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Complex Regional Pain Syndrome (CRPS) is a disorder characterized by continued debilitating pain that is inordinate to the provoking event. Overall, pain may evolve from trauma to a peripheral nerve or to a region without direct nerve involvement. A key characterization of the syndrome is the disproportionate amount of pain experienced in relation to the exciting event. The pain pattern is often associated with a multitude of disturbances, ranging from sensory and motor deficits, vasomotor disturbances, sudomotor disturbances, edema and/or trophic changes all of which tend to present at distinct times throughout the course of the syndrome.

Originally classified by the International Association for the Study of Pain (IASP) in 1994 and formally updated to accept the Budapest Criteria of 2003 due to the increased statistical measures and currently considered the most accepted diagnostic approach,1, 2 the classification of CRPS brings about two different etiologies with differing presentations: a) CRPS type I (previously Reflex Sympathetic Dystrophy) develops after trauma or injury and does not involve a specific peripheral nerve and b) CRPS type II (previously Causalgia) develops after peripheral nerve injury.1

CRPS usually develops after trauma; however there is no relation between severity of injury and development of this disorder and in some cases there is no precipitating event. This syndrome is characterized by regional pain with or without a specific nerve injury and does not necessarily need to follow a dermatomal pattern.1

CRPS nomenclature has evolved through the years. It was previously referred to in the literature as Reflex Sympathetic Dystrophy, Algodystrophy, Causalgia, Sudeck’s atrophy among others.


CRPS I has a higher propensity to develop after an injury and can be due to several precipitating events ranging from sprains, fractures, visceral disease or even immobilization, while CRPS II is known to occur after obvious peripheral nerve damage3 and can be related to a multitude of initial events.

The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. 4 Evidence for dysfunction of both the innate and adaptive immune systems in CRPS is presented, through measured cytokines and other inflammatory mediators in the skin of affected limbs. Additional results from studies of mediator levels in animal models are evaluated in this context. Similarly, the production of autoantibodies and the potential targets of those antibodies from human, animal, and translational studies is reviewed. Compelling evidence of autoinflammation in skin and muscle of the affected limb has been collected from CRPS patients and laboratory animals. Cytokines including IL-1β, IL-6, TNFα, and others are reliably identified during the acute phases of the syndrome. More recently, autoimmune contributions have been suggested by the discovery of self-directed pain-promoting IgG and IgM antibodies in CRPS patients and model animals. Both the autoimmune and the autoinflammatory components of CRPS appear to be regulated by neuropeptide-containing peripheral nerve fibers and the sympathetic nervous system. 5

CRPS most often develops after acute tissue trauma including fractures, crushing injuries, sprains and surgeries. Patients may also develop CRPS after burns, stroke, frostbite, injections or local infections.  However, it has been reported in cases without any identifiable precipitating event.6 There is currently no evidence that any particular injury regularly manifests as CRPS or that the severity of injury is related to the development of this syndrome.

Epidemiology including risk factors and primary prevention

Literature reports a frequency of 26.2 per 100,000 persons per year for CRPS I and 5.5 per 100,000 persons per year for CRPS II.6,7,8 with higher propensity for female gender compared to males at a 4:1 ratio, and an increased incidence from 61 to 70 years old.7 Overall highest frequency occurs in the fourth decade of life with no differences in race noted. Fractures are the most common precipitating event and more often involved in the upper extremity.6

The development of CRPS following surgery is a major cause of concern as this complicates post-operative management and has significant clinical ramifications. Operative procedures of the shoulder, distal radius, carpal tunnel and Dupuytren’s contracture have been shown to be associated with the manifestation of CRPS. The incidence of CRPS following shoulder, distal radius, carpal tunnel and Dupuytren’s contracture surgery is estimated to be between 0.9-11%, 22-39%, 2-5% and 4.5-40%, respectively. Although less studied, surgical treatment of the lower limb is also associated with the development of CRPS. In a prospective study of patients with tibial fractures, the incidence of CRPS following surgical repair was documented at 31%; 33.3% of patients treated with intramedullary nailing, 28.6% of patients treated with nails and screws and 28.6% of patients treated with external fixation.9


The physiological process of CRPS is not completely delineated. Several theoretical mechanisms have been proposed, which include; sympathetically maintained pain, sensory and motor dysfunction, peripheral and central sensitization, and protective disuse. A large majority believe that continued noxious stimuli related to damaged areas may lead to sensitization of the peripheral and central nervous system. Peripheral injured nociceptors lead to an overexpression of neurotransmitters and eventual hypersensitivity due to repetitive stimulation. 

