Complex Regional Pain Syndrome


Complex regional pain syndrome remains an enigmatic condition to manage due to its diverse etiology, varying clinical course, and lack of definitive treatments that are universally effective. Though there continues to be debate with regards to the pathophysiology of CRPS, significant advances have been made in gaining deeper understanding of the peripheral and central pathophysiological mechanisms governing the development and elaboration of CRPS. The conceptual framework focuses on the neurobiological changes occurring peripherally and centrally and has enabled examination of linkages between changes in cutaneous innervation, release of inflammatory mediators, peripheral sensitization, involvement of the sympathetic system, and resultant central sensitization with cortical reorganization. These advances necessarily precede the much needed innovation in available treatment modalities. The current paradigm centers on a multimodal pharmacologic therapy in the setting of a comprehensive multidisciplinary team-based approach aimed at effective pain control, functional restoration, and modalities to enhance psychological well-being as important components of care. The use of other potential therapies aimed at the immunological/inflammatory basis of CRPS, including naltrexone (a glial cell modulator), and immunoglobulin IV are also considered in this chapter. Finally the role of neuromodulation (spinal cord stimulation) and possible use of intrathecal baclofen for refractory dystonia are addressed as options for appropriately selected patients.


Budapest criteria, IASP diagnostic criteria, integrative approaches, interventional therapies, pharmacologic treatments


The literature is replete with accounts of the history of the early description of complex regional pain syndrome (CRPS) as part of any publication on the subject. A brief reiteration of this history helps underscore the magnitude of the discovery and highlight the challenges faced by clinicians and researchers alike in moving the discovery forward. CRPS types 1 and 2 (formerly known as reflex sympathetic dystrophy [RSD] and causalgia, respectively) was first reported by Weir Mitchell over a century ago following his observations that Civil War soldiers with peripheral nerve damage from gunshot wounds developed a constant burning pain, which he called causalgia. Almost half a century after Mitchell’s observation, Sudeck in 1900 observed muscle atrophy and bony demineralization as a complication of infection in the limbs. The radiographic changes started as a “patchy osteoporosis of the small bones of the hands or feet and the distal metaphysis of the forearm or tibial bones”; hence, the name Sudeck dystrophy, due to the presence of patchy osteoporosis. Almost five decades later in 1947, the term reflex sympathetic dystrophy was coined by Evans to reflect the assumption that the sympathetic nervous system was involved in the abnormal activity observed in the periphery.

In 1994, the Special Consensus Group of the International Association for the Study of Pain (IASP) met in Orlando to review the criteria for the clinical diagnosis of patients presenting with CRPS/RSD. The need for such a consensus among physicians charged with the care of these patients arose from the recognition of the presence of an inhomogeneous set of signs and symptoms that were hitherto used to diagnose the disease with the resultant difficulty in confirming that all practitioners were treating the same condition. In addition, there was lack of evidence for a reflex mechanism and the variable presence of dystrophy. The term CRPS was therefore considered broad enough to allow the inclusion of patients who may show varying levels of sympathetic nervous system involvement in maintaining pain through the course of the disease process, hence the term sympathetically mediated pain (SMP) or sympathetically independent pain (SIP) ( Table 27.1 ).

TABLE 27.1

International Association for the Study of Pain Diagnostic Criteria for CRPS 1 and CRPS 2

Source: Stanton-Hicks M: Complex regional pain syndrome. Anesthesiol Clin North Am . 21:733-744, 2003.

CRPS 1 (Reflex Sympathetic Dystrophy) a CRPS 2 (Causalgia) b

  • 1.

    The presence of an initiating noxious event or a cause of immobilization.

  • 1.

    The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve.

  • 2.

    Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event.

  • 2.

    Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain.

  • 3.

    Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain.

  • 3.

    This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.

  • 4.

    This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.

CRPS, Complex regional pain syndrome.

a Criteria 2 through 4 must be satisfied.

b All three criteria must be satisfied.

