Complex Regional Pain Syndromes 

Updated: Jun 20, 2018
Author: Gaurav Gupta, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

Background

In 1994, a consensus group of pain medicine experts gathered by the International Association for the Study of Pain (IASP) agreed on diagnostic criteria for reflex sympathetic dystrophy (RSD) and causalgia, and renamed them complex regional pain syndrome (CRPS) types I and II, respectively. These designations were determined by the type of inciting event, rather than by any differences in clinical presentation or pathophysiology. Many experts felt that the IASP diagnostic criteria were ambiguous; however, these criteria were developed as just a starting point, and the IASP fully intended to validate them through clinical research studies.[1]

CRPS type I requirements feature causation by an initiating noxious event, such as a crush or soft tissue injury; or by immobilization, such as a tight cast or frozen shoulder. CRPS type II is characterized by the presence of a defined nerve injury. Both types demonstrate continuing pain, allodynia, or hyperalgesia that is usually disproportionate to the inciting event. At some point during the syndrome's development, both show evidence of edema, changes in skin blood flow revealed by color changes and skin temperature changes greater than 1.1°C from the homologous body part, or abnormal sudomotor activity in the painful region. Both types require the exclusion of any other condition that might account for the degree of pain and dysfunction seen.[2]

The 1994 IASP criteria have proven to be extremely sensitive (ie, they rarely miss a true case of CRPS). However, since their inception, the 1994 taxonomy has been criticized by experts on clinical criteria validation and specialists in pain medicine on the grounds that the criteria are insufficiently specific (ie, use of the criteria results in overdiagnosis of CRPS). A small single center validation study demonstrated empirically that the 1994 CRPS criteria did indeed cause overdiagnosis of the syndrome.[2]

In response to such concerns, investigators used factor analysis to categorize 123 patients with CRPS into 4 statistically distinct subgroups.[3] This resulted in modified diagnostic criteria felt to be valuable for further validation studies.[3, 4]

In 2003, a closed workshop was held in Budapest, Hungary to study and resolve this matter. Experts in CRPS published the results of this workshop in a 2007 review article[5] showing that the modified criteria, mentioned above, produced better discrimination between CRPS and non-CRPS neuropathic pain, yielding better diagnostic accuracy than the original unmodified criteria.[5]

The study results indicated that when 2 of 4 sign categories were present and 3 of 4 symptom categories were present, the resultant sensitivity was 0.85 and the specificity was 0.69 for a clinical diagnosis of CRPS. This appeared to be a good compromise between identifying as many patients as possible in the clinical context and substantially reducing the high level of false-positive diagnoses associated with the 1994 IASP criteria. However, a higher specificity is required to meet research criteria, so the committee recommended that 2 of the 4 sign categories and all 4 symptom categories must be positive for the diagnosis to be made in a research setting, resulting in a sensitivity of 0.70 and specificity of 0.94.

Due to the combination of increased specificity and reduced sensitivity, about 15% of patients previously diagnosed with CRPS were considered "without a diagnosis." Therefore, a third diagnostic subtype, complex regional pain syndrome not otherwise specified (CRPS-NOS), was recommended to categorize those patients.[6] These new IASP diagnostic criteria have been submitted to the medical committee for Classification of Chronic Pain of the IASP for future revision of formal taxonomy and diagnostic criteria. 

The criteria are given here in hopes that higher specificity for the identification of CRPS will enhance research into the pathoetiology of this disorder without creating a reduced, or even harmful, rate of clinical diagnosis that could deny affected patients access to treatment. In addition, these criteria may result in more cost-effective approaches for the management of this disorder.[5, 7, 6]  These criteria, as listed below, are given in the most current version of the IASP's Complex regional pain syndrome: practical diagnostic and treatment guidelines (4th edition)[8]  where they are described as "state of the art" diagnostic criteria and "practical" guidelines. 

IASP-proposed revised CRPS clinical diagnostic criteria

A clinical diagnosis of CRPS can be made when the following criteria are met:

  • Continuing pain that is disproportionate to any inciting event

  • At least 1 symptom reported in at least 3 of the following categories:

    • Sensory: Hyperesthesia or allodynia

    • Vasomotor: Temperature asymmetry, skin color changes, skin color asymmetry

    • Sudomotor/edema: Edema, sweating changes, or sweating asymmetry

    • Motor/trophic: Decreased range of motion, motor dysfunction (eg, weakness, tremor, dystonia), or trophic changes (eg, hair, nail, skin)

  • At least 1 sign at time of evaluation in at least 2 of the following categories:

    • Sensory: Evidence of hyperalgesia (to pinprick), allodynia (to light touch, temperature sensation, deep somatic pressure, or joint movement)

    • Vasomotor: Evidence of temperature asymmetry (>1°C), skin color changes or asymmetry

    • Sudomotor/edema: Evidence of edema, sweating changes, or sweating asymmetry

    • Motor/trophic: Evidence of decreased range of motion, motor dysfunction (eg, weakness, tremor, dystonia), or trophic changes (eg, hair, nail, skin)

  • No other diagnosis better explaining the signs and symptoms

In addition, a slightly modified version of the above listing is used for CRPS research (as opposed to clinical) criteria. For these rules one must have the CRPS characteristics present in all four of the symptom categories and in at least two out of the four sign categories.

Pathophysiology

Hypothetical mechanisms

In most cases, experts believe that CRPS develops when persistent noxious stimuli from an injured body region leads to peripheral and central sensitization, whereby primary afferent nociceptive mechanisms demonstrate abnormally heightened sensation, including spontaneous pain and hyperalgesia. Allodynia and hyperalgesia occur when central nervous system (CNS) somatosensory processing misinterprets normal nonpainful mechanical stimuli, such as light touching of the skin, as painful. Therefore, skin in the injured area becomes more sensitive to all stimuli, even nonpainful stimuli. In addition, the sensitization can extend beyond the originally injured area, thus enlarging the region of aberrant pain perception.

A similar impairment of CNS processing leads to motor aberrancies, such as weakness or tremor in the affected area. The peripheral and central sensitization associated with impaired CNS processing is linked to proposed disturbances within the sympathetic nervous system (SNS) that lead to sympathetic hyperactivity adversely affecting the injured area. Studies suggest that an augmented inflammatory response coupled with impaired healing further contribute to the refractory nature of malevolent CRPS.[9, 1, 10, 11, 12, 13]

Peripheral and central sensitization

Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order interspinal synapses.[9, 1, 10, 11, 12]

Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold, polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged, enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP, algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes. Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the endings of nociceptive afferents where they can instigate ortho- and retrograde actions including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.

Chronic CNS sensitization is engendered through afferent processing by second-order nociceptor-specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord. WDR neurons contribute more to sensitivity than nociceptor-specific neurons, because both nociceptive and non-nociceptive afferents converge to synapse on a single WDR neuron, and WDR neurons respond with equal intensity regardless of whether the neural signal is noxious (hyperalgesia) or not.

