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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
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
Page 1 of 4

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 (initiated by an identifiable nerve injury) and Type 2 (with no known 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

Last updated on: March 4, 2019
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