The overstimulation of the peripheral nervous system leads to increased nociceptive awareness in the central nervous system. A distorted perception of nociceptive stimuli causes a continuous torrent of downstream ramifications and an ongoing exaggerated response to the initial stimuli.

The involvement of the sympathetic nervous system is not fully understood and has lost some of its significance over time.10 There may be a relation to increased catecholamine concentrations and subsequent interactions among nociceptive neurons.11,12 Additional mechanisms revolve around the body’s active inflammatory response in an attempt to heal injured areas. Inflammatory markers released into the bloodstream and injured tissue lead to vasodilation and eventual engorgement, presenting as edema, warmth, or signs of inflammation.12

Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn’t develop CRPS remains unclear. A new overarching hypothesis that may explain the condition invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. 13

Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF.3 These substances may produce plasma extravasation and vasodilation, thereby producing localized edema, warmth and erythema characteristic of CRPS. 10

Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia. 10

The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time. 10

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Initial symptoms of CRPS typically develop within 6 weeks of the precipitating event. 12,14 Early symptoms tend to include edema, sensory changes, distal vasomotor changes, and pain at the area of insult. Over time, symptoms become less localized.

3 defined stages have been described, with initial stages lasting up to 6 months:

  1. Stage 1 (acute): edema, vasomotor dysregulation, severe tenderness, and allodynia.   
  2. Stage 2 (dystrophic): skin and muscle atrophy, brittle nails and atrophy, intense proximal pain, mottled skin, and brawny edema.
  3. Stage 3 (atrophic): skin becomes pale, smooth, shiny, and cyanotic, contractures and flexion deformities, pain decreases, and vasomotor changes stop.

Currently, there is little support for these sequential stages, and there is new evidence supporting CRPS described as three different subtypes: a) subtype 1 is characterized by vasomotor changes, b) subtype 2 by neuropathic pain and sensory disturbances, and c) subtype 3 by motor limitation and trophic skin changes. 15

Pain in itself has a multitude of different features or presentations, from burning, stabbing, or a dragging character, to throbbing and constricting. A large proportion of pain is located in deeper structures (muscles, tendons, bones) as compared to the more superficial locations.

Autonomic and trophic changes have a propensity for hyperemic or livid features and a larger majority of individuals show no alteration in the growth of hair and nails. Edema or areas of swelling present most of the time and changing in sweating patterns are inconsistent among individuals. Reduced strength is more prevalent than normal strength and almost half have some form of movement disorder. Sensory disorders tend to be the most consistent deficit and could be increased or decreased at the time of exam. 16

Specific secondary or associated conditions and complications

Secondary complications from CRPS include sequelae of disuse including contractures as well as altered sensation of the affected limb. Infection, edema, dystonia, and myoclonus can also occur. Dystrophic changes of nails, skin, and hair, osteopenia (Sudeck’s atrophy), and small nerve fiber dropout may occur. Impaired sympathetic vasoconstriction may also occur and lead to presyncope or syncope.

Essentials of Assessment


A detailed history of present illness is essential. The most common complaints are hyperesthesia and/or allodynia. Pain is often described as hot, burning, and ache-like, and can either follow a dermatomal or a nondermatomal distribution.  It is relieved with medication and rest, and is exacerbated by temperature changes, limb movement, stress and physical activity. Signs and symptoms are highly variable between patients, and often change over time.

History of recent surgery or trauma, including sprains, crush injuries and fractures should be thoroughly assessed as this may be a trigger for CRPS.