Hyperalgesia and allodynia initially develop at the injury site. However, after CNS sensitization occurs through WDR neural activity, the area of pain expands beyond the initial region of tissue pathology. The peripheral changes described eventually cause an injury environment, where primary afferents, including nociceptors, demonstrate an increased sensitivity to circulating or experimentally injected subcutaneous norepinephrine.[14, 1, 10, 11, 12, 15, 16, 17, 18, 19, 20]

In addition to functional CNS sensitization, recent investigations have explored the possibility that the brain of those with CRPS may differ structurally from brains of those without CRPS. Studies of small numbers of patients from various authors suggest that patients with CRPS may have, for example, diminished thickness of the prefrontal cortex[21]  or diminished gray matter volume in certain regions related to pain perception but greater gray matter volume in other regions.[22]  Another group found evidence that the choroid plexus is enlarged in CRPS.[23]   More recently, van Velzen et al. studied 19 of their own patients and conducted a review of the existing literature. They failed to find any specific differences in the structure of function of the brain in CRPS patients and they also concluded that prior results in the literature were inconsistent with regard to the location and amount of the supposed changes as well as in the direction of the changes.[24] At present, the idea that structural brain changes may underly CRPS remains intriguing but inconclusive.

Sympathetically maintained pain (SMP)

For decades, CRPS was thought to be caused by SNS hyperactivity, and the pain experienced by those who suffer from CRPS was believed to be SMP. SNS involvement in CRPS is supported clinically by the presence of abnormal patterns in skin temperature, skin color, and sweating in the affected extremities. Surgical and chemical sympathectomy can relieve pain in some cases. However, under normal physiological circumstances, there is no interaction between the sympathetic and peripheral afferent nociceptive neurons.[14, 1, 25, 26, 27] Furthermore, multiple discrepancies undermine the possibility of SNS involvement. These discrepancies include the following: (1) plasma catecholamine concentrations are lower in CRPS-affected limbs[28, 29] , (2) most CRPS patients do not obtain significant or lasting pain relief from sympathetic blocks[30, 31] , and (3) skin temperature does not correlate with the activity of sympathetic vasoconstrictor neurons.[32]

To explain these incongruities, the pathophysiology of SMP was hypothesized to involve an abnormal coupling between sympathetic efferent and nociceptive afferent neurons.[33] Two possible conditions may lead to pathological coupling: interactions between sympathetic efferents and intact or regenerating peripheral nociceptive C-fiber neurons, or between sympathetic vasoconstrictor neurons and afferent somata within the dorsal root ganglion (DRG).[34]

This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury.[35] Therefore, an increased number of targeted and functionally upregulated adrenoreceptors on lesioned nociceptive afferents, which has been demonstrated, would explain how reduced SNS activity in CRPS is capable of maintaining pain.[26, 1]

Evidence suggests that early autonomic symptoms and signs of CRPS are indicative of CNS dysfunction.[36] Wasner et al suggest that warmth of the affected extremity in the early stages of CRPS I is caused by the functional inhibition of central cutaneous vasoconstrictor activity, leading to cutaneous vasodilation.[27] However, over time, this inhibition may lead to adrenergic hypersensitivity from peripheral denervation and/or sympathetic denervation.

Thus, in CRPS I, the early inhibition of central cutaneous vasoconstrictor activity leads to vasodilation in the denervated area causing it to feel warm. The later increased sensitivity to circulating catecholamines due to upregulation of cutaneous adrenoreceptors causes vasoconstriction and coolness. Interestingly, studies of direct nerve injuries (CRPS II) show the same results. Initially, vasodilation is present within the denervated area, causing the skin adjacent and on the same side to become abnormally warm at first and then change to a chronically cold status. Other mechanisms include an increased density of cutaneous α-adrenoreceptors and a pathological upregulation of α-adrenergic receptors.[14, 1, 31, 25, 33, 34, 35, 36, 27]

Based on recent clinical studies, patients with neuropathic pain presenting with similar clinical signs and symptoms can be clearly divided into 2 groups by the positive and negative effects of selective sympathetic blockade, selective activation of sympathetic activity, and antagonism of α-adrenergic receptor mechanisms.[37] Pain relieved by sympatholytic procedures is considered to be SMP. SMP is now defined as a symptom or underlying mechanism in a subset of patients with neuropathic disorders. CRPS is one such neuropathic disorder. However, SMP is not a clinical entity per se. Nor is it a sine qua non for CRPS as was previously believed. Thus, the positive effect of sympathetic blockade is not essential for the diagnosis of CRPS. On the other hand, the only way to differentiate between SMP and sympathetically independent pain (SIP) is to test the efficacy of a correctly applied sympatholytic intervention.[38]

Sensory and motor dysfunction

In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia.[39] Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. These abnormal patterns are due to altered central afferent processing and have been delineated with functional imaging studies.[40, 41, 42]

Likewise, the evidence to date supports the presence of similar mechanisms involving abnormalities of CNS motor processing (rather than pain, edema, disuse, trophic changes, or nerve injury) that are responsible for causing impairments of muscle strength in the involved distal extremity. Kinematic analysis studies suggest that motor deficits are probably due to impaired integration of visual and sensory afferent input within the parietal cortex.[43] Also, an increased amplitude of physiological tremor due to CNS mechanisms is common, occurring in about 50% of patients under observation.[44]

CRPS can also be linked to structural and functional changes in the brain cortex related to sensory and motor function. Patients with early-onset CRPS demonstrate decreased cerebral perfusion and grey matter volume in the somatosensory cortex. Patients with late-onset disease demonstrate decreased cerebral perfusion in the motor cortex.[45] These findings indicate CRPS has effects on higher level motor and sensory processing in the CNS.

Aberrant healing and exaggerated inflammation

After tissue injury, the body's response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.

At the site of injury, peripheral C-fiber nociceptors transmit pain messages that cause ortho- and retrograde release of SP and CGRP into the damaged tissues, resulting in vasodilation, extravasation of pronociceptive mediators, reactivation and further sensitization of C-fiber afferents, and increased tissue comorbidity in the injured area.[14, 10] These neuropeptides prompt the physical signs of inflammation, including redness, warmth, and swelling, that are also commonly present in early CRPS. Also, algogenic substances are released, which increase nociception and initiate the process of peripheral sensitization previously discussed. Skin sensitivity and tenderness spread into adjacent regions, which are thought to be caused by secondary hyperalgesia from CNS alterations that are consistent with the described sensitization process.

Protective disuse

Decreased use of an injured body part would appear to be a normal postinjury reaction. After injury, the organism protects and guards the injured body part to optimize healing and prevent reinjury. A normally healing organism gradually increases its use of the injured region, which aids in recovery and reintegration of the body part into the organism’s normal sense of self. However, excessive protection and guarding, such as casting or splinting, is commonly promoted by care providers, increasing the patient’s disuse of the extremity and promoting fear-avoidance, which may progress into a neurological neglect-like syndrome.

This phenomenon has been postulated as a cause in some patients with CRPS.[44] Many of the symptoms and signs of CRPS are consistent with those that would naturally develop from lack of use. For example, an unused dependent limb eventually develops swelling (dependent edema), coolness (decreased blood flow), and trophic changes (decreased blood flow).[14, 1, 46]

Epidemiology

Frequency

A population-based study by Sandroni et al showed an incidence of approximately 5.5 per 100,000 person-years at risk and a prevalence of about 21 per 100,000 for CRPS type I.[47] The same study showed an incidence of 0.8 per 100,000 and a prevalence of about 4 per 100,000 for CRPS type II.[47, 14] Therefore, the incidence of CRPS type I is higher than that of CRPS type II.[47, 14] The reported incidence of CRPS type I is 1-2% after various fractures[14] , while that of CRPS type II approximates 1-5% after peripheral nerve injury[14, 48] . The incidence of CRPS is 12% after a brain injury[49] and 5% after a myocardial infarction[50] .

