Complex regional pain syndrome (CRPS) is a consensus-defined clinical neuropathic pain syndrome with an illustrious history and fascinating ever-elucidating pathophysiology. CRPS incorporates 2 previously distinct pain conditions: causalgia (now CRPS II) and reflex sympathetic dystrophy (now CRPS I). CRPS presents with pain, hyperalgesia, and allodynia as well as motor, vasomotor, sudomotor, and trophic changes, most often induced by limb trauma or immobilization. It is likely that peripheral nerve injury produces neuroinflammation peripherally and centrally in the dorsal horn, thalamus, and elsewhere in the nervous system, resulting in peripheral and central sensitization, enhancement of symptomatology, and spread to other anatomical areas. Multiple cortical changes have been demonstrated on fMRI when symptoms are most manifest, which seem to return to normal with clinical improvement. Long-term anatomical changes in the brain may also be present when studied with structural MRI. Treatment is based on restoration of limb function and relief of pain and other symptoms. However, the absence of “gold-standard” testing and controversies regarding diagnostic criteria, pathophysiology, and therapy serve to highlight how much of this condition is uncertain, not validated, or simply not known.
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• Complex regional pain syndrome (CRPS) is a consensus-defined clinically diagnosed pain syndrome with hyperalgesia, allodynia, vasomotor, sudomotor, motor, and trophic symptoms and signs initiated by trauma and/or immobilization.
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• There is no “gold-standard” diagnostic test; the diagnosis remains “clinical” at present.
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• The pathophysiology, although incompletely understood, involves microvascular changes, neuroinflammation, and neuromodulation at multiple peripheral and central nervous system levels.
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• Treatment is directed toward restoration of limb function. There are no FDA-approved medications. Therapies of proven value in other neuropathic pain states are of some benefit in CRPS.
Historical note and terminology
Complex regional pain syndrome (CRPS) is a diagnostic clinical taxon initially created by expert panel consensus for the International Association for the Study of Pain (IASP) in 1993 to incorporate 2 theretofore distinct pain conditions, causalgia (now CRPS Type II) and reflex sympathetic dystrophy (now CRPS Type I), under 1 umbrella with specific descriptive criteria.
After several probable earlier reports, Mitchell and colleagues characterized CRPS II in detail in soldiers suffering from bullet or shrapnel injuries to peripheral nerves during the American Civil War. They described an acute and chronic regional pain condition with a unique burning quality to the pain, in 3 publications from 1864 to 1872 (262; 260; Mitchell 1872; 316; 421); in combining the Greek terms for burning (“kausos”) and pain (“algos”) they coined the term “causalgia.” Mitchell and colleagues also described vasomotor and sudomotor clinical features and allodynia, hyperalgesia, and psychological sequelae, but the cardinal and inviolate symptom was burning pain. The syndrome sometimes resolved in weeks or months, but Mitchell’s son, John, found some of the original patients with persistent pain when reevaluated more than 25 years after injury (259). When causalgia was more formally defined by the Nerve Injuries Committee of the British Medical Research Council in 1920, some of the descriptions of the pain were “spontaneous,” “hot,” “burning,” “intense,” “diffuse,” “persistent pain exacerbations,” “excited by mild stimuli,” and “tending to lead to profound changes in the patient’s mental state” (248).
Causalgia continued to be reported, with the vast majority of cases consequent to wartime peripheral nerve injuries. However, starting with Homans, civilian cases were also described, most frequently following fractures, minor traumas, immobilization, and surgery; these were not deemed as serious, nor attributable to direct nerve injury, and were labeled minor or mimo-causalgia, algodystrophy, Sudeck atrophy, posttraumatic spreading neuralgia, posttraumatic neurovascular pain syndrome, etc. (169; 170; 113; 162; 422; 289; 378). It was not until the 1980s that reports appeared of civilian patients with symptoms as severe as wartime patients (370; 171); thereafter the distinction between “major” and “minor” causalgia was abandoned. The most important of the causalgia-related conditions not thought due to specific nerve injury was reflex sympathetic dystrophy.