To make a clinical diagnosis of CRPS, the following criteria (the Budapest criteria) must be met: 17

  • The patient must have continuing pain, which is disproportionate to any inciting event.
  • The patient must have at least one symptom in 3 of the 4 following categories:
CategoriesSample Symptoms
SensorySensory reports of hyperesthesia and/or allodynia
VasomotorReport of temperature asymmetry and/or skin color changes
Sudomotor/edemaReport of edema and/or sweating changes and/or sweating asymmetry
Motor/trophicReport of decreased range of motion and/or motor dysfunction (weakness, tremor, or dystonia) and/or trophic changes (hair, nail, or skin)
  • The patient must display at least one sign during the physical exam in 2 of the 4 categories:
CategoriesSample Signs
SensoryEvidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)
VasomotorEvidence of temperature asymmetry between limbs and/or skin color changes/asymmetry
Sudomotor/edemaEvidence of edema and/or sweating changes/asymmetry
Motor/trophicEvidence of decreased range of motion and/or motor dysfunction (manual muscle testing weakness, tremor, or dystonia) and/or trophic changes (hair, nail, skin)
  • There is no other diagnosis that better explains the symptoms and signs.
  • A diagnostic subtype called CRPS-not otherwise specified (NOS) was created that would capture those patients who did not meet the new clinical criteria but whose signs and symptoms could not be better elucidated by any other diagnosis .1

The Budapest criteria has been reported to have sensitivity of 0.99 and specificity of 0.79. 17

Physical examination

The patient must display quasi-objective findings on the exam in at least 2 of the 4 categories. Examination tools should include pin, temperature tape or infrared thermometer, von Frey testing or weighted pin, algometer, and goniometer.

Sensory signs are elicited through light touch and pinprick. Light touch can be performed with a cotton-tipped swab or soft brush. Motor changes can present as reduced range of motion and tremors. Trophic changes may manifest as growth or loss of hair and nail changes.

Vasomotor signs can be detected by assessing skin color and measuring skin temperature in affected and contralateral limbs. CRPS may spread to other extremities, and it may be important to measure skin temperature in arms and legs. The examiner must also assess for sudomotor changes (sweating changes/asymmetry) and edema. Trophic changes manifest as shiny, edematous, and erythematous skin findings with loss of hair.

There are isolated findings in CRPS, which are more suggestive of other conditions on the differential. Limited and painful joint range of motion can be found with adhesive capsulitis. Skin warmth and swelling around the joints may be the first finding for inflammatory arthritis. Red, hot, and painful extremities can be found in erythromelalgia, although this condition is frequently symmetric, while CRPS is at least initially unilateral. Cold limbs might indicate vascular insufficiency. Neuropathic pain can be exquisite in postherpetic neuralgia and shingles. In each of these cases, other physical examination findings may assist in organizing the differential when considering CRPS.

Functional assessment

An impaired limb can be disabling. Inquiry into how patients minimize discomfort while pursuing activities of daily living, including bathing and dressing, can guide functional restoration efforts. Because upper extremities are more frequently affected by CRPS, dominant hand function may be affected. Physical impairment may exceed those found with limb amputations and patients may demonstrate distress similar to that found with other chronic pain conditions. Additionally, neuropsychological changes such as asomatognosia, or “neglect-like” changes, in the absence of any brain lesion have been reported. 18

Laboratory studies

At this time, no laboratory studies are used for the assessment of CRPS. Testing to exclude other diagnoses on the differential, including vascular studies to evaluate compromised limb perfusion, electrodiagnostics for specific neuropathies, and rheumatologic laboratory studies to evaluate for arthritis, may be helpful. While multiple biomarkers have been studied with varied results, currently none are accepted for routine clinical use. 19


Although plain films may reveal patchy osteoporosis at periarticular regions in the affected limb, imaging studies are not routinely used for the diagnosis of CRPS due to low sensitivity. Magnetic resonance imaging (MRI) is occasionally performed to evaluate for other muscle, joint, or soft tissue etiologies of pain.20 Triple phase bone scans have also commonly been used in evaluating CRPS. A 2017 meta-analysis found that bone scintigraphy does add any value to the diagnosis of CRPS and should not be used to confirm the diagnosis. However, a negative bone scan may help to exclude the disease or rule out other etiologies. 21

Supplemental assessment tools

Historically, the diagnosis of CRPS required abrupt and transient relief from pain and dysesthesia with a systemic chemical sympatholysis (Bier Block) and/or a diagnostic sympathetic block with a stellate ganglion block or a lumbar paravertebral block.22 However, as the role of the sympathetic nervous system in the pathogenesis of CRPS remains unclear and contradictory, it is now widely accepted that a positive response to sympathetic block is not diagnostic of CRPS. Rather, such a response is an important indicator of sympathetically maintained pain. 22 Further, a 2013 Cochrane review found that limited data do not support the use of local anesthetic sympathetic blockade for reducing pain in CRPS. 23

Autonomic tests such as resting sweat output (RSO), the resting skin temperature (RST), and the quantitative sudomotor axon reflex test (QSART) have been used to evaluate CRPS.22 Quantitative sweat tests and sudomotor axon reflex are sometimes used to assess sudomotor dysfunction, but are rarely used and have limited availability. Electrodiagnostic testing may be useful in the diagnosis of CRPS type II to demonstrate nerve injury, although tolerance to this examination may be limited.

