Complex Chronic Pain Disorders

Complex Chronic Pain Disorders By Don L. Goldenberg, MD – Feb 2019

The pathophysiology of and approaches to 3 commonly seen pain conditions: CRPS, EDS, and SFN.

  • Complex regional pain syndrome (CRPS),
  • Ehlers-Danlos syndrome (EDS), and
  • small fiber neuropathy (SFN)

are three important and complex chronic pain disorders.  

They share a number of characteristics as described in Table I. Each of these conditions are difficult to diagnose, especially since their diagnostic criteria have been revised and recently updated.1,2 Their pathophysiology is not well understood, but there is emerging evidence that central pain is important. As demonstrated in this review, treatment is evolving and best approached with multidisciplinary methods.

Complex Regional Pain Syndrome (CRPS)

Diagnosis, Clinical Features

Complex regional pain syndrome, or CRPS, is defined as a chronic, regional pain disorder in which the pain is out of proportion, both in duration and in severity, to the usual expected course.

It is characterized by severe pain in an extremity, often following major or minor trauma. Initially, the affected limb is swollen with vasomotor changes; later, the extremity is often atrophied with skin tightness, flexion contractures, and subsequent osteopenia.

CRPS is more common in women3 and has been subdivided into Type 1 (initiated by an identifiable nerve injury) and Type 2 (with no known nerve injury).

many patients with this disorder meet the diagnostic criteria for fibromyalgia.


CRPS, as do EDS and SFN, involves peripheral, immune, and central factors.

Allodynia and hyperalgesia characterize CRPS (as well as fibromyalgia, as noted) and imaging studies have demonstrated similar structural and functional changes to those found in patients with fibromyalgia.

These changes have included alterations in whole-brain gray matter volume as well as white matter functional connectivity

There is also evidence for both central and peripheral neuroinflammation in patients with CRPS, including increases in pro-inflammatory cytokines in the blood and cerebrospinal fluid.


Since there is no uniformly effective treatment for CRPS, preventing its development following a known precipitating event is paramount

Early mobilization is considered the most important method to prevent CRPS after such an injury.

There has been some evidence that Vitamin C may be helpful to accelerate bone healing and, therefore, may reduce the likelihood of CRPS following a fracture, although this theory remains controversial.

Ehlers-Danlos/Joint Hypermobility

Diagnosis, Clinical Features

Ehlers-Danlos syndrome, or EDS, includes a group of genetic disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility.

Although there are a number of subtypes of EDS, this review will focus on hypermobile EDS (hEDS), the most common type.

The other types of EDS include those with cardiac and vascular manifestations. Most of these are rare and have specific genetic inheritance traits (eg, EDS with kyphoscoliotic, cornea, myopathic, and scleral abnormalities).

hEDS may have no major skin abnormalities and no known single genetic defect has been identified. hEDS overlaps clinically with Joint Hypermobility Syndrome (JHS), with some experts considering these two conditions to be the same disorder.However,  JHS has no specific genetic basis or markers.

The prevalence of hEDS ranges from 0.01% to 1% and this wide range is likely related to inclusion or exclusion of cases of JHS.

Joint hypermobility is the most common clinical manifestation of hEDS.

The diagnosis of hEDS is made clinically if the subject has generalized joint hypermobility and a number of other features with a positive family history.

in all suspected cases of EDS, referral to an expert in clinical genetics may be recommended.

JHS is much more common than EDS and may be difficult to differentiate from hEDS. It is present in 5% to 10% of the general population.

Clinical manifestations include joint hypermobility using the Beighton Hypermobility Scale, skin fragility, and chronic widespread pain. There is also often a family history of joint hypermobility.

More than 90% of 466 adults with EDS reported joint pain and 42% had a diagnosis of fibromyalgia. Joint hypermobility was a strong risk factor for CWP.

There is a significant clinical overlap of hEDS and JHS with fibromyalgia/CWP.

Both EDS and JHS have been associated with

  • chronic fatigue,
  • chronic abdominal and pelvic pain,
  • high rates of irritable bowel syndrome,
  • temporomandibular joint disorder, and
  • vulvodynia.


Genetic alterations vary in each of the EDS subtypes, most being autosomal dominant

in hEDS, the exact mutations have not been located.

Joint hypermobility may lead to

  • overuse injury,
  • joint subluxations,
  • traumatic arthritis, and
  • secondary osteoarthritis.

These peripheral factors interact with central factors in patients with EDS/JHS

Patients with EDS exhibit hyperalgesia and allodynia.

This has been true of me since early childhood, though my pain didn’t become chronic until I was in my 40’s.

