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16 Articles in Volume 19, Issue #2
Analgesics of the Future: Inside the Potential of Glial Cell Modulators
APPs as Leaders in Pain Management
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 1)
Complex Chronic Pain Disorders
Efficacy of Chiropractic Care for Back Pain: A Clinical Summary
Hydrodissection for the Treatment of Abdominal Pain Caused by Post-Operative Adhesions
Letters: The Word "Catastrophizing;" AIPM Ceases Operations; Patient Questions
Management of Severe Radiculopathy in a Pregnant Patient
Managing Pain in Adults with Intellectual Disabilities
Pain in the Courtroom: An Excerpt
Q&A with Howard L. Fields: How Patients’ Expectations May Control Pain
Special Report: CGRP Monoclonal Antibodies for Chronic Migraine
The Management of Chronic Overlapping Pain Conditions
Vibration for Chronic Pain
What are the dangers of loperamide abuse?
When Patient Education Fails to Improve Outcomes: A Low Back Pain Case

Complex Chronic Pain Disorders

The pathophysiology of and approaches to 3 commonly seen pain conditions: CRPS, EDS, and SFN.
Pages 26-32

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. In the past, CRPS has been termed causalgia, Sudeck’s atrophy, shoulder-hand syndrome, and reflex sympathetic dystrophy (RSD). It is characterized by severe pain in an extremity, often following major or minor trauma.3 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   (with no known nerve injury) and Type 2 (initiated by an identifiable nerve injury).

As with each of the complex, chronic pain disorders described herein, there are no definitive diagnostic tests for CRPS, and various clinical classification criteria have been proposed. The Modified Budapest Criteria are generally used (see Table II).1 These criteria include persistent pain—out of proportion to any inciting event—and a combination of signs and symptoms that include sensory, vasomotor, and atrophic findings. In a study of more than 1,000 patients with CRPS, certain etiologic triggers and specific signs provided more specificity in distinguishing CRPS from other chronic pain conditions.3 The most common inciting event is an upper extremity fracture. Skin temperature change was found to be less helpful in the diagnosis of CRPS than previously considered.

Although the diagnosis is made primarily on the signs and symptoms (see Table II), tests such as bone scintigraphy, MRI, or nerve conduction studies may be useful, primarily for excluding other conditions. More sophisticated testing might include Doppler measurements of skin temperature and tone and quantitative sensory testing (QST). The diagnosis of CRPS may be confirmed with three-phase bone scintigraphy, which typically reveals diffuse periarticular increased uptake in the third phase of the bone scan.3 However, a negative bone scan does not exclude the diagnosis.

Traditionally, CRPS was believed to evolve from an acute Stage 1, manifest by a painful, swollen, red, and warm extremity, to a dystrophic Stage 2, with the extremity cool and cyanotic, and finally to an irreversible, atrophic extremity Stage 3. However, often CRPS does not evolve in this orderly fashion.3 Patients with CRPS often report regional or widespread pain prior to or after diagnosis.4 Indeed, many patients with this disorder meet the diagnostic criteria for fibromyalgia. This may be particularly important in CRPS following upper extremity trauma. A database of 60,000 patients recovering from a fracture of the distal radius found only 0.2% were diagnosed with CRPS.5 The strongest association for CRPS was concurrent fibromyalgia, with an odds ratio of 16. The longer the patient has had CRPS, the more likely that individual will also suffer from chronic widespread pain (CWP) or fibromyalgia.

The Modified Budapest Criteria have been helpful in providing uniformity for clinical trials and research, but are quite restrictive and likely capture only subjects with the most severe forms of CRPS. There has also been limited research regarding the impact of symptom duration and the utility of Type 1 and Type 2 CRPS. In contrast to chronic pain conditions, such as fibromyalgia, there are currently no scales to document the symptom severity in CRPS. Thus, major challenges remain in its classification and diagnostic criteria (see Table III). Although no biomarkers for CRPS have been validated, phenotypic features, such as initiating traumatic events, psychological factors (such as catastrophizing), a prior history of regional or widespread pain, and duration of symptoms may be useful in stratifying patients and selecting suitable therapy (see Table IV).6


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.7 The changes seemed to vary with the time duration of CRPS. In the early stage, for example, there was reduced gray matter volume and perfusion in brain areas associated with spatial body perception in the somatosensory cortex and the limbic systems; in the later stage, there was increased perfusion in the motor cortex but no changes in gray matter volume.7 Furthermore, in the later stage of CRPS, gray matter volume in pain processing regions was negatively correlated with average pain levels. Patients with CRPS had greater inter-network functional connectivity between the attention and salience networks as compared with healthy controls.8 This connectivity was particularly prominent in those CRPS subjects with high levels of negative pain appraisal (ie, catastrophizing).

