On the face of it, fibromyalgia (FM) and complex regional pain syndrome (CRPS) appear to be very different disorders. Both can cause severe pain, but in fibromyalgia the pain is generally widespread and less intense (relative to CRPS, anyway), and more intense and localized in CRPS.

Both can be triggered by injuries but in CRPS the area surrounding the site of the injury often turns color, starts sweating, swells, loses hair, and becomes intensely painful – so painful that in the most severe cases amputation has been done. That kind of vivid, localized, and intense response does not occur in fibromyalgia.


The local manifestations of complex regional pain syndrome, Is a similar process occurring in fibromyalgia?

CRPS is not always localized, though. The inflammation and/or pain present can spread to other parts of the body. Nor are visible signs of inflammation lacking in FM. People with FM can experience swelling, reddened skin, and similar symptoms.

Could these two diseases form the opposite ends of a chronic inflammatory pain spectrum?  An Australian researcher, Geoffrey Littlejohn, believes yes.

Littlejohn, G. Neurogenic Inflammation in Fibromyalgia and Complex Regional Pain Syndrome. Nat. Rev. Rheumatol, 4 August 2015

Littlejohn believes one of the ties that bind the two illnesses together is central sensitization. Pain pathways in the brain and spinal cord in both disorders clearly are interpreting innocuous stimuli such as touch or movement as pain. Similar parts of the brain – the cingulate, insula, prefrontal cortex, and parietal lobe – are affected in each. Increased levels of glutamate – an excitatory neurotransmitter – and similar kinds of autonomic nervous system dysfunction are present in each as well.

Allodynia (an extreme sensitivity to touch) is often associated with fibromyalgia but Littlejohn has found that it commonly occurs in CRPS as well.

Neurogenic Inflammation


The key to his hypothesis, however, is a particular type of inflammation called neurogenic or nerve-induced inflammation. Neurogenic inflammation was identified as early as 1910 when researchers found that removing the sensory nerves could block the inflammatory effects of mustard oil. Driven by activation of the sensory nerves neurogenic inflammation can produce a wide variety of disturbing symptoms. (One of which is the feeling of acid being placed under the skin.)

substance P

Substance P is one of the neuropeptides that triggers neurogenic inflammation.

Neurogenic inflammation begins when unmyelinated C nerve fibers begin producing pro-inflammatory neuropeptides such as the substance P, VIP, and CGRP.  In an attempt to speed immune factors to the site of the injury these peptides increase skin blood flows and vascular permeability. Mast cells, keratinocytes, dendritic cells, and T lymphocytes all converge on the scene. Mast cells release a large number of substances, some of which sensitize the nerve endings in the area causing them to further increase the inflammation and the pain present.

That’s all well and good in the short term. Immune factors begin healing the injury and the pain produced by substance P and other substances keeps us from using the injured area.  In CRPS and perhaps fibromyalgia, though, the inflammatory process accelerates instead of being tamped down.

In CRPS the inflammatory result of the C-nerve fiber activation  –  the color changes, the sweating, swelling and hair loss – are stunningly visual. If CRPS proceeds, bone loss, deformity, joint problems and skin ulceration may occur. The visual aspect of CRPS makes it the easiest pain syndrome of all to diagnose.


Fibromyalgia is often described as an “invisible illness” but Littlejohn asserts that many FM patients experience visual manifestations of neurogenic inflammation as well. Like the pain in FM, neurogenic inflammation present occurs in a more diffuse manner. Littlejohn believes it shows up in swelling, skin discoloration (livedo reticularis), dermatographia, erythema (reddened skin), cutaneous dysaesthesia, allodynia, cold-induced vasospasm, and Raynaud’s phenomenon.