Evans, in 2 seminal papers (123; 124), building on evidence from Leriche, Livingston, and others that the sympathetic nervous system is reflexively involved in posttraumatic limb disorders, appended the term “reflex sympathetic dystrophy” to “a most disabling, often extremely painful, malady following minor sprains, ordinary fractures, or, in military or civil life trauma to blood vessels or nerves….Pain may be moderate, mild, or absent. The true diagnostic features are those disorders initiated by perversions of reflex sympathetic stimulation, namely increased rubor or pallor, sweating, edema, atrophy of skin, and spotty or even cystic atrophy of bone” (123). “The syndrome is characterized only at times by the excruciating, burning pain that has given it the term ‘causalgia,’ hence a misnomer.” Further, he states: “Either cervical or paralumbar sympathetic procaine block comprises a diagnostic therapeutic test. The relief of pain may be almost miraculous, but need not be so dramatic as to establish the diagnosis, provided relief of other phenomena is also noted” (123; 124).
In so doing, Evans conflated the terms “causalgia” and “reflex sympathetic dystrophy,” expanded the boundaries of originating injuries, diminished the role of pain in the syndrome, and, most importantly, emphasized sympathetic nervous system overactivity as clinically necessary and as an underlying pathophysiological etiologic mechanism – with reduction of this overactivity through sympathetic blockade serving both diagnostic and therapeutic purposes. The term “reflex sympathetic dystrophy” quickly caught on and became the favored diagnosis over the next 5 decades. Injury to a specific nerve was not requisite; reflexive sympathetic overactivity as a consequence of “prolonged bombardment of pain impulses,” however, was (124).
Over the years, an absence of well-codified diagnostic criteria or decision rules prevailed; this inhibited accurate diagnosis, research, clinical trial creation, and assessment of therapeutic and prognostic outcome measures. Further, the term “reflex sympathetic dystrophy” was clearly problematic in that the “reflex” component was unspecified and hypothetical, the “sympathetic” component not always present clinically and not pathophysiologically determinative, and the “dystrophy” component uncommon.
In response, the IASP convened a workshop in 1993 in Orlando, which developed descriptive criteria intended to be inclusive and sensitive and standardize the diagnosis of these conditions (see Table 1) (253; 364). Descriptive symptom-based consensus criteria were deemed acceptable because of successful similar efforts in the fields of headache and psychiatry, where pathophysiologically-based diagnostic criteria were also inadequate. The resultant overarching terminology defined a new category: “complex regional pain syndrome” or “CRPS”; reflex sympathetic dystrophy became “CRPS I,” and causalgia “CRPS II.” Merskey commented that the controversial issue of the relationship of sympathetic activity to the pain was resolved by adding to the description of CRPS I that the pain might be “sympathetically maintained,” “sympathetically independent,” or a combination (252). “Sympathetically maintained” pain improved with sympathetic blockade; “sympathetically independent” pain did not.
Table 1. IASP’s 1993 Diagnostic Criteria for CRPS
CRPS I (reflex sympathetic dystrophy)
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1. The presence of an initiating noxious event or a cause of immobilization.
2. Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event.
3. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain.
4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.
Note: Criteria 2 through 4 must be satisfied.
CRPS II (causalgia)
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1. The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve.
2. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain.
3. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.
Note: All 3 criteria must be satisfied.
The IASP consensus was enormously helpful in that it provided defined criteria, encompassed a range of regional pain conditions associated with vasomotor and sudomotor disturbances, and removed etiopathophysiologic presumptions. Its consensus origin and lack of pathophysiologic support notwithstanding, the term “complex regional pain syndrome” was quickly adopted and entered the medical lexicon. However, criticisms soon arose, mostly because the criteria were consensus-based, dependent on accurate patient self-reportage, invalidated in empirical studies, and made CRPS a diagnosis of exclusion (128; 54; 157; 159; 155; 229; 59). This review cannot evaluate all of these criticisms; however, discussion of the initial studies of empirical validation of the 1993 IASP CRPS criteria is relevant, as their concerns formed the nidus of the latest IASP-approved revisions (2012). These studies determined that sensitivity of the criteria was high (0.98), but specificity was poor (0.36); there was a tendency to over-diagnosis; a positive diagnosis could be correct in as few as 40% of cases (indeed, 37% of patients with diabetic neuropathy could meet the criteria for CRPS) (128); and the criteria for dysautonomia were overly vague (129; 54; 157). Adding motor and trophic change criteria, initially thought unhelpful (129), was later found valuable (54; 157). Separating evidence of vasomotor dysfunction from sudomotor signs and symptoms also improved validity (157).