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.9 This cross-communication of certain cytokines and chemokines with nociceptive pathways may be responsible for allodynia and hyperalgesia.


Since there is no uniformly effective treatment for CRPS, preventing its development following a known precipitating event is paramount (see Table V). To that end, an integrated patient and clinician education program, including written material and visual aids, resulted in a significant reduction in the incidence of CRPS following distal radius fractures.10 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.10

Optimal treatment goals include pain reduction and restoration of normal limb function, best achieved with a multidisciplinary approach.11 A rehabilitation specialist, including physical and occupational therapy, is recommended. Physical therapy may be directed at improving range of motion and avoiding immobilization. Occupational therapy may include methods to reduce edema and improve function. A number of methods have claimed to promote pain desensitization in patients with CRPS, including stress-loading using scrubbing and carrying techniques, mirror visual feedback, pain-exposure physical therapy, and graded motor imagery.11

Multidisciplinary management should include mental health professionals. Individual counseling, cognitive behavioral therapy (CBT), and specific pain-coping and pain desensitization techniques may be useful. Co-existing major mood disturbances should be identified and treated.

There are limited data on the utility of pharmacotherapy in the treatment of CRPS, but a short course of corticosteroids, especially in early stages, and/or bisphosphonates may be recommended based on systematic reviews.11 Gabapentin, pregabalin, NSAIDs, tricyclics such as amitriptyline and similar medications, nasal calcitonin, as well as topical anesthetics and capsaicin have been useful in small trials. There have been reports suggesting improvement with ketamine infusions, memantine, intravenous immunoglobulin, epidural clonidine, clonidine, and injections of botulinum toxin A, but these interventions have not been tested in randomized clinical trials (RCTs) to date. In patients not responding to pharmacotherapy, peripheral sympathetic blockade, including lumbar/thoracic, stellate ganglion, brachial plexus blocks, sympathectomy, and spinal cord stimulation have been performed with mixed results and, again, a lack of RCTs.11 There are encouraging but limited data on the utility of transcranial magnetic stimulation in the treatment of CRPS.12 Although opioids were often used in the past to treat CRPS, there is no long-term data to support their efficacy and current recommendations do not support their use, other than for short-time duration.11

Although the outcome of patients with CRPS is highly variable, one study found that six years after the diagnosis, two-thirds of subjects still met criteria for CRPS.13 One-third were unable to work and disability and litigation issues were common. Recurrence of CRPS ranges from 10% to 30%.

(Source: 123RF)

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).

Classical EDS is characterized by joint hypermobility and skin hyperextensibility and has a specific genetic abnormality in DNA collagen sequencing. However, 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.14 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.14

Joint hypermobility is the most common clinical manifestation of hEDS.14 Hypermobility is best evaluated with the Beighton Hypermobility Scale (see Table VI). 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. However, each of the EDS subtypes has different diagnostic criteria and, in certain types, genetic testing provides excellent sensitivity and specificity. Therefore, 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.14,15 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.

There is a significant clinical overlap of hEDS and JHS with fibromyalgia/CWP.16 More than 90% of 466 adults with EDS reported joint pain and 42% had a diagnosis of fibromyalgia.17 Joint hypermobility was a strong risk factor for CWP.17 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 classic EDS, mutations have been identified in two collagen genes, but in hEDS, the exact mutations have not been located.15 The cardiac and vascular EDS subtypes have genetic mutations involving different forms of procollagen and collagen.

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. Pressure pain thresholds (PPTs) in hEDS subjects were significantly lower than in controls.18 Patients with either hEDS or JHS exhibited reduced cold and heat pain thresholds and increased wind-up.18 EDS/JHS has also been associated with a high prevalence of psychiatric disorders, including depression, anxiety, and eating disorders.19 Neuroimaging has demonstrated increased reactivity in pain and emotion processing. Autonomic nervous system dysfunction, including dysautonomia, has also been common.