Weird things would hurt, like hitting a volleyball or dribbling a basketball or even clapping my hands too long.

My skin was always unusually fragile and every new shoe would bring on awful blisters until they were broken in (often it was my feet that were broken-in, not the shoes).

Patients with either hEDS or JHS exhibited reduced cold and heat pain thresholds and increased wind-up.

I’ve always been sensitive to and had an inconsistent response to temperatures.

Pressure pain thresholds (PPTs) in hEDS subjects were significantly lower than in controls.

This was most noticeable with wrinkles in bedsheets that formed angry red welts after sleeping.

EDS/JHS has also been associated with a high prevalence of psychiatric disorders, including depression, anxiety, and eating disorders.

I’ve struggled with these since puberty.

Neuroimaging has demonstrated increased reactivity in pain and emotion processing.

I am exquisitely sensitive to pain of all kinds, physical, emotional, and mental.

Autonomic nervous system dysfunction, including dysautonomia, has also been common.

When I was in my best shape from bicycling, I experienced light-headedness every time I stood up from sitting a while. It gradually went away as I stopped exercising so much – perhaps because my resting heart rate wasn’t so low anymore?


Treatment for hEDS/JHS is similar, other than the important role of a geneticist in the diagnosis and management of hEDS. This approach may include genetic counseling and expert advice, such as cardiovascular and ophthalmologic monitoring, if classical EDS is suspected.

Otherwise, the principles of treating EDS and JHS involve

  • patient and family education,
  • psychosocial therapy,
  • joint function,
  • skin and soft-tissue management, and
  • chronic pain management (see Table VII)

There are no studies, however, to determine optimal

  • physical therapy,
  • manual therapy,
  • joint stabilization, or
  • neuromuscular taping;

avoidance of excessive stretching have been advocated.

I wish I’d know this earlier before I started doing yoga, which is all about “opening the joints” to increase the range of motion. I didn’t find yoga appealing because the poses were “unnatural”, but so many people kept telling me to try it, insisting it would improve my pain, that I finally decided to give it a try.

As with all exercise I do, I pushed myself hard to excel and did considerable damage over the 3 years I was practicing at least twice weekly. My hips will never be the same.

While medications play a role in pain management, there have been no systematic reviews on this approach; pharmacologic options are generally considered to be adjunct to non-pharmacologic multidisciplinary therapy.

Peripheral nerve blocks or similar procedures have not been adequately studied but have been used in patients not responding to other chronic pain management.

Dermatology referral may be recommended in selected patients and some experts have advocated using Vitamin C for its potential role in skin and joint healing.

Small Fiber Neuropathy

The most common symptoms may be divided into a pain or autonomic category (see Table VIII).

A formal diagnosis may be considered in patients with distal extremity pain, numbness, and paresthesias with normal general neurologic examination and normal nerve conduction velocity studies.

Confirmatory diagnosis in most studies has been based on a skin biopsy, demonstrating reduced intraepidermal nerve fiber (IENF) density compared to normative data, using bright-field immunohistochemistry or immunofluorescence

Abnormal quantitative sensory testing (QST) for thermal pain, vibratory sensation, quantitative sweat testing, and autonomic testing such as heart rate variability have been advocated for confirming a SFN diagnosis in some studies

There is also evidence that medium or large nerve fibers may be affected in SFN based on plantar nerve conduction


The cause of SFN is unknown and no associated disease is present in 50% of cases.

In a cohort of 921 patients with SFN,

  • sodium channel gene mutations were found in 17%;
  • immune disorders, most commonly sarcoidosis and Sjogren’s syndrome, in 13%;
  • diabetes in 8%; and
  • vitamin B12 deficiency in 5%

The mechanism of focal pain in SFN has been assumed to be related to peripheral nerve injury and damage. However, many patients with SFN also report chronic widespread pain. Interestingly, patients with fibromyalgia often report neuropathic symptoms and elevated neuropathic PainDETECT scores.

A majority of fibromyalgia patients were found to have hyperexcitable C nociceptors, similar to those in SFN.

Spontaneous pain hyperactivity was found in

  • 31% of silent nociceptors in fibromyalgia,
  • 34% in small fiber neuropathy, and
  • 2.2% in controls

A systematic review of 222 fibromyalgia patients reported a 50% prevalence of SFN, confirmed by skin biopsy and/or corneal confocal microscopy

In a group of fibromyalgia patients, 40% of skin biopsies were positive for SFN compared to 3% of controls

In patients with fibromyalgia, paresthesias and symptoms of dysautonomia may predict associated SFN.