In 2004, a group of researchers met in Budapest to develop the diagnostic criteria for CRPS (table-Budapest Consensus group criteria). The group endorsed the subtype grouping of CRPS (1 and 2), and in addition approved a codified criteria developed from an empirically based research modification of the earlier IASP diagnostic criteria. The IASP Taxonomy Committee approved the Budapest or “new” IASP criteria in 2012 to help promote further research, recognizing the paucity of strong evidence for efficacy of treatments for CRPS as articulated in rigorous systematic reviews.


There is a paucity of epidemiologic data or outcome studies on CRPS, reflecting the absence of a universal agreement on the set of signs and symptoms that should be present to make the diagnosis in this group of patients. There is growing interest in characterizing the factors that determine the role of inflammatory mediators in the development of the peripheral clinical manifestations of CRPS. An epidemiologic study demonstrated that patients with CRPS also tend to have a history of asthma and migraine headaches. In both these disorders, neuropeptides may play a significant role in the pathophysiology of the disease process. Although the true incidence of CRPS is unknown, results of two epidemiologic studies indicate that the incidence per person-years at risk of the disease ranges from 5.46 to 26.6/100,000 person-years at risk. It occurs more commonly in females than males, with a ratio of 2:3 to 3:1, and with increasing age. Veldman et al. in a prospective study of 829 patients, 76% of whom were female, found that the age ranged from 9 to 85 years (median age 42 years) with only 12 patients younger than 14 years. Allen and colleagues reviewed epidemiologic data from a tertiary pain center on 134 patients. They found that the CRPS symptoms had existed for a mean duration of 30 months prior to presentation, most patients had seen on average 4.8 physicians before referral to the tertiary center, 17% had pending lawsuits, and 54% had a workers’ compensation claim related to CRPS. This study also examined the types of occupation held by CRPS patients at the time of injury. People in the service industries, such as restaurant workers and police officers, suffered almost twice as much as people in other professions, possibly related to the physical activity related to the job. Other associated features that have been identified include the presence of social stressors at the time of development of the condition. In spite of this finding, no specific psychological factors or personality trait has been found to predispose an individual to developing CRPS.

In a web-based epidemiologic survey of CRPS, Sharma and colleagues surveyed 1359 subjects to examine multiple variables (risk factors), including sociodemographic factors. The authors concluded that CRPS commonly occurs among younger females and often results from work-related injuries or surgery. The study also revealed that CRPS is associated with sleep disturbance, functional impairment, and suicidal ideation. de Mos et al. examined outcomes of the disease with regard to the extent of long-lasting impairments. In a retrospective analysis for an average of 5.8 years, 102 patients with CRPS were compared with matched reference patients with similar injuries without CRPS. Sixteen percent of the CRPS patients reported the CRPS to be still progressive, 31% were incapable of working, and the patients with poorest outcomes were those with upper extremity involvement. The authors concluded that although severe outcomes were rare, the majority of CRPS patients experience persistent impairment at 2 years or more after onset of the condition.

Given the paucity of information on the long-term prognosis of CRPS patients, a web-based CRPS-UK Registry has been developed and made accessible to centers experienced in diagnosing and managing patients with CRPS. Such registries are likely to provide additional insight on the long-term outcome of patients with CRPS.


CRPS types 1 and 2 differ only by the presence (type 2) or absence (type 1) of evidence of nerve injury. Pain is the hallmark of the condition, and commonly manifests as spontaneous pain, with hyperalgesia and allodynia. Associated signs include vasomotor and sudomotor disturbances, active and passive movement disorders, and trophic changes. CRPS type 2 develops after defined nerve injury, whereas CRPS type 1 develops following minor or major injuries with little or no obvious damage to the nerves in the involved extremity.