A study from the Netherlands showed a total incidence of CRPS of approximately four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA.[51] The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years with females affected at least three times more often than males. The highest incidence occurred in females aged 61-70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%).[51]

Mortality/Morbidity

Despite treatment, many patients are left with varying degrees of chronic pain, trophic changes, and disability. Pain is the most important factor leading to disability. Some have suggested that the aggressive treatment of pain in an acute setting could reduce the incidence of CRPS type I; however, further studies are needed to support this contention. Remissions followed by relapses have also been described. The frequency of the HLA-DQ1 antigen appears to be higher in patients with CRPS than in controls, and HLA-DR13 is associated with progression towards multifocal or generalized dystonia.[52, 53] Recently, a new HLA I locus was detected that may predict the spontaneous onset of CRPS.[54]

Race-, sex-, and age-related demographics

CRPS affects all races; no differences in incidence or prevalence have been observed.

Females experience CRPS more commonly than males do by a ratio that varies from 2:1 to 4:1.[14, 55, 47, 56, 57, 4, 58]

CRPS is distributed across age groups, but reaches its peak incidence between 37 and 50 years.[14, 55, 47, 56, 57, 4, 58] CRPS has an increased incidence in adolescents, compared with children, with females affected more frequently at a ratio of 4:1 and increased occurrence in the lower extremities rather than the upper by a ratio of 5.3:1. The mean age of onset is 12.5 years in a cohort of 396 children. The highest incidence of the disease appears to be in adults aged 40-49 years. CRPS appears frequently in almost every age group except children. CRPS type I has been seen in children, but the incidence is much lower than in adults.

 

Presentation

History

No specific diagnostic tests identify the presence of CRPS and no objective guidelines verify its existence. The current criteria for diagnosing CRPS are based mainly on physical examinations and a careful analysis of patient history.

Often, symptoms of CRPS type I begin immediately, days, or weeks after an injury, usually in a distal extremity. Rarely, the onset can be months after the injury. Usually, only one limb is involved, but in a few cases, the involvement is bilateral (4-5%), and even more rarely, 3 or 4 extremities are affected. CRPS type I can be acute (lasting < 2 months) or chronic (>2 months). Approximately half of patients with CRPS type I report it to be related to an on-the-job injury.

Clinical features of CRPS type I are influenced by the following:

  • Duration: As many as 80% of patients with the initial symptoms of CRPS type I are cured within 18 months from its onset, either spontaneously or with treatment. A longer duration of CRPS is related to a significantly greater likelihood of abnormalities of sensation and less of sweating abnormalities or edema.

  • Location: Pain and other symptoms can be located anywhere in the body. The extremities are involved most often, although other locations such as external genitalia or the nose may also be involved. Patients may have pain at the ulnar styloid process after a Colles fracture or at the lateral malleolus after a sprain. Frozen shoulder and/or tendinitis of the biceps often accompany CRPS type I in the hand.

Symptoms of CRPS type I include the following:

  • Spontaneous pain: Pain that is not limited to the territory of a single peripheral nerve is the cardinal feature of CRPS. The pain's character can be burning (occurring most often), aching, throbbing, or tingling. The pain is aggravated by activity of the affected extremity, and its severity is typically disproportionate to the inciting event.

  • Difficulty/inability in using the affected extremity

  • Neglect-like symptoms: These include cognitive neglect, in which the limb may feel foreign, and motor neglect, in which directed mental and visual attention are needed to move the limb.

  • Altered skin temperature: This is often noted as a difference in skin temperature between affected and unaffected limbs. At onset, the affected extremity is warmer in two thirds of cases and colder in one-third. Many patients report a history of warmer extremities at onset and colder extremities later in the evolution of the disease. Some authors distinguish between primarily cold reflex sympathetic dystrophy and primarily warm reflex sympathetic dystrophy.

  • Rapid fatigability: This is almost invariably present in the later stages.

Physical

Physical symptoms/characteristics of CRPS may include the following:

  • Some impairment of motor function is present in about 80-90% of patients at some point in the disease and consists of paresis, pseudoparalysis, or clumsiness.

  • Range of motion is often limited secondary to motor deficit and/or pain. Tremor of the affected limb is present in about half of patients in the later stages.

  • Dystonia of the affected foot or hand is described in 10% of patients in the later stages.

  • Muscle spasms are present in 25% of patients who have longer-duration CRPS type I.

  • Hypoesthesia is described in about 70% of patients and is most often present in a glovelike or stockinglike distribution. Hemihypoesthesia has also been described; hypothermesthesia and loss of proprioception are described in some cases.

  • Anesthesia dolorosa is sometimes present; this is when an area has lost its sensitivity to touch at the same time that severe pain is present.

  • Allodynia (ie, pain to touch) is described in 70-80% of patients.

  • Hyperpathia (ie, an exaggerated response to painful stimuli) is also present in 70-80% of patients.

  • Abnormal sweating is a sign of autonomic dysfunction. About half of the patients have hyperhidrosis.

  • Edema is secondary to autonomic dysfunction. Sometimes, persistent edema is caused by infection of the atrophied soft tissues.

  • Altered skin color is related to vasomotor changes. Skin discoloration and atrophy may occur later. Brown-gray, scaly pigmentation of the skin on the affected limb is described in some studies.

  • Atrophy of the soft tissues, muscles, and bones can also occur. These trophic changes are not included in the IASP diagnostic criteria because their pathophysiology is unknown thus far, so they might result from simple disuse of the affected extremity.

  • Altered skin temperature reflects vasomotor instability and leads to primarily cold CRPS, primarily warm CRPS, or secondarily cold CRPS. At the time of assessment by a physician, approximately 5-10% do not have a significant difference in skin temperature, about 40-45% have a warmer affected extremity, and 40-45% have a colder affected extremity.

  • Hypotrichosis is often noticed in the affected area. Other times, hypertrichosis is present, and it is considered a sign of sympathetic dysfunction. However, both are irrelevant for establishing the diagnosis.

  • Altered nail growth is also a sign of sympathetic dysfunction; however, it is not reliable for diagnostic purposes.

Causes

Most often, CRPS type I is initiated by trauma to an extremity. Such injuries account for more than 90% of patients with CRPS type I.

  • Injuries precipitating the development of CRPS, in order of decreasing frequency, are as follows: (1) sprain/strain, (2) surgical wounds, (3) fractures, (4) contusion/crush injury, and (5) rarely, other injuries such as venipuncture, lacerations, burns, inflammatory processes, electric shock, and spinal cord injuries.

  • Spontaneous cases/unknown causes account for approximately 5% of patients and may be explained by minor injuries that have been forgotten.

  • Unusual, disputed precipitating events include visceral lesions, CNS lesions (eg, strokes, tumors, brain injury, amyotrophic lateral sclerosis, meningitis, syringomyelia), peripheral vascular bypass procedures, arteriovenous grafts for hemodialysis, carpal tunnel surgery, and spinal cord injury.

 

DDx

Diagnostic Considerations

Differential Diagnosis

The risk of overdiagnosing CRPS must be taken into account. A detailed history and physical examination, as well as the aforementioned specifications, including testing, are necessary to differentiate CRPS from other neuropathic and pain syndromes.