Cutaneous dysaesthesia produces sensations like burning, wetness, itching, electric shock, and pins and needles. It is sometimes described as feeling as if acid was placed under the skin. The sensations can be so severe as to be incapacitating.

neurogenic inflammation fibromyalgia

Some of the marks of neurogenic inflammation in fibromyalgia

Dermatographia occurs when brushing the skin leaves a reddened mark. Livedo reticularis occurs as a lace-like purplish discoloration of the skin that’s often found in the lower limbs.  Raynaud’s phenomenon refers to a discoloration – a whitening – of the fingers and toes.

While these features have not been as deeply explored in fibromyalgia as in CRPS, increased mast cell numbers in the skin of FM patients suggests neurogenic inflammation is present. The small fiber neuropathy found may be involved as well.

Central Nervous System Origin?

The signs of neurogenic inflammation in CRPS and FM may occur in the body, but Littlejohn asserts that activated astrocytes and microglial in the brain could translate into both central nervous system and peripheral inflammation.

Neuropeptide Triggers

Two neuropeptides, substance P and BDNF are markedly elevated in the brains of FM and/or CRPS patients.  (Substance P is not elevated in chronic fatigue syndrome but BDNF may be).

Littlejohn proposes that elevated levels of these neuropeptides in the regions of the brain responsible for regulating emotion could explain why stress is such a common exacerbating factor in FM.

Cytokine Patterns

The C-nerve fibers, astrocytes, and microglial cells that amplify pain also produce cytokines that can sensitize neurons and affect HPA axis and sympathetic nervous system functioning. The cytokine picture in fibromyalgia is unclear but it’s clear that cytokine levels are increased early in the afflicted area in CRPS but then subside later on.

Littlejohn believes this initial period of increased immune activation produces central nervous system alterations (central sensitization) that become the dominant feature of the disease later, and ultimately drive the problems in the periphery.

A similar pattern of increased immune activation followed by a downregulation has been found by both the Lipkin/Hornig and the Dubbo teams in ME/CFS. In the Dubbo studies, Lloyd suggested that early immune activation reset the central nervous system in people who came down with ME/CFS following an infection.

Littlejohn proposes a similar process is occurring in CRPS and FM.

Spectrum Disorder(s)?

We often think of chronic fatigue syndrome and fibromyalgia as spectrum disorders with pain predominating in FM but with severe fatigue common, and fatigue predominating in ME/CFS but with pain common.

Littlejohn’s analysis suggests that FM and CRPS might be spectrum disorders as well. In both diseases, the effects of central sensitization are seen in a more widespread manner in FM and or a more localized manner in CRPS.

Update – After notching an autoimmune connection in CRPS, Goebel finds one in fibromyalgia and long COVID.

Something in the Blood II: Long-COVID / Fibromyalgia Autoimmune Connection Found

Other Neurogenic Inflammation Disorders

Many of the disorders now associated with neurogenic inflammation have not traditionally been tied to inflammation. Several so-called functional disorders that cause pain and fatigue but not the expected manifestations of tissue injury and inflammation may be “invisible” neurogenic inflammation disorders.

Migraine: Littlejohn focuses on CRPS and FM but a similar process occurs in migraine. In migraine substance P and other neuropeptides cause increased cerebral blood flows, mast cell degranulation, and the release of the pro-inflammatory factors associated with neurogenic inflammation.

The pro-inflammatory response causes the neurons in the trigeminal nerve to act up – producing the throbbing of a migraine. The nerve excitation can then spread causing allodynia in different parts of the body. Migraine, then,  is a neurogenic inflammatory disorder in which the visual signs of inflammation are hidden.  Many migraineurs, interestingly enough, experience an ME/CFS-like state following a migraine.

Migraine is a neurogenic inflammatory disorder

Migraine is a neurogenic inflammatory disorder

Interstitial Cystitis  – Neurogenic inflammation is suspected in interstitial cystitis or painful bladder syndrome – a common comorbid condition in FM and ME/CFS.  One hypothesis proposes that hyperactive C-nerve fibers and mast cell activation cause even small distensions of the bladder to produce pain in IC.  The hallmarks of neurogenic inflammation process including edema, vasodilation and increased numbers of nerve fibers and mast cells have been found in the bladder tissue in IC patients. Increased levels of substance P in the nerves further suggest that a neurogenic inflammatory process is present.