There continues to be considerable debate in the literature vis-à-vis the pathophysiology of CRPS. The existing framework focuses on the neurobiological changes, peripherally and centrally. This conceptual compartmentalization allows for examination of the changes in cutaneous innervation, ensuing peripheral sensitization associated with release of inflammatory mediators, involvement of the sympathetic system, and ultimately central sensitization with cortical reorganization.

Peripheral/Afferent Mechanisms

There is evidence that inflammation plays an important role in the elaboration and maintenance of CRPS. Recent studies have demonstrated the presence of increased levels of two neuropeptides associated with inflammatory processes; these include calcitonin gene-related peptide and substance P in patients with CRPS. This line of reasoning is supported by observations that the current use of angiotensin-converting enzyme inhibitors is associated with an increased risk of CRPS, given that angiotensin-converting enzyme is involved in the metabolism of neuropeptides. Furthermore, the role of cytokines in the generation of the peripheral manifestations continues to stimulate the interest of investigators. Independent lines of research have demonstrated that, in patients with CRPS, levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) are increased in skin blisters and biopsies in affected limbs compared with unaffected limbs in patients with CRPS post limb fractures. In addition, there is evidence that there is an associated increase in the level of soluble receptors to the proinflammatory cytokines TNF-α, IL-1 and IL-8, during the early stages of CRPS (within 3 months). Conversely, antiinflammatory cytokines, including IL-4, IL-10 and transforming growth factor beta 1 (TGFβ1), are lower. Interestingly, it was established that the cutaneous blisters in affected limbs of CRPS patients contain more tryptase compared with unaffected limbs. Given that tryptase is a marker of mast cell activity, it is thought that mast cells may be involved in the release of cytokines.

Another line of investigation aimed at elucidating the peripheral mechanisms includes the imbalance between peripheral vasodilators such as nitric oxide and vasoconstrictors such as endothelin-1. Groeneweg et al. demonstrated that, in artificial blisters in the affected limbs of patients with CRPS, the levels of nitric oxide were lower and the level of endothelin-1 was higher than in the unaffected limb. This imbalance is thought to be due to cytokine-induced inhibition of endothelial nitric oxide, and induction of the transcription of preproendothelin-1. Cytokines also stimulate smooth muscle inducible nitric oxide synthase, leading to production of nitric oxide in muscle and ultimate formation of peroxynitrite (ONOO–) which affects the integrity of the endothelium. A combination of the release of inflammatory cytokines, associated hypoxia due to imbalance of peripheral vasoconstrictors and vasodilators, and formation of free radicals serve as profound peripheral nociceptive stimuli. This potent chronic activation of peripheral nociceptors may account for the sensitization and sensory changes associated with CRPS.

Altered Cutaneous Innervation Following Injury

Current evidence favors the hypothesis that some degree of nerve injury is required, however trivial, to initiate the cascade of events associated with CRPS. Oaklander et al. in 2006 demonstrated that persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons, which subserve pain and autonomic function, were responsible for the symptoms reported in CRPS 1. The authors found that significantly lower densities of epidermal neuritis (on average 29% lower) were observed in CRPS-affected extremities as compared with the contralateral unaffected limb. Similar changes in neurite density were not seen in non-CRPS conditions such as osteoarthritis. In a study to determine if objective evidence for the presence of nerve damage in CRPS 1 exists, Albrecht et al. in 2006 examined the skin samples from amputated upper and lower extremities from two CRPS patients to detect evidence of nerve injury, using immunofluorescence techniques. They found a reduction in C and A-delta fiber density in the CRPS-affected limbs compared with the nonaffected sites on the same limb, as well as compared with healthy controls. In addition, abnormalities in the innervations around hair follicles and sweat glands were also observed. The causal relationship of these changes relative to the onset of CRPS is unclear.