Neuropathy (eg, diabetic polyneuropathy) may also present with spontaneous pain, skin color changes, and motor deficit that are distinguished from CRPS by the patient’s history and their symmetrical distribution. Furthermore, all kinds of inflammatory, rheumatological, and infectious conditions might induce intense unilateral skin warming. Unilateral arterial or venous occlusive diseases can cause unilateral pain and vascular abnormalities, and therefore must be excluded when diagnosing CRPS. The repetitive artificial occlusion of blood supply to one limb can be seen in psychiatric, factitious disorders when individuals induce secondary structural changes in the blood vessels and cause abnormalities in perfusion that mimic the symptoms and signs of CRPS.

Posttraumatic neuralgia

Many patients with posttraumatic neuropathy have pain but not the full clinical profile of CRPS type II. In these cases, pain is located largely within the territory of the injured nerve, which contrasts with patients with CRPS type II. Although patients with neuropathy often describe the pain as burning, they exhibit a less complex clinical picture than patients with CRPS type II and do not show marked swelling or the progressive spread of symptoms.

The principal symptoms for posttraumatic neuropathy are spontaneous burning pain, hyperalgesia, and mechanical allodynia. These sensory symptoms are confined to the territory of the affected peripheral nerve, although the allodynia may extend beyond the nerve territory's border by some centimeters. Both spontaneous and evoked pain is felt superficially, not deep inside the extremity, and the intensity of both is independent of the position of the extremity.

Patients with posttraumatic neuropathy usually obtain relief with sympatholytic procedures, although much less often than patients with CRPS. Following the IASP classification, it is possible to choose the term posttraumatic neuralgia for this type of neuropathic pain (pain within the territory of the lesioned nerve). However, the new definition of CRPS type II also includes the statement that symptoms can be limited to the territory of a single peripheral nerve. Therefore, the term CRPS type II could be applied to these localized posttraumatic neuropathies, even though they are different syndromes with different underlying mechanisms, which highlights the problems with this definition of CRPS II.

Diagnostic considerations

  • CNS

    • Brain (stroke, neoplasm, encephalitis)

    • Spinal cord (trauma, transverse myelitis, either structural or tumor-related syringomyelia)

    • Tabies dorsalis

    • Multiple sclerosis

    • Poliomyelitis

  • Radiculopathy

    • Structural (eg, due to structural impingement of a diskal, osteophyte-, or tumor-related nature)

    • Metabolic (eg, diabetes, vasculitis infectious)

    • Neoplastic

  • Plexopathy

    • Infectious

    • Autoimmune/idiopathic

    • Tumor (primary or secondary neoplasm), especially Pancoast syndrome

    • Trauma (macro or cumulative)

    • Entrapment (thoracic outlet syndrome)

  • Neuropathy

    • Focal

      • Diabetes

      • Inflammatory or infectious (Lyme), sarcoid

      • Posttraumatic

      • Entrapment (eg, carpal tunnel, cubital tunnel)

      • Toxic

      • Neoplastic (neuroma)

    • Multifocal (mononeuritis multiplex)

      • Diabetes

      • Vasculitis

      • Infectious

      • Toxic

    • Bilateral or diffuse

      • Diabetes

      • Alcohol

      • Nutritional

      • Guillain Barre syndrome or chronic inflammatory demyelinating polyneuropathy

      • Porphyria

  • Vascular disorders

    • Raynaud phenomena

    • Peripheral atherosclerotic disease

    • Arterial insufficiency

    • Phlebothrombosis

  • Monomelic amyotrophy

  • Psychological

    • Hysteria

    • Somatoform disorder, including malingering

  • Movement disorders

  • Metabolic or systemic (eg, renal failure, amyloidosis)

  • Autoimmune or rheumatological disorder

  • Infectious (eg, viral, fungal, Lyme) Iatrogenic (eg, prescribed medication)

  • Demyelinating (CIDP, paresis or sensory deficiency due to multiple sclerosis)

  • Toxic exposure (eg, vinca alkaloids, heavy metals)

 

Workup

Laboratory Studies

No specific diagnostic tests confirm the presence of CRPS. However, the differential diagnosis includes other neuropathic conditions, as well as a host of metabolic, systemic, vascular, and rheumatological disorders. Excluding other treatable but serious causes is indicated even in cases that present with the classic signs and symptoms.

  • Blood work for inflammatory arthropathy and vasculitis is indicated, which, in its basic form, includes complete blood count (CBC), erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, complement fixation panel, serum immunoelectrophoresis, and a bone scan. Workup for diabetes should also include a test for hemoglobin A1c.

  • Electromyography (EMG) and nerve conduction studies are helpful in determining the neuroanatomy behind the symptoms and therefore in identifying the etiological process. For example, they confirm the presence of nerve injury, CRPS type II, nerve root avulsion, or a painful neuropathy due to diabetes, which may present with autonomic dysfunction.

  • Vascular studies of the affected limb(s) should also be considered.

Imaging Studies

Osseous changes are common in CRPS; therefore, most standard diagnostic test results used to support or refute clinical evidence for this diagnosis demonstrate changes, or a lack thereof, in the bones and joints.

Radiography

In the chronic stages of CRPS, plain radiographs may reveal endosteal and intracortical excavation, resorption of subperiosteal and trabecular bone, localized bone demineralization, and/or osteoporosis.[59]

Bone scintigraphy

See the list below:

  • Compared with radiography, 3-phase bone scintigraphy has higher sensitivity (97% vs 73%) and specificity (86% vs 57%) in early postfracture CRPS.[60]

  • 3-phase bone scintigraphy can provide valuable information during the first year and is useful in differentiating CRPS from other pain syndromes.[61] Homogeneous unilateral hypoperfusion in the perfusion and blood-pool phases is considered characteristic of CRPS and repudiates osteoporosis due to inactivity. These 2 initial phases are seen at 30 seconds and 2 minutes postinjection, respectively. At 3 hours postinjection, the mineralization phase shows increased unilateral periarticular uptake. This pathological uptake is thought to be highly sensitive and specific to CRPS.[60, 62] On the other hand, scintigraphy only shows significant changes during the first year. Additionally, this test is less valuable in children than in adults due to its higher variability.[63]

Magnetic resonance imaging (MRI)

MRI scans have demonstrated changes in joints (joint effusion) and soft tissues with CRPS with high sensitivity but less specificity.[64]

Other Tests

Quantitative sensory testing

Bedside testing for allodynia and hyperalgesia is important to remove subjectivity from the sensory portion of the examination when confirming the diagnosis of CRPS. Detailed sensory testing can document impairment of warm and cold sensations; heat pain; static, dynamic, and pinprick allodynia; heat and mechanical hyperalgesia; and temporal summation.[65, 66]

Autonomic function testing (AFT)

AFT includes infrared thermometry, infrared thermography, quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test (TST), and laser Doppler flowmetry. Skin temperature differences can be easily assessed by infrared thermometry or thermography.[67] Currently, a characteristic sensory pattern has not been identified. Such a pattern would allow clinicians to determine the presence of CRPS and quantify the individual signs of each patient so that responses to successful treatments can be measured and documented. Caution is necessary with AFT since autonomic differences are dependent on environmental conditions that can alter pertinent test dynamics within minutes. Therefore, measurements should be repeated at the beginning, middle, and end of a patient visit.

In a study of 21 patients with CRPS, enhanced sudomotor output was demonstrated with QSART and TST in the affected limb compared with the contralateral limb within the mean disease duration of 5 weeks.[68] At a mean duration of 94 weeks, TST findings remained abnormal, whereas QSART showed no differences from healthy subjects.