Early predictions of outcomes

Early diagnosis and intervention in CRPS is associated with improved outcome and function. Although pain may decrease over time, detrimental changes arise from neuroplasticity. Additionally, long-term deficits in muscles, bones, and nerves are seen if the syndrome advances or goes undiagnosed and untreated. Recurrence of CRPS is not uncommon; estimates of recurrence range from about 10 to 30 percent, with the higher rates occurring in younger patients, including children.24,25


Weather may exacerbate CRPS symptoms. Tobacco and alcohol use is reported in 56% and 78% of patients with CRPS, respectively.

Social role and social support system

The most pragmatic assessment of pain must include biological, psychological, and sociological aspects.1 Secondary psychological responses and dysfunction are ubiquitous.

A 2020 cross-sectional study showed patients with CRPS with more negative disease perceptions experienced greater pain, disability, and kinesiophobia. Psychological stress may influence disease progression as patients with higher levels of anxiety, perception of disability, and pain-related fear have been shown to have a worsened disease course. Plasma levels of epinephrine and norepinephrine were elevated in a sample of CRPS patients compared with healthy control subjects. While theoretically, stress and emotional distress could elevate these catecholamines, a causal relationship between social and environmental influences and the development of CRPS is far from proven. Further, catastrophizing, commonly seen in CRPS, has been shown to increase pro-inflammatory cytokines which may also be linked to disease progression. 26, 27, 28

Addressing psychologic and social factors can improve outcomes. The role of psychologic and social factors must be viewed with caution. It is critical to identify and aggressively treat all spheres of the pain experience.1

Rehabilitation Management and Treatments

For Expanded Details, See Complex Regional Pain Syndrome Part 2: Management and Treatment

Coordination of care

CRPS syndrome is not only biologically complex, due to its unclear pathophysiological background, but also frequently contains social and psychological components which makes successful treatment even more difficult to achieve.1 Functional restoration is best achieved through an interdisciplinary model and includes physical therapy, occupational therapy, recreational therapy, vocational rehabilitation, cognitive behavioral therapy, and medical oversight. This program emphasizes physical activity (“reanimation”), desensitization, and normalization of sympathetic tone in the affected limb and involves a steady progression from the most gentle, least invasive interventions to the ideal of complete rehabilitation in all aspects of the patient’s life.1

Management of CRPS is difficult due to its unknown pathogenesis and psychosocial components. 29 In order to increase the likelihood of better outcome, a multidisciplinary approach is recommended in the management of CRPS including physical therapy, occupational therapy, recreational therapy, vocational rehabilitation, cognitive behavioral therapy, and medical oversight. 28

The goal is to restore and maximize function of the affected limb, minimize pain, and improve quality of life. This should be started as soon as the diagnosis is made. Referral to pain management is appropriate if conservative management yields no improvement.

Patient & family education

CRPS patients must be personally committed to health improvement. Functional restoration is difficult without lifestyle modification, as well as integration of rehabilitative techniques. Families must also be educated in supportive efforts to restore function.

It is important to educate patients regarding the goals of therapy. Although the patient will likely experience pain during therapy, it is necessary to prevent complications from disuse such as contractures and altered sensation. Patients and families should also be educated about possible behavioral effects of CRPS such as depression, anxiety, suicidal ideation, and anger to enforce supportive efforts as pain with no clear cause may be difficult to accept. 30

Metabolites were associated with psychological disorders including depression, anxiety, suicidal ideation and anger in CRPS patients, showing pathological interactions between a painful body and mind. 30

Emerging/unique Interventions

Emerging research suggests including the early stages of movement (activation of premotor and primary motor cortices) through graded motor imagery (GMI) or mirror visual feedback (MVF) therapy in treatment of CRPS.1 The mechanism of action of these therapies is still unclear.1 MVF therapy first asks the patient to close his/her eyes and describe both the affected and unaffected limb (i.e., size, location, and any perceived differences), followed by imagined movements of both extremities.31 The movements for the program are focused on painful joints and those that are just proximal and distal to the joint.1 The participant is then invited to look at the mirrored limb without movement in order to try to achieve useful recovery. 1