Peripheral Sensitization

Peripheral sensitization resulting from the persistent nociceptive afferent activity as a result of the initial tissue trauma is thought to occur. Following tissue injury, primary afferent fibers in the traumatized area release neuropeptides such as bradykinin and substance P. The peptides sensitize nociceptors, increase their response to noxious stimuli, and reduce their threshold to mechanical and thermal stimuli. These neurophysiologic changes may account for the hyperalgesia and allodynia pathognomonic of CRPS. Furthermore, the local hyperalgesia is limited to the affected limb and not seen in the contralateral unaffected limb. Examination of the extent of sensory impairment in 24 patients with CRPS 1 revealed that up to half of the patients with chronic CRPS 1 develop hyperesthesia to pinprick and temperature on the affected side or in the upper quadrant of the ipsilateral side. The patients also demonstrated a higher incidence of hyperalgesia and mechanical allodynia in addition to motor impairment. These changes suggested a more widespread alteration of sensory perception in the pathophysiology of CRPS in this group of patients.

The motor system may also be affected as evidenced by a reduction in range of motion, commonly seen in patients with CRPS, that is not explained by the presence of pain-induced kinesiophobia. The presence of severe dystonia in affected and unaffected limbs has also been documented, manifesting as flexion of the fingers, wrists, elbows, and plantar flexion of the toes. The fact that the dystonia responds to intrathecal baclofen indicates that gamma-aminobutyric acid (GABA)-mediated mechanisms may play a role in the development of dystonia in CRPS.

Central Sensitization

The mechanism by which central sensitization occurs is akin to that described in peripheral sensitization. Persistent nociceptive input associated with nerve injury from tissue trauma results in increased activity of nociceptive neurons in the spinal cord. The central sensitization is mediated by the induced release of neuropeptides such as bradykinin and substance P, and the excitatory neurotransmitter glutamate acting at the spinal receptors for N -methyl- d -aspartic acid (NMDA), α-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid (AMPA) and neurokinin-1. This activity results in enhanced response to nonnoxious stimuli (allodynia) and noxious stimuli (hyperalgesia). CRPS patients demonstrate significantly increased wind-up to repeated stimuli applied to the affected limb compared with the unaffected contralateral limb or other limbs. These findings suggest the possibility of central sensitization as a mechanism of persistence of the symptoms associated with CRPS.

Reports suggest that cortical reorganization, manifesting as changes in sensory mapping and activation patterns, might ensue. These changes have been observed, using functional magnetic resonance imaging, and can account for some of the sensory disturbances noted. These include changes in tactile discrimination and referred sensations and alteration in the perception of body habitus (see below Cortical Reorganization).

Sympathetically Mediated Pain

There has been an indication of an interaction between the sympathetic noradrenergic neurons in the periphery and the primary afferent neurons as part of the underlying mechanism of SMP in patients with CRPS 1. Intradermal injection of epinephrine in CRPS patients results in the return of allodynia and spontaneous pain that had previously been relieved by sympathetic blockade, suggesting a peripheral adrenoceptor mediated mechanism in some patients. Spontaneous pain may also be relieved by an infusion of the α-adrenergic blocker phentolamine. It has also been suggested that sympathetic innervations of deep somatic tissues may be as important as cutaneous innervations as a determinant of the sympatho-afferent coupling that occurs particularly in the acute phase of CRPS.

Inflammatory Mediators

As outlined earlier, elaboration of inflammatory mechanisms may be responsible for the peripheral changes seen in the acute phase of CRPS. This may occur either through the classic cascade of release of proinflammatory cytokines (interleukin-1β, IL-2, IL-6, and tumor necrosis factor-α) from mast cells and lymphocytes following tissue trauma or secondary to neurogenic inflammation causing the release of cytokines and neuropeptides (including substance P and calcitonin gene–related peptide [CGRP]). The neuropeptides can increase tissue permeability and cause vasodilatation, giving rise to the “warm CRPS” with edema. Substance P and TNF-α can engender osteoclastic activity, which may contribute to the osteoporosis seen in CRPS. In addition, CGRP can cause an increase in hair growth and sudomotor activity observed in CRPS patients.

Cortical Reorganization

In recent years, imaging studies, such as functional MRI (fMRI) and single-photon emission CT (SPECT), and mapping techniques based on electroencephalography (EEG) and magnetoencephalography (MEG) have indicated an important role of the central nervous system (CNS) in the pathogenesis of CRPS (see Schwenkreis et al. and Bailey et al. for reviews). Cortical reorganization in central somatosensory and motor networks that may result in altered central processing of tactile and nociceptive stimuli and cerebral organization of movement have been reported. For example, Maihofner et al. observed increased strength of magnetic fields and reduced distance between thumb and little finger representation in contralateral S1 cortex after tactile stimulation of the affected hand. Moreover, they observed a shift of the cortical S1 representation of the affected hand toward the lip representation and reported a correlation between the amount of cortical reorganization and the intensity of CRPS pain and the extent of mechanical hyperalgesia. In a follow-up study in the same group of patients a year or more after therapy, Maihofner et al. found a reversal of cortical reorganization with clinical improvement, suggesting a relationship between S1 reorganization and chronic pain. The changes in cortical representations may explain not only the pain, but also a number of the other clinical features occurring in the course of the disease. Neurorehabilitative strategies that are targeted at restoring this impaired sensorimotor function, using strategies such as mirror therapies, are being investigated.

Clinical Features

Since the publication of the diagnostic criteria for CRPS by IASP in 1994 (see Table 27.1 ), major strides have been made to further refine the diagnostic criteria based on internal and external validation studies. This culminated in the Budapest Consensus in 2007 in which the diagnostic criteria was refined to include stricter criteria for clinical diagnosis and research studies. The inclusion of “motor and trophic signs and symptoms” in addition to separating vasomotor signs and symptoms from sudomotor category improved specificity without losing sensitivity ( Tables 27.2 and 27.3 ).

TABLE 27.2

Proposed Clinical Diagnostic Criteria for CRPS

General definition of the syndrome: CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is 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:

  • 1.

    Continuing pain, which is disproportionate to any inciting event

  • 2.

    Must report at least one symptom in three of the four following categories:

    • Sensory: Reports of hyperesthesia and/or allodynia

    • Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry

    • Sudomotor/edema: Evidence 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, nail, skin)

  • 3.

    Must display at least one sign at time of evaluation in two or more of the following categories:

    • 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 (<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, nail, skin)

  • 4.

    There is no other diagnosis that better explains the signs and symptoms

Note: For research purposes, diagnostic decision rule should be at least one symptom in all four symptom categories and at least one sign (observed at evaluation) in two or more sign categories.

TABLE 27.3

Summary of Decision Rules

Source: Harden N, Bruehl S, Stanton-Hicks M, et al: Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med . 8:326-331, 2007.

Criteria/Decision Rule for Proposed Criteria Sensitivity Specificity
2+ sign categories and 2+ symptom categories 0.94 0.36
2+ sign categories and 3+ symptom categories 0.85 0.69
2+ sign categories and 4+ symptom categories 0.70 0.94
3+ sign categories and 2+ symptom categories 0.76 0.81
3+ sign categories and 3+ symptom categories 0.70 0.83
3+ sign categories and 4+ symptom categories 0.86 0.75

The difference between CRPS 1 and 2 is the presence of a definable nerve injury (in CRPS 2 only). The signs and symptoms of both conditions are clinically indistinguishable and include sensory changes, edema, and vasomotor and sudomotor abnormalities. Pain is the key feature for both CRPS 1 and 2 with up to 81% of patients meeting the criteria for CRPS having pain. With CRPS 1, the pain and associated clinical signs and symptoms are typically out of proportion to the inciting event. The pain is typically described as a burning, deep-seated ache with a shooting quality and associated allodynia or hyperalgesia. Symptoms indicative of vasomotor abnormalities occurs in 86.9%, and sudomotor changes including hyperhidrosis/hypohidrosis occur in 52.9% of patients with CRPS. Kinesiophobia and motor weakness have been reported in 74.6% and edema in 79.7%.


The diagnostic criteria for CRPS types 1 and 2 continue to be based on the patient’s symptoms and signs (see Table 27.2 ). The current revised diagnostic criteria were developed to enhance the specificity and sensitivity of the previous diagnostic criteria. Studies on the external and internal validation of the IASP criteria suggest that patients should demonstrate at least one symptom in each of the following categories: sensory (hyperesthesia—increased sensitivity to sensory stimulation), vasomotor changes (temperature abnormalities, including skin and color changes), sudomotor (fluid retention—sweating abnormalities, edema), or motor (decreased range of motion, weakness, tremor, dyskinesia, or neglect). In addition, signs in at least two of the four categories indicated above should be noted on physical examination of the patient. A complete history and physical examination, including a through neurologic and vascular examination, will help differentiate from more common conditions that may mimic CRPS. These include neurologic conditions such as painful diabetic neuropathy, entrapment syndromes, discogenic disease, and thoracic outlet syndrome. In addition, vascular conditions should be considered as possible causes in the differential diagnosis, including deep venous thrombosis, cellulitis, vascular insufficiency, lymphedema, and erythromelalgia.

Currently, there is no diagnostic test considered to be a gold standard or objective test that is specific for CRPS. The following tests have been found to help make the diagnosis even though a negative result may not necessarily rule out the possibility of CRPS.

Quantitative Sensory Testing

This involves the use of standardized psychophysical tests of thermal, thermal pain, and vibratory thresholds to assess the function of large fiber, myelinated small fiber, and unmyelinated small afferent fibers. Static and dynamic allodynia, allodynia associated with pinprick, hyperalgesia related to mechanical and heat stimuli, and temporal summation (increased pain to repeated stimuli) may be abnormal in patients with CRPS. Since no specific sensory pattern has been recognized with CRPS, assessment of the signs and changes over time may provide a tool to track response to treatment.

Autonomic Function Tests

This includes infrared thermometry and thermography, quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test (TST), and laser Doppler flowmetry. The limitation of these tests is that most require special equipment and a setup that make clinical applications less viable. In addition, the specificity of abnormalities in these tests in the diagnosis of CRPS or their role as predictors of treatment success is unclear.

Temperature Measurement

The use of infrared thermometry and infrared thermography to assess small skin temperature differences between the sides of the body is reported to achieve sensitivity in the order of 76% and specificity of 100%. The utility of this test clinically is dependent on maintaining controlled thermoregulation during measurements. This is difficult to achieve in most clinical situations. Therefore the measurements should be made under conditions where thermoregulation can be controlled to detect differences on both sides for enhanced accuracy of the test. The direction of the temperature difference is dependent on the duration of the disease. Earlier in the disease process the affected limb may demonstrate elevated temperatures, while later on in the more chronic phase of the disease the affected side may show lower temperature compared to the unaffected side.

Vascular Abnormalities

In patients with the disease of less than 4 months’ duration, vascular reflex responses may be assessed using Doppler flowmetry. The affected extremity may demonstrate higher perfusion. In patients with duration of disease less than 15 months, skin perfusion was found to be either higher or lower, while in patients with a mean duration of 28 months the affected limb demonstrated a lower perfusion and ultimately lower temperatures.

Trophic Changes

The value of a three-phase bone scintigraphy is in the ability to detect pathologic delayed uptake in the distal bones, such as metacarpophalangeal or metacarpal bones. This is thought to be highly sensitive, although the specificity for CRPS has been questioned. X-ray bone densitometry has also been reported to have a high sensitivity and specificity for CRPS. The ease with which these tests may be performed in clinical practice increases its potential usefulness. Most of these changes have been reported to occur within the first year of the disease.

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Sep 21, 2019 | Posted by in PAIN MEDICINE | Comments Off on Complex Regional Pain Syndrome
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