In a study using laser Doppler flowmetry to assess vascular reflex responses, 3 different vascular regulation patterns were demonstrated in CRPS type I. With short-term CRPS (ie, with a mean duration of 4 mo), the affected limb showed higher perfusion than the contralateral limb. In patients with a mean CRPS duration of 15 months, the affected limb showed either higher or lower skin perfusion than the contralateral limb. Finally, in patients with a mean CRPS duration of greater than 20 months, the affected limb showed lower perfusion of the skin. Skin temperature changed correspondingly for each pattern.[27]

Neurogenic inflammation

In the fluid of artificially produced blisters, significantly higher levels of proinflammatory mediators and vasoactive substances, such as interleukin-6, tumor necrosis factor-alpha, tryptase, and endothelin-1, were observed in the affected extremities of patients with CRPS type I compared to the uninvolved extremities. Also, nitrate/nitrite levels have been shown to be reduced.[69, 70, 71] Findings such as these may lead to diagnostic tools in the future. However, a direct relationship between the signs and symptoms of CRPS type I and these proinflammatory mediators cannot be assumed because these findings are still in evidence after the CRPS improves.[72]

Skin biopsies

One hypothesis is that CRPS type I is caused by persistent minimal nerve injury, particularly distal degeneration of the small-diameter axons.[73] This theory was investigated in studies where quantitative mechanical and thermal sensory testing was performed, followed by quantification analysis of epidermal neuritic densities and skin biopsies. Axonal densities were diminished at CRPS-affected sites in 17 of 18 patients by an average of 29%. Control subjects had no painful-site neurite reductions; however, the relationship of these findings to distinct pathophysiological mechanisms remains unclear.[74]

Muscle biopsies

Skeletal muscles in the affected extremities demonstrate (1) a decrease in type 1 fibers, (2) an increase in lipofuscin pigment, (3) atrophic fibers with a slight angular appearance, and (4) severely thickened basal membrane layers in the capillaries.

Peripheral nerve biopsies

In the affected extremities, efferent nerve fibers are unchanged histologically; with afferent fibers, only C fibers have demonstrated histopathological abnormalities, which consist of denervation of the Schwann cell stacks, miniature axon sprouts, and an obvious increase in collagen pockets. C-fiber loss may be noted as well. Sometimes, multiple basal membranes surround the small endoneural vessels.

 

Treatment

Medical Care

Pharmacotherapy

Due to a lack of information on the pathophysiology of CRPS and the similar absence of consistent objective diagnostic criteria, clinical trials that demonstrate effective therapies are difficult to perform. Therefore, only a few evidence-based treatment regimens are currently available. In fact, 4 literature reviews and outcome studies found very little consistent information regarding the pharmacological agents and methods available for the treatment of CRPS.[75, 76, 77]

Corticosteroids

Pulsed doses of steroids (60-80 mg/d for 2 wk) have been reported as beneficial for CRPS in a small, uncontrolled case series.[78] Two small, single blind trials of 10 and 17 patients with early-stage CRPS (within 2-3 mo of injury) also reported clinical improvement after 4 or 12 weeks of oral corticosteroid therapy.[79, 80] No long-term follow-up data were reported in any of these studies.

Clinical experience has shown that the use of corticosteroids in patients with CRPS who have had symptoms for more than 6 months has little efficacy. Also, many patients report the return of their pain and other symptoms after the corticosteroid dose was tapered. However, some experts recommend the use of corticosteroids, especially in the early stages of CRPS. One study demonstrated that orally administered prednisone, 10 mg tid., was effective in improving the entire clinical status (up to 75%) of acute CRPS (< 13 wk).[79] No evidence has been obtained with regard to the efficacy of other immunomodulating therapies in treating CRPS.[59]

Calcium-regulating drugs

Calcitonin administered intranasally tid has been demonstrated to significantly reduce pain in patients with CRPS.[81] Intravenous (IV) clodronate (300 mg daily) and alendronate (either 7.5 mg/d IV or 40 mg/d orally) have been shown to significantly improve pain, swelling, and range of movement in patients with acute CRPS.[82, 83, 84] The mechanism of action of these compounds is unknown.

Opioids

Opioids are effective for the treatment of postoperative inflammatory, cancer-related pain, and many other painful conditions. However, their use for CRPS has not been systematically studied. Thus far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. Even without solid scientific support, though, most experts believe that opioids should be given as part of a comprehensive pain treatment program for CRPS. Opioids should be prescribed immediately if other medications do not provide sufficient analgesia.[59]

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs have not been investigated for the treatment of CRPS; however, mild-to-moderate pain would be a common sense indication.[59]

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)

TCAs have been studied at length for various neuropathic conditions, including diabetic neuropathy and postherpetic neuralgia, but not in CRPS. Serotonin and norepinephrine reuptake inhibitors, such as amitriptyline, and more selective norepinephrine reuptake inhibitors, such as desipramine, have demonstrated benefit in both of the aforementioned neuropathic pain models. Amitriptyline has been shown to be active in central pain and painful posttraumatic neuropathy. Usually, analgesic dosages are lower than those required for antidepressant effects (eg, 75-100 mg/d of amitriptyline with onset of pain relief in about 2 wk and peaking at 4-6 wk). The effectiveness of SSRIs for significantly reducing neuropathic pain has not been demonstrated. No studies have been performed in patients with CRPS.[59]

Sodium channel blocking agents

An IV lidocaine infusion has been shown to be effective in uncontrolled trials for reducing spontaneous and evoked pain with both CRPS types I and II.[85, 86, 87] Mexiletine is not active in central pain and shows poor efficacy in painful diabetic neuropathy. The use of oral mexiletine has not been studied, but clinical experience suggests a benefit for some CRPS patients. Contraindications include side effects that are mainly related to cardiac conduction abnormalities, reduced left ventricular function, and coronary heart disease.[1] The topical 5% lidocaine patch has also been reported to produce clinically significant pain relief under the application site in several patients with CRPS in an uncontrolled series.[88]

Gamma-aminobutyric acid (GABA) agonists

Intrathecally administered baclofen has been shown to be an effective treatment for dystonia and CRPS.[89] No other trials of GABA agonists being used to treat CRPS have been published. No evidence supports baclofen, valproic acid, vigabatrin, or benzodiazepines having an analgesic effect for CRPS or other neuropathic pain conditions.[59]

Gabapentin

Two studies demonstrated promising preliminary evidence for an analgesic effect from gabapentin for patients with CRPS.[90, 91] A randomized, double-blind, placebo-controlled trial showed that gabapentin was mildly beneficial for pain and sensory symptoms in CRPS type I.[92] Gabapentin has been shown to be effective in treating other neuropathic pain conditions, such as diabetic neuropathy and postherpetic neuralgia.[93]

Calcium channel blockers

A small, uncontrolled case series showed improvement in patients with CRPS using the calcium channel blocker nifedipine. No randomized, controlled trials have been performed. The reported clinical experience with these agents has been meager, although the literature describes significant relief in some.[1]

Beta-blockers

Clinical experience is poor; however, benefit was demonstrated in some case reports. A placebo-controlled trial did not demonstrate statistically significant efficacy for the beta-blocker propranolol.[94]

Oral sympatholytic agents

Like sympathetic blocks, oral sympatholytic agents should, in theory, provide symptom and pain relief for patients with CRPS and other neuropathic SMP. However, no randomized, prospective, controlled study has assessed the efficacy of these agents[1] , although case reports and case series have reported benefit from prazosin[95] , phenoxybenzamine[96] , and terazosin.[97] The clinical use of these drugs is frequently fraught with adverse side effects, including orthostatic hypotension and depression.[1]

Clonidine

A small, uncontrolled study of patients with CRPS with SMP reported reduced allodynia from transdermal clonidine, but only in the skin directly under the transdermal patch.[98] Clinical experience has been scant with systemic clonidine, but occasional case reports have shown that some patients achieved significant relief without intolerable side effects.[99, 100] No controlled, long-term, and/or prospective studies designed to assess the efficacy of systemic clonidine have yet been published. However, a new formulation of topical clonidine gel with minimal systemic activity was studied in an open-label, uncontrolled pilot study that decreased allodynia and hyperalgesia in some patients with CRPS.[101]

Interventional Procedures

Therapeutic techniques used to block sympathetic activity include the following:

  • Injections of local anesthetic around the sympathetic paravertebral ganglia that project to the affected body part (sympathetic ganglion blocks).

  • Regional IV applications of guanethidine, bretylium, or reserpine (all of which deplete norepinephrine in the postganglionic axon) to an isolated extremity blocked with a tourniquet (intravenous regional sympatholysis).

Many uncontrolled surveys in the literature examine the effect of sympathetic interventions on CRPS, and approximately 70% of patients report full or partial responses.[102] However, the efficacy of these procedures is still a subject of controversy.[76, 103] In fact, their specificity and long-term results, as well as the techniques themselves, have not been adequately evaluated.

One controlled study in patients with CRPS type I found that sympathetic ganglion blocks using local anesthetic had the same immediate effect on pain as a control injection with saline.[104] However, after 24 hours, patients in the local anesthetic group remained markedly improved relative to the control group, indicating the delayed efficacy of this particular intervention. With this data in mind, the aforementioned uncontrolled studies must be interpreted cautiously.

Most data regarding efficacy must be scrutinized for failing to look at the long-term outcomes of these interventions. A meta‑analysis of studies assessing the effect of local anesthetic sympathetic blockade for the treatment of CRPS showed that the literature was inadequate to draw any conclusions regarding the effectiveness of this procedure, mainly due to small sample sizes and a lack of long-term follow-up.[105]

Selective sympathetic ganglion nerve blocks

Selective sympathetic ganglion nerve blocks, by their nature, present a variety of difficulties to researchers developing preferred methodological practices. First, these procedures' actual success rate in blocking sympathetic activity is unknown.[106] In addition, no placebo-controlled trials have been published. Most importantly, the mechanism of pain relief is also unknown. Some postulate that the benefit is derived from local anesthetic activity on peripheral somatic nerve fibers, not sympathetic fibers themselves, due to local anesthetic systemic actions or local spillage and spread of the injectate.[106, 107, 108, 109] Some patients who have reported transient pain relief with sympathetic blocks have also reported such results after an IV infusion of lidocaine.[1]

Intravenous regional sympathetic block

Studies assessing IV regional sympathetic blocks have been performed using several agents. Guanethidine is thought to act by depleting norepinephrine, although the drug has also been shown to have serotonergic and anticholinergic activity.[110] In a literature review, 7 controlled trials concluded that IV regional blocks with guanethidine provide little analgesia compared with a placebo or no treatment.[111, 112, 113, 114, 115, 116, 117, 76] One study demonstrated that applying a series of guanethidine blocks did not result in a better outcome than using just one.[117]

Bretylium has also been used to achieve an IV regional sympathetic block. Its proposed mechanism of action is thought to be similar to guanethidine's. A single non‑placebo-controlled study of IV bretylium regional sympathetic block compared bretylium with lidocaine in 12 patients and reported that bretylium resulted in a significantly longer duration of pain relief.[118]

Other controlled trials compared different agents that can be used for IV regional sympathetic blocks, including droperidol, ketanserin, reserpine, and atropine.[1] Droperidol, an alpha-adrenergic antagonist, provided no pain relief for 6 patients who responded to prior stellate ganglion blocks.[119] Ketanserin, a serotonin type-2 antagonist, was studied in 9 patients who reported significant pain relief for several weeks compared with saline.[120] Two controlled studies assessed reserpine, another norepinephrine-depleting drug, in patients who experienced prior relief from stellate ganglion blocks, but these studies reported no significant pain relief.[112, 113] No pain relief from anticholinergic atropine was reported in patients who had previously responded to IV guanethidine regional sympathetic blockade, either.[121]

Another significant question is the mechanism of pain relief with IV regional sympathetic blocks. The beneficial responses associated with this procedure may result solely from the ischemic tourniquet block rather than the injected medication. Significant A-β and A-δ fiber conduction blockage with clinically evident sensory changes has been demonstrated with only a tourniquet.[122]

Intravenous phentolamine infusion

Phentolamine’s primary mechanism of activity is believed to occur via α-1 adrenergic antagonism, although the drug also has serotonergic, histaminergic, and cholinergic activities[86] , along with local anesthetic properties.[123] Controlled clinical trials showed mixed results and poor methodology.[37, 124] One study reported that phentolamine infusion was less sensitive but more specific than stellate ganglion block for the diagnosis of SMP.[109] An uncontrolled report observed that some patients with CRPS experience days or weeks of pain relief after 1 phentolamine infusion, although some of those reported that peak pain relief did not arrive until several days after phentolamine infusion.[125]

Phentolamine infusion has several advantages over sympathetic blockades—it is minimally invasive, not operator-dependent, and has systemic activity that allows for the simultaneous treatment of multiple body regions with SMP. Whether phentolamine has a dose-response relationship is unclear; therefore, some patients may need higher doses to see an effect.[126]

Ketamine infusion

The rationale for using ketamine to treat CRPS is based on its strong ability to block NMDA receptors.[127, 128, 129, 130] Experimental evidence suggests that the symptoms of CRPS are generated by a sufficiently intense or prolonged painful stimulus that causes increased and prolonged glutamate release from nociceptive first-order afferents. The glutamate stimulates NMDA receptors on second-order neurons within the spinal cord that produce wind-up and central sensitization. Therefore, blocking NMDA receptors might also block cellular mechanisms supporting that sensitization.[129, 131, 132]

Although the rationale for using ketamine seems reasonable, studies to date have not yet validated its benefit using objective outcome parameters with double-blind, randomized, controlled methodology. Furthermore, several different research teams have struggled to determine (1) the optimal dosing and duration of infusions, (2) whether the infusions are more effective in an inpatient versus outpatient setting, (3) whether ketamine is best used as an adjunct to regional anesthetic blocks rather than on its own, (4) whether it is best used in cases of established refractory CRPS, (5) when it should be applied during the evolution of symptoms, and (6) if treatment is more beneficial when adjunctive medications are used in concert with IV ketamine.[133, 134]

A 2004 study examined 33 patients who were diagnosed with CRPS and underwent ketamine treatment at least once. Due to a relapse of symptoms, 12 of the 33 were offered a second course of therapy, and 2 received a third. Following the initial course of therapy, 25 (76%) of the 33 patients experienced complete pain relief, 6 (18%) experienced partial relief, and 2 (6%) received no relief. When the therapy was repeated, all 12 patients experienced complete relief of their pain due to CRPS.[134]

In a 2008 study, 20 patients with refractory CRPS received IV ketamine in anesthetic doses over 5 days to determine the efficacy of ketamine in improving pain, any associated movement disorders, quality of life, and ability to work. Significant pain relief was observed at 1 month (93.5 ± 11.1%), 3 months (89.4 ± 17.0%), and 6 months (79.3 ± 25.3%) following treatment. The complete suspension of CRPS was observed in all patients at 1 month, in 17 at 3 months, and in 16 at 6 months. Quality of life, associated movement disorders, and the ability to work were significantly improved in most patients at 3 and 6 months.[135]

Sixty patients with chronic CRPS type I and severe pain participated in a double-blind, randomized, placebo-controlled parallel group trial that was published in 2009. Thirty patients were given a 4.2-day IV infusion of low-dose ketamine, and the other 30 were given a placebo, using an individualized, stepwise tailoring of dosage based on the extent of pain relief relative to side effects such as nausea, vomiting, and psychomimetic symptoms. The primary outcome of the study was measured in the pain score (numerical rating 0-10) throughout the 12-week study. The lowest pain score (2.68 ± 0.51 with ketamine, 5.45 ± 0.48 with placebo) occurred at the end of week 1. By week 12, any significant differences in pain relief between groups was lost. Treatment did not cause significant functional improvement; however, treatment with ketaminewassafe,withpsychomimetic side effects that were acceptable to most patients.[136]

A randomized, double-blind, placebo-controlled study followed patients for 3 months after treatment. All patients were infused intravenously with normal saline with or without ketamine for 4 hours (25 mL/h) daily for 10 days. The maximum ketamine infusion rate was .35 mg/kg/h and did not exceed 25 mg/h over a 4-hour period. Patients in both groups received clonidine and versed. This study reported statistically significant reductions in many pain parameters only in the treatment group. The placebo group reported no benefit from treatment along any parameter.[137]

Methods of ketamine infusion include the following:

  • Hospital-based

    • A 5-day inpatient stay allows ketamine to be infused through an IV line starting at a dose of 20 mg/h of ketamine, which is increased by 5-mg increments to a maximum of 40 mg/h. Clonidine 0.1-0.2 mg daily or bid is used as an adjunct. Lorazepam 1-2 mg is useful when dysphoria or hallucinations occur. Other medications can be used to treat problems such as nausea, vomiting, and headaches.

    • Following discharge from the hospital, patients are enrolled in an outpatient infusion program. Initially, they are treated 1-2 times per week with a 4-hour IV infusion of 100-200 mg of ketamine. The frequency of outpatient treatment is reduced over time to 2 outpatient treatments per week, every other week for 1 month, then 1 treatment every other week for a month, then monthly for 3 months, and then every 3 months. This treatment approach is a guideline; some patients require more frequent treatments and some require close follow-up with monthly intersession outpatient evaluations.[134, 137]

  • Outpatient: Recommendations vary; however, one experienced and published physician advises 10 daily treatments over 2 consecutive weeks in an outpatient infusion suite. Patients received from 70-200 mg/d of ketamine in titrating doses over the 10-day time frame and then placed in the outpatient weaning program as previously described.[134, 137]

CNS side effects can include dysphoria, hallucinations, night terrors, and flashbacks. Advised precautions include daily comprehensive metabolic profiles to ensure that no abnormalities in liver function develop. Data from one center showed that ketamine infusion was provided on an outpatient basis for refractory or otherwise difficult cases of CRPS; 66-80% of those patients showed an overall improvement as measured by increased function, reduced medication requirements, or both.[134, 137]

Intravenous immunoglobulin

A small study suggested that intravenous immunoglobulin (IVIG) can provide relief for people suffering from CRPS. Thirteen people with a CRPS duration of 6-30 months and who reported a pain intensity of at least 5 on an 11-point scale for 7 consecutive days were included in the study. One subject dropped out due to pregnancy. Of the remaining 12, half of the subjects received 1 dose of IVIG 0.5 g and the other half received a placebo (saline). Six days after infusion, when the discomfort from the injection and any other transient side effects had subsided, subjects were asked to rate their pain every day for the subsequent 2 weeks. Five subjects reported mean pain scores at least 2 points lower with IVIG than with saline, and 3 of the 5 reported pain scores at least 50% lower.[138]

Study limitations included the smaller number of subjects and the higher cost of IVIG than the alternatives that have shown similar efficacy, such as ketamine, magnesium, and tadalafil. A preliminary study of magnesium in 2009 showed promising results in CRPS.[139] However, a more complete study from 2013 showed magnesium to have no significant benefit over placebo.[140] A study investigating the effect of tadalafil on the microcirculation in patients with cold CRPS found that the drug did not reduce temperature asymmetry compared to placebo, but did significantly reduce pain.[141]

One editorial in response to the IVIG study expressed concern regarding adequate blinding of the study, since it failed to show any placebo response.[142] Moreover, the treatment response was within the range of expected placebo responses.

This study, despite its shortcomings, provides additional evidence that the immune system plays a key role in generating chronic and disproportionate pain characteristics such as those seen with CRPS. Other researchers have found antineural autoantibodies in patients with CRPS. IVIG interferes with those antibodies, downregulates proinflammatory cytokines (which are thought to play an important role in CRPS pain), and reduces hyperalgesia in both the CNS and the peripheral nervous system.

Patients with CRPS are more likely than healthy persons to show evidence of cytokines and other proinflammatory markers in tissue fluids, including cerebrospinal fluid. In his editorial, Dr. Schwartzman agreed that the immune system helps CRPS. Pain is not only dependent on the neurons that transmit it, but probably also on microglia and astrocytes, which make cytokines and stimulate pain processing.[137]

Epidural clonidine

One double-blind, controlled trial reported statistically significant pain relief from epidural clonidine injections in patients with SMP-related CRPS.[143] However, this study also reported significant adverse events with both single injections and with an open-label, continuous epidural infusion.

Surgical sympathectomy

Limited evidence is available regarding the efficacy of surgical sympathectomy. Four open-label studies have reported some long-lasting benefits in treating both CRPS types I and II.[144, 145, 146, 147] The most important factor in obtaining a positive outcome is having the procedure take place within 12 months of the inciting event.[144, 146] An irreversible sympathectomy may be effective in select cases owing to the risk of developing adaptive supersensitivity, even on nociceptive neurons, and having a subsequent increase and prolongation of pain. However, these procedures should not be widely recommended.[59]

Spinal cord stimulation/neuromodulation

One prospective, comparative, randomized study had 36 patients with chronic upper extremity CRPS undergo trial epidural spinal cord stimulation (SCS) and physical therapy and 18 other patients were treated with physical therapy alone. Of the SCS group, 24 patients had a successful trial and received a permanent implant. At 6-month follow-up, the SCS group had a significantly greater reduction in pain and a higher percentage was rated as “much improved” overall. However, there were no clinically significant functional improvements, which led the authors to conclude that SCS was a valid treatment for CRPS of the upper extremities (short-term) just for pain relief and improved quality of life.[148] In a follow-up study, the SCS group was found to cost $4,000 more in the first year in terms of various medical expenses; however, a lifetime analysis revealed that SCS reduced expenditures by $60,000 per patient for the same cost parameters.[149]