The key to successfully managing CRPS is controlling the patient’s pain in order to participate in therapy. Rehabilitative therapy coupled with pharmacotherapy is the gold standard. Asides from nonopioid oral analgesics and adjuvant medication for neuropathic pain, interventional procedures are used in those with refractory pain. Trigger point injections, sympathetic nerve blocks 32, and implanted devices such as spinal cord and dorsal root ganglion stimulator are currently being used. However, due to small limited studies, their efficacy is still under question. 33, 34 Spinal cord stimulation (SCS) has been reported to be ineffective in 47% of CRPS patients. Consequently, DRG stimulation is being investigated as an alternate neural target. The safety and effectiveness of DRG stimulation for the relief of CRPS compared with traditional and newer SCS systems is unknown. 35

In recent years, discovery of pathophysiologic mechanisms of CRPS has led to significant strides in the understanding of the disease process. Continued elucidation of the underlying pathophysiological mechanisms will allow for the development of more targeted and effective evidence-based therapy protocols. 36

Cutting Edge/ Emerging and Unique Concepts and Practice

For Expanded Details, See Complex Regional Pain Syndrome Part 2: Management and Treatment

Research is ongoing in the realm of immune testing, genotypic, and phenotypic testing (e.g. functional MRI) to investigate whether these areas can contribute to the diagnosis of chronic pain conditions, including CRPS. Sympathetic adrenergic nerves travel along arteries and nerves and are found in the adventitia (outer wall of a blood vessel).  In view of this, some clinicians are performing sonographically guided peripheral nerve blocks and peripheral perivascular sympathetic blocks for CRPS management in patients.  Currently, there is ongoing research about this management. At the moment, the diagnosis of CRPS still relies mostly on clinical evaluation and no particular laboratory or imaging study alone can provide a diagnosis.

Multiple cutting-edge diagnostic studies and procedures are being explored to manage chronic pain conditions such as CRPS. Brain metabolites and peripheral biomarkers associated with neuroinflammation are currently being investigated to further understand the pathophysiology of CRPS. 37

Elevated neuroinflammation levels were associated primarily with lipids in the brain and pH, glucose, CO2, basophil, and creatinine in the peripheral parameters in CRPS patients. 37

Use of positron emission tomography to track innate immune cells and follow the progression or CRPS during the acute phase may potentially lead to phase-specific therapeutics. 38 Inflammation involving activation and recruitment of immune cells, including myeloid cells (i.e., macrophages, microglia), was noted in CRPS. Positron emission tomography (PET) of translocator protein-18 kDa (TSPO) is a method for noninvasively tracking these activated immune cells. PET tracer uptake quantification in the tibia revealed increased peripheral inflammation between 2 days to 7 weeks. Centralized inflammation was detected in the spinal cord and brain of fractured mice at 7 and 21 days after injury. 38

Aside from spinal cord stimulators, neural level procedures targeting the dorsal root ganglion are being investigated, from implanting DRG stimulators to lesioning the dorsal root entry zones. 35

Gaps in the Evidence- Based Knowledge

For Expanded Details, See Complex Regional Pain Syndrome Part 2: Management and Treatment

Although there are many controversies in our current knowledge or CRPS, there are many promising studies that could better help understand its pathophysiology. Ongoing studies investigating the condition up to a cellular level can also contribute to our understanding.


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Original Version of the Topic:

Sunjay Mathur, MD. Complex regional pain syndrome Part 1: Essentials of Assessment and Diagnosis. Published 8/9/2012.

Previous Revision(s) of the Topic:

Luis Baerga-Varela, MD, Rafael Arias-Berrios, MD, Shirley Grigg, MD, Natalia M. Betances Ramírez, MD, Juan Galloza Otero, MD. Complex regional pain syndrome Part 1: Essentials of Assessment and Diagnosis. Published 8/16/2016.

Author Disclosures

Laurentiu Dinescu, MD
Nothing to Disclose

Justin Faye, MD
Nothing to Disclose

Alec Guerzon, MD
Nothing to Disclose

Michael Mosier, MD
Nothing to Disclose