Treatment for hEDS/JHS is similar, other than the important role of a geneticist in the diagnosis and management of hEDS.20 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. 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.20

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

Diagnosis, Clinical Features

Small fiber neuropathy, or SFN, is a peripheral neuropathy affecting small, thinly myelinated or unmyelinated nerve fibers.21 The disorder has been associated with a variety of diseases, including diabetes mellitus, sarcoidosis, primary amyloidosis, and Sjogren’s syndrome.22 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.23 This test is usually performed on the lateral distal leg and thigh. The sensitivity and specificity for SFN is 65% to 90%. Corneal confocal microscopy has demonstrated abnormal small fiber density in the sub-basal layer of the cornea, although this requires ophthalmologic expertise. 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.24 However, electromyography and nerve conduction studies should be reserved for cases where there is a question of large fiber neuropathy causing symptoms, or in those with concurrent small and large fiber neuropathy.


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%.22

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.25 A majority of fibromyalgia patients were found to have hyperexcitable C nociceptors, similar to those in SFN.26 Spontaneous pain hyperactivity was found in 31% of silent nociceptors in fibromyalgia, 34% in small fiber neuropathy, and 2.2% in controls.

In a group of fibromyalgia patients, 40% of skin biopsies were positive for SFN compared to 3% of controls.27 A systematic review of 222 fibromyalgia patients reported a 50% prevalence of SFN, confirmed by skin biopsy and/or corneal confocal microscopy.28 In patients with fibromyalgia, paresthesias and symptoms of dysautonomia may predict associated SFN.28 Compared to controls, fibromyalgia patients had reduced IENF density at both the thigh and calf.29 There was an inverse correlation between the calf IENF density and IL-2 levels, a marker of T-cell/macrophage activation. These investigators also reported a high prevalence of a mixed polyneuropathy, with evidence of SFN and electrodiagnostic changes suggestive of a chronic inflammatory demyelinating polyneuropathy.30

Another study found that 40% of fibromyalgia patients had reduced epidermal nerve fiber density (ENFD) including 28% in distal (calf) and 12% in the proximal (thigh) extremity.31 Sural and medial plantar nerve conduction abnormalities correlated with reduced IENF density. Obesity and metabolic syndrome were more common in the fibromyalgia subset with reduced IENF density. 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 conditions (see Table IX). 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.

Autonomic nervous system dysfunction is prominent in SFN as well as in FM/CWP. Fibromyalgia or chronic widespread pain overlap with irritable bowel syndrome, chronic fatigue syndrome, and chronic pelvic/bladder pain syndromes. These conditions may also be associated with SFN. For example, 64% of patients with chronic pelvic pain had skin biopsy evidence for SFN.32 In those patients, 38% met criteria for fibromyalgia, 33% for irritable bowel syndrome, and 38% for migraine. Fibromyalgia, or chronic fatigue syndrome, are associated with chronic fatigue, mood disturbances, sleep disturbances, and chronic headaches in the vast majority of patients. These symptoms can be better explained by a central rather than peripheral nervous system unifying hypothesis. There are no neuroimaging studies of the central nervous system in SFN.

Furthermore, decreased IENF density may be a disease epiphenomenon rather than causal. Abnormal IENF density has not correlated well with neuropathic symptom severity or outcomes. Decreased IENF density has been found in other chronic pain disorders and in conditions not typically associated with pain, such as amyotrophic lateral sclerosis. IENF loss was present in 70% of patients with amyotrophic lateral sclerosis (ALS) and did not correlate with disease onset, phenotype, symptoms, or severity.33 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.34


The first step in the treatment of SFN is to identify and treat any underlying disease (see Table X). Extrapolating from treating other neuropathic diseases, optimal management of associated diseases such as diabetes mellitus, HIV infection, or systemic, immune disorders should help to prevent the progression of SFN. 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.35 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,36 where both gabapentin and tramadol provided significant pain reduction in comparison to diphenhydramine. It is advised that treatment for SFN conform to the recommended guidelines for managing general neuropathic pain.37 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.38 Topical lidocaine may be used for focal neuropathic pain. Most guidelines reserve tramadol as a second-line agent and recommend limiting the use of opioids.37 OnabotulinumtoxinA, capsaicin, topical anesthetics, and analgesics have shown benefit in small series as have nerve root injections, transcutaneous electrical nerve stimulation, acupuncture, and tissue massage.


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.

Last updated on: April 12, 2019
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