivity, but patients with fibromyalgia lack consistent evidence for inflammatory soft tissue abnormalities.” (Peripheral and central sensitization in fibromyalgia: pathogenetic role, Roland Staud 1, Michael L Smitherman Curr Pain Headache Rep . 2002 Aug;6(4):259-66. doi: 10.1007/s11916-002-0046-1.

Mild loss of peripheral receptors[edit]

Vecchio et al studied fibromyalgia patients using skin biopsies with quantification of intraepidermal nerve fibre density (IENFD) at the thigh and distal leg. They found that the patients often showed “a mild loss of peripheral nociceptors at the thigh rather than distal small fibre neuropathy. The argued that the significance of these findings along with the other findings in their study indicated that "Significance: Central impairment of pain processing likely underlies FM, which in most patients is associated with mild proximal small fibre pathology." (Peripheral and central nervous system correlates in fibromyalgia. Eleonora Vecchio 1, Raffaella Lombardi 2, Matilde Paolini 2, Giuseppe Libro 1, Marianna Delussi 1, Katia Ricci 1, Silvia G Quitadamo 1, Eleonora Gentile 1, Francesco Girolamo 3, Florenzo Iannone 4, Giuseppe Lauria 2 5, Marina de Tommaso 1 Eur J Pain . 2020 Sep;24(8):1537-1547. doi: 10.1002/ejp.1607. Epub 2020 Jun 16

Possible mechanisms for sensitization of channels and receptors in fibromyalgia[edit]

Staud states: “Peripheral and central abnormalities of nociception have been described in musculoskeletal pain patients. Important nociceptive systems in the skin and deep tissues of these patients seem to undergo profound changes, resulting in sensitization of the hyperpolarization-activated cyclic nucleotide-gated ion channels, transient receptor potential channels, acid-sensing ion channel receptors, and purino-receptors.” (Staud gives the following reference for this last point: Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition. Nielsen LA1, Henriksson KG. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):465-80.)

Staud further states: “Tissue mediators of inflammation and nerve growth factors can excite these receptors and cause extensive changes in pain sensitivity.” (Mechanical and heat hyperalgesia highly predict clinical pain intensity in patients with chronic musculoskeletal pain syndromes. Staud R1, Weyl EE, Price DD, Robinson ME. J Pain. 2012 Aug;13(8):725-35 available in full online at: