FMS & CFS: Neurogenic Inflammation Connection

Fibromyalgia and Complex Regional Pain Syndrome: the Neurogenic Inflammation Connection – Health Rising

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.  

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 believes one of the ties that binds the two illnesses 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 feeling of acid being placed under the skin.)


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.

increased numbers of mast cell numbers in the skin of FM patients suggests neurogenic inflammation is present. The small fiber neuropathy found may be involved as well.

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.

  • Migrainee – 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.

  • 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.

  • Irritable Bowel Syndrome – IBS is a complex disease which features several different “sensitizing pathways” including possibly neurogenic inflammation.

Further study is needed but substance P, VIP and mast cells levels have been found to be increased in IBS.

  • Asthma – is another hidden neurogenic disorder. In asthma the immune response to an allergens 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.


Neurogenic inflammation is generally believed to be set off by an infection or autoimmune reaction. The treatment of neurogenic inflammation, though, involves treating either

  1. the nervous system component of inflammation or
  2. attacking the consequences of neurogenic inflammation.

If FM and CRPS are both neurogenic inflammatory disorders then the treatments for both disease 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 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, ibidulast and minocyline 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

  • propanolol,
  • phenoxybenzamine,
  • gabapentin and
  • 5-hycroxytryptamine-noradrenaline reuptake inhibitors

might be helpful.  Using mind/body techniques to reduce the stress response may be helpful as well.

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.  


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 an 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.


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


1 thought on “FMS & CFS: Neurogenic Inflammation Connection

  1. Payne Hertz

    I have known about low dose naltrexone for over 16 years and have never been able to get a doctor to prescribe it for me. If we had drug freedom in this country I could have tried it myself 16 years ago and who knows, maybe saved myself some time in hell or possibly have seen a reduction in my symptoms at least.

    Most of us don’t have the luxury of waiting for “science” or generally accepted practice to catch up with us; we need to have the freedom to try different things now and hope for the best. Let us decide what risks we are willing to take with our own lives.

    Liked by 1 person


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