Another study found that 40% of fibromyalgia patients had reduced epidermal nerve fiber density (ENFD)

The finding of SFN in 40% to 50% of patients with fibromyalgia has fueled a reevaluation of the role of central versus peripheral pain in fibromyalgia and other poorly understood chronic pain condition

Patients with SFN and chronic widespread pain/fibromyalgia both report allodynia and hyperalgesia, with neuropathic pain descriptors.

However, in SFN this is usually confined to the distal extremities, whereas, in FM/CWP the pain is widespread. There is no neurophysiologic evidence of SFN in the neck, shoulders, chest wall, and buttocks, all painful locations in FM/CWP.

Fibromyalgia or chronic widespread pain overlap with

  • irritable bowel syndrome,
  • chronic fatigue syndrome, and
  • chronic pelvic/bladder pain syndromes

Autonomic nervous system dysfunction is prominent in SFN as well as in FM/CWP.

Furthermore, decreased IENF density may be a disease epiphenomenon rather than causal.

Is small fiber pathology responsible for chronic pain, or a result of chronic pain? This question was addressed in a rodent experimental model in which increasing levels of glutamate in the insula, a characteristic of neuroimaging findings in fibromyalgia, correlated with increased pain behavior and decreased peripheral nerve fibers.


The first step in the treatment of SFN is to identify and treat any underlying disease

There have been no controlled studies on medications in the treatment of SFN associated with a systemic disease. In one report, SFN was present in 143 patients with sarcoidosis

The majority of these patients responded either to intravenous immunoglobulin or anti-TNF medication, or a combination of both.

In the only randomized clinical trial of SFN, 18 patients were treated with gabapentin, tramadol, or diphenhydramine, where both gabapentin and tramadol provided significant pain reduction in comparison to diphenhydramine.

First-line agents typically include

  • tricyclic antidepressants (particularly amitriptyline),
  • anticonvulsants such as gabapentin and pregabalin, and
  • the dual reuptake inhibitor duloxetine;
  • the anticonvulsant lacosamide has been used in a proof of principle SFN report and in patients with sodium-channel genetic mutation causing SFN


Complex regional pain syndrome, Ehlers-Danlos syndrome, and small fiber neuropathy represent common, chronic pain conditions with poorly understood pathophysiology.

They are often difficult to diagnose and to treat as pathophysiologic mechanisms of these disorders involve both peripheral and central pain mechanisms.

As such, they cannot be easily pigeonholed as neurologic, inflammatory, or immune diseases.

Until these diseases are better understood, treatment may be similar, focused on multidisciplinary pain management with judicious use of similar medications.

4 thoughts on “Complex Chronic Pain Disorders

  1. canarensis

    I’ve always read that CRPS is in extremities…I’ve never seen any possible diagnosis of my own post-surgical permanent pain, which occurred after thoracic surgery to remove a tumor on my esophagus in 2001. The lower front rib corner on that side has been permanently, insanely painful & hyper-reactive ever since, with burning/numbness tho w/o the redness & swelling. The only “real” dx I’ve ever gotten was from my wonderful (now retired, alas) NC neuro who described it as “really pissed-off nociceptors.”

    Though I suppose the dx is moot, since the overwhelming trend is to refuse to do anything about it –or anything useful (I’ve tried ever “alternative” treatment that exists, of course; most exacerbated it greatly the rest did nothing but wipe out my savings).

    And of course, they mention only the usual diversionary meds…gaba, anti-depressants, anti-convulsants, etc etc. Those do help some folks, which is great, but the universal assertions these days are, (A) they help everybody, & (B) no other option can even be considered (i.e. opioids) even if the patient (read, “addict”) *claims* they are effective (& the others were not at all effective &/or had dire side FX). (I tried them all, too; they didn’t do anything at all AND had dire side FX).

    Lordy I’m tired of all this sadistic insanity.


    1. Zyp Czyk Post author

      I luckily have zero experience with CRPS, thank goodness, but it sounds like a real nightmare. I don’t have any true “chronic pain” really, because my pain location varies so much depending on if and how I use my body. With my constant misalignment of bones & tissues, my pain is better described as “chronic acute pain” due to repeated micro-tears of muscles, tendons, ligaments, and other tissues.

      I did find Lyrica useful after I learned to take it “as needed” and not get “used to it”. It’s useful for those times that I’m being attacked from so many different pains that it becomes an all-over achy pain that opioids can’t relieve – at least not in the amounts I’m willing to take. Then, a hefty dose of up to 75-150mg Lyrica really calms things down. And that break might be enough to get me out of the pain-loop again.



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