These criticisms and validation issues prompted another workshop in Budapest in 2003 wherein new criteria were proposed to improve diagnosis and internal and external validity and create more lenient clinical criteria to enhance sensitivity, with more restrictive research criteria to enhance specificity (see Table 2). The subtypes of CRPS I and II were retained and a third subtype added, CRPS not otherwise specified (CRPS NOS), for patients previously diagnosed with CRPS who now “did not fully meet the new clinical criteria but whose symptoms could not better be explained by another diagnosis” (about 15%) and to satisfy certain special interest groups who resisted the change (155; 159). These criteria were approved by the IASP in 2012 and are supported in the recent UK guidelines (326). The new consensus criteria are hobbled by similar and additional concerns. Loeser, in commenting on the 1993 IASP criteria, stated that discussion of the sensitivity and specificity of diagnostic criteria absent a determinative gold standard represents a tautology (229). The new standards, with the subtype CRPS NOS, take the tautology conundrum to an even higher level – nobody presenting with a regional chronic pain can be verified as NOT having CRPS.
Validation efforts continue to be problematic. Regarding the 2003 Budapest criteria, Harden and colleagues compared 113 CRPS I patients meeting the 1993 IASP/CRPS criteria to 47 patients with non-CRPS neuropathic pain, most having had a specific nerve injury (45%) or radiculopathy (30%), mostly due to surgical (50%) or crush (30%) injuries (158). Although the manuscript does not allow for a detailed analysis of the non-CRPS patients, many had symptomatic hyperesthesia (63.8%), temperature asymmetry (38.3%), and asymmetric edema (40.4%) as well as trophic (38.3%) and motor (46.7%) changes; there were also signs of hyperalgesia (43.5%), allodynia (29.8%), a colder affected side (85.7%), asymmetric skin color (36.2%), and edema (24.2%) on clinical examination. The frequency of these features in the non-CRPS neuropathic pain group suggests that some of them had CRPS II, thereby invalidating the comparisons and sensitivity and specificity calculations on which the validation estimates are based. The tautology criticism was not addressed in this paper but remains a conundrum. Benzon and colleagues accept the validity of the Budapest criteria and urge their use in the clinical setting and in research studies (30).
In a study of 975 patients satisfying the Orlando criteria, 71.5% met the Budapest clinical criteria, and 45.8% met the Budapest research criteria (397). Because of the more restrictive Budapest criteria, especially the inclusion of motor symptoms and signs, patients fulfilling those criteria had lower quality of life scores than the total group, suggesting more severe disease.
An additional complication is raised by Sumitani and colleagues who did a validity study of the 1993 IASP/CRPS criteria in Japanese patients (368). They did not find the 1993 criteria efficacious in their population and created new Japan-specific criteria of greater diagnostic accuracy, somewhat different from the 1993 and 2003 criteria. They and Bruehl raise the daunting possibility of geographic diagnostic criteria, perhaps secondary to cultural specificity of CRPS expression, although acknowledging the serious limitations to such an approach vis a vie international standardization of research and therapeutic trials (53).
Table 2. 2003 Clinical Diagnostic Criteria for CRPS (IASP-Approved in 2012)
General definition: CRPS describes an array of painful conditions characterized by continuing (spontaneous and/or evoked) regional pain seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time.
To make the clinical diagnosis, the following criteria must be met:
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1. Continuing pain, which is disproportionate to any inciting event
2. Must report at least one symptom in three of the four following categories:
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- Sensory: reports of hyperesthesia and/or allodynia
- Vasomotor: reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
- Sudomotor/edema: reports of edema and/or sweating changes and/or sweating asymmetry
- Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin)
3. Must display at least one sign at time of evaluation in two or more of the following categories:
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- Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
- Vasomotor: evidence of temperature asymmetry (greater than 1°C) and/or skin color changes and/or asymmetry
- Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating asymmetry
- Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin)
4. There is no other diagnosis that better explains the signs and symptoms
For research purposes: Must report at least one symptom in all four symptom categories and at least one sign (observed at evaluation) in two or more sign categories.