Irritable Bowel Syndrome – IBS is a complex disease that features several different “sensitizing pathways” including possibly neurogenic inflammation. Further study is needed but substance P, VIP, and mast cell levels have been found to be increased in IBS.

It’s notable that the problem of painful distension crops up in several neurogenic inflammatory disorders. Distention of the blood vessels near the trigeminal nerve in migraine, distention of the bladder in interstitial cystitis/painful bladder syndrome, and distension of the gut in IBS are a cause for pain in these disorders.

Asthma – is potentially another hidden neurogenic disorder. In asthma, the immune response to an allergen or toxin appears to set the stage for the neurogenic inflammation that follows. Recent studies suggest that the bronchial spasms found in asthma are produced by hypersensitive sensory neurons in the lungs linked to the vagus nerve.

(Could a similar process be producing the shortness of breath in ME/CFS?) Van Elzakker’s vagus nerve hypothesis proposes that smoldering infections associated with the vagus nerve produce a similar process in ME/CFS.

Neurogenic inflammation; i.e. nerve induced inflammation – appears to play at least a role in many inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis, nephritis, parasitic infections or various skin disorders


Neurogenic inflammation is generally believed to be set off by an infection or autoimmune reaction. The treatment of neurogenic inflammation, though, involves treating either a) the nervous system component of inflammation or b) attacking the consequences of neurogenic inflammation.

If FM and CRPS are both neurogenic inflammatory disorders then the treatments for both diseases will overlap – and indeed they do.

Littlejohn asserts that neuropeptides – whether occurring in the body or the brain – trigger FM and CRPS. Unfortunately, no drugs that are available now target the neuropeptides known to be upregulated in FM and CRPS.

Drugs that target “normal” types of inflammation such as TNF-a inhibitors or NSAIDS have not proven helpful in either CRPS or FM.

Drugs that reduce central nervous system activity and which target the microglia, however, such as low-dose naltrexone, ibudilast and minocycline can be successful. Drugs that target the NMDA receptors on activated microglia (ketamine) or glutamate (memantine)  have shown to be helpful as well.

Because activation of the stress response system also drives some of the problems found in the periphery, stress response reducing drugs such as propranolol, phenoxybenzamine, gabapentin, and 5-hydroxytryptamine-noradrenaline reuptake inhibitors might be helpful.  Using mind/body techniques to reduce the stress response may be helpful as well.

Littlejohn does not mention them but botox and capsaicin-containing creams may be helpful in reducing the pain of neurogenic inflammation occurring near the skin.

Littlejohn also does not mention magnesium deficiency but a few studies suggest magnesium deficiency may be able to cause neurogenic inflammation as well.  In a rat model, reduced magnesium levels triggered the production of substance P and other neuropeptides which, in turn, triggered the release of histamine and other substances.  The study suggested that even mildly low magnesium levels may be able to trigger neurogenic inflammation.  (An upcoming blog will indicate that magnesium deficiency can be associated with Epstein-barr virus activation.)


Littlejohn believes that the processes of central sensitization and neurogenic inflammation are both at play in CRPS and fibromyalgia.  It should be noted that neurogenic inflammation; i.e. sensory nerve-induced inflammation – is not always visible. Other disorders with a neurogenic inflammation component include migraine, interstitial cystitis, asthma, and IBS.

The treatment of the neuro-immune inflammation in these disorders primarily involves reducing the abnormal nerve activation that triggers the inflammatory response. A variety of drugs that reduce central nervous system activation or sympathetic nervous system activity may be helpful. Mind/body practices may be helpful as well.

  • Let us know if you experience symptoms of neurogenic inflammation (swelling, skin discoloration (livedo reticularis), dermatographia, cutaneous dysaesthesia, allodynia, etc.) in our FM and ME/CFS neuroinflammation poll here.





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