Both consensus panels promulgated IASP CRPS criteria iterations to delineate a regional neuropathic pain disorder with substantial autonomic, eg, vasomotor and sudomotor, dysfunction as requisite components, and differentiate it (CRPS) from other regional neuropathic pain disorders without dysautonomia (129; 54; 157; 155; 159; 59). An obvious consequence is that these other regional pain conditions without past or present evidence of autonomic dysfunction are not CRPS; they have been labeled “posttraumatic neuralgia” and postulated as having different underlying mechanisms (411). Without a diagnostic “gold standard” and/or specific pathophysiological mechanisms for CRPS or the “neuralgias,” are such distinctions clinically or pathophysiologically relevant or merely the mindset of the workshops’ panelists? Are there necessary and sufficient causes of CRPS that produce a pain syndrome with autonomic dysfunction that differ from those resulting in non-dysautonomic regional pain or no pain at all? Oaklander and Horowitz consider CRPS and posttraumatic neuralgia as endophenotypes along a spectrum of consequences of peripheral nerve injuries that predominantly affect small myelinated and unmyelinated nerve fibers (281). Experimental approaches to this issue alone may be inadequate, as animals cannot voice pain complaints. However, 2 clinical models exist that may be illuminating – needlestick-nerve injuries and shingles followed by postherpetic neuralgia of the distal limb.
Phlebotomy for blood sampling, blood donation, insertion of intravenous lines, or intravenous administration of medication has the uncommon risk of peripheral (cutaneous) nerve injury during the procedure. The proximity of cutaneous nerves to accessible superficial veins at the usual phlebotomy sites – antecubital fossa, radial surface of wrist, and dorsum of hand – allows for inadvertent and unavoidable contact between needle and nerve (172; 426). The situation satisfies many elements of an experimental model: procedure and instrument (hypodermic needle) are always identical, exact timing of injury is known, and the same cutaneous nerves are always affected (173). Clinically, such nerve injuries encompass a broad spectrum of symptoms and signs with most patients experiencing a “burning,” “lancinating,” “shooting,” “electrical” pain with the needle in situ (173; 174) and gradual resolution over weeks to months (276; 174). However, rare patients develop full-blown CRPS II with sensory, vasomotor, sudomotor, and motor/trophic symptoms and signs that last for years (172; 173; 174). The mechanism of nerve injury is the same; the consequences are far different.
Presently, there is no clear pathophysiologic explanation for the panoply of clinical consequences arising from identical venipuncture-induced nerve injuries. One can suspect preferential involvement of A delta and somatic and post-ganglionic sympathetic C fibers and/or individual propensity to certain forms of inflammation (173) in the CRPS patients, but creating inviolable distinctions between patients who satisfy the CRPS criteria because of autonomic features and those who do not, in the context of identical trauma, seems unreasonable. (A specific patient serves to illustrate this conundrum – see the “Clinical vignette” section.)
Rarely shingles and postherpetic neuralgia will involve a distal limb with the development of the symptoms and signs of CRPS. The vast majority of shingles/ postherpetic neuralgia cases occur in the torso and face without CRPS phenomena; therefore, in shingles/ postherpetic neuralgia of a limb, specific distal microvascular anatomy and gravity are likely to play a role in the development of CRPS (278).
The incomplete understanding of CRPS pathophysiology and lack of “gold-standard” diagnostic testing makes the value of arbitrary consensus criteria uncertain. Perez and colleagues compared 3 different diagnostic sets in 372 patients suspected of having CRPS I and found uniformity between sets to be poor (292). This may lead to different therapeutic and study populations and compromise therapy and research; they proposed that future studies explicitly reference diagnostic criteria and clinical features. A review raises the question as to whether CRPS I and II are similar enough to be included under the same umbrella, introduces the possibility that there are subgroups within this terminology, and concludes that CRPS “is a poorly defined term used to describe a variety of disorders characterized by pain disproportional to the inciting event” (45). These authors opine that the diagnostic criteria of CRPS I are “unreliable” and that CRPS I should be abandoned as a legitimate diagnosis (46). Bass also suggests the term “CRPS” should be abandoned – because of iatrogenic harm (22). He feels that the diagnosis itself “has the potential to cause considerable disability, especially in vulnerable people...and encourage[s] the adoption of the sick role…patients often become excessively bodily focused and the suspicion of ‘disease’ heightens bodily awareness and reinforces the belief that the patient is ill. Disability often ensues” (22).