A study published in 1998 looked at 36 patients with advanced CRPS of longer than 2 years duration who had completed a successful SCS trial. Patients were treated with either SCS or peripheral nerve stimulation, or both. At 36 months after implantation, visual analogue scale (VAS) pain measures averaged a 53% improvement, analgesic consumption was reduced in most patients, and up to 41% of patients had returned to some type of modified work.[150]

A literature review of SCS use with CRPS showed that overall results were judged as “good to excellent” in more than 72% of patients over time periods of 8-40 months. Therefore, this review strongly supported SCS as a treatment for patients with CRPS.[151]

A retrospective, 3-year, multicenter study of 101 patients with CRPS type I looked at the effectiveness of octapolar (8 electrode sites) versus quadripolar (4 sites) systems, as well as high frequency and multiprogram parameters. VAS reduction approached 70% with dual-octapolar systems and 50% in the quadripolar group. High frequency (>250 Hz) was found to be essential for obtaining adequate analgesia in 15% of the patients with dual-octapolar systems. Overall satisfaction with SCS was 91% in the dual-octapolar group versus 70% in the quadripolar group. At the end of the study, 86.3% of the quadripolar systems and 97.2% of the dual-octapolar systems were still being used.[152] A comprehensive review published in 2013 considering safety, cost, and efficacy suggested that SCS should be used earlier than it commonly is at present and that it should not be considered to be a last resort.[153]

Spinal cord stimulation has also demonstrated immunomodulatory properties in patients with CRPS. Kriek et al. measured inflammatory cytokines, chemokines, and growth factors from the interstial fluid from skin blisters before and after SCS therapy in patients with CRPS. They found expression of both pro- and anti-inflammatory cytokines decreased in the affected and contralateral extremity, correlating with improvement of sensory symptoms. Additionally, SCS attenuated T-cell activation, improved peripheral tissue oxygenation, and decreased anti-angiogenetic activity.[154]  Immunomodulatory therapies may play a future role in the treatment of CRPS. Further research is necessary to validate the potential of immunotherapy as a treatment modality.

Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is a non-invasive procedure for stimulation of the motor cortex. TMS has been used to study the physiological characteristics of CRPS type I. Through TMS, sensory and motor hyperexcitability is demonstrated bilaterally in neurons of the cerebral cortex, and localizing to regions corresponding to the affected limb within the central nervous system rather than the entire hemisphere.[155] TMS may also have therapeutic benefit. Pleger et al. studied the analgesic efficiency of repetitive transcranial magnetic simulation applied to the motor cortex contralateral to the CRPS-affected side. Seven out of ten patients reported decreased pain intensities, with maximum effect 15 mins after stimulation was initiated.[156] Peripheral magnetic stimulation has also been demonstrated to increased osteoclast apoptosis, osteoblast viability, bone protein and matrix calcification, antioxidant protein, and the levels of adenosine receptors, while it decreased the levels of pro-inflammatory cytokines. These findings indicate a potential therapeutic benefit to address the impairments in bone function and elevation of pro-inflammatory cytokines observed in CRPS. Further studies are needed to explore the therapeutic role of magnetic stimulation in CRPS patients.[157]

Physical and Occupational Therapy

Clinical experience clearly indicates that physiotherapy is vital for the successful treatment of CRPS. It is a requisite for the patient’s rehabilitation to provide the best recovery of function and quality of life. Standardized physical therapy has been shown to produce long-term relief of both pain and physical dysfunction, especially in children.[158]

Physical and, to a lesser extent, occupational therapy can reduce pain and improve active mobility in CRPS type I.[159] Patients who initially have less pain and better motor function are likely to benefit the most from physical therapy.[160] Physical therapy for CRPS has been shown to be both more effective and less costly than either occupational therapy or control treatments.[161] Recent studies have demonstrated that a combination of hand laterality, recognition training, imagination of movements, and mirror movements reduce pain and disability in patients with CRPSs.[162] Therefore, physiotherapy, occupational therapy and attentional training are essential for an eventual successful outcome.[59]

Psychological Therapy

A prospective, randomized, single-blinded trial of cognitive behavioral therapy was conducted, together with physical therapy of different intensities, in both children and adults, and resulted in a long-lasting reduction of all symptoms in both arms.[163] Additionally, fear of reinjury from moving the affected limb is thought to be a possible predictor of chronic disability. Thus, in a small group of patients, graded exposure therapy was found to successfully reduce pain-related fear, pain intensity, and disability.[164]

Therapeutic Guidelines

Treatment of CRPS should be immediate and directed toward the full restoration of function in the affected extremity. This objective is best accomplished via a comprehensive, interdisciplinary treatment regimen with an emphasis on pain management and functional restoration.[165, 8] Pain specialists include neurologists, anesthesiologists, orthopedic surgeons, physiotherapists, psychologists, and general practitioners.

CPRS: complex regional pain syndrome; SMP: sympath CPRS: complex regional pain syndrome; SMP: sympathetically maintained pain.

Treatment for CRPS is most effective when applied in a cohesive multidisciplinary venue. The treating physician should be aggressive with medical therapies, systematically experimenting with opportunistic pharmaceutical approaches to eliminate the patient’s pain. If the pain and other CRPS symptoms evade satisfactory treatment, then alternative or additional medications should be considered. All treatments work best when applied early, and early-stage CRPS is easier to treat as well. First-line analgesics and coanalgesics for CRPS are opioids, tricyclic antidepressants, gabapentin (or pregabalin), and carbamazepine. In addition, a course of corticosteroids can be considered if inflammatory signs and symptoms predominate.

Sympatholytic procedures, such as sympathetic ganglion blocks, help identify the central pain component maintained by the SNS. Calcium-regulating agents and gabapentoids have been shown to help with acute refractory neuropathic pain. For intractable cases, SCS, IV ketamine, hyperbaric oxygen therapy (HBOT), and epidural clonidine should be strongly considered, especially SCS.[166, 59, 167]

Psychological therapies that include stress management, supportive psychotherapy, and the treatment of psychological comorbidities should also be initiated early as an integral component of the multidisciplinary approach. Psychological treatments, including cognitive behavioral therapies, are frequently used strategies. Identifying an individual’s coping style and then reinforcing healthy coping behaviors; discovering contributing environmental or operant factors; and determining, then treating, associated emotional states are often necessary for steering a chronic pain process to a successful outcome.[166, 59, 167]

Perhaps the most important component of multidisciplinary treatment is active physiotherapy, which is best instituted in a slowly progressive and active, rather than passive, manner. The severity of the disease determines the therapeutic regimen. Pain reduction is the precondition for all interventions, and applied therapies for CRPS should not be painful.

In the acute stages of CRPS when the patient still suffers from severe pain at rest, it is usually impossible to carry out intensive active physical therapy. Painful or aggressive physiotherapy interventions at this stage may lead to deterioration. Therefore, progressive, but cautious, mobilization is indicated. If the affected extremity is too painful to be actively moved, then contralateral physical therapy can be applied. When the resting pain subsides, physical therapy can progress to active isometric strengthening, followed by active isotonic training. Functional restoration should be performed in combination with sensory desensitization programs until the complete recuperation of motor function occurs.[97, 59, 14]

Surgical Care

Surgical sympathectomy is only likely to provide complete pain relief for patients demonstrating transient complete relief with paravertebral sympathetic ganglion blockade.

  • The reported incidence of complete relief ranged from 58-100% and the duration of follow-up varied from 6 months to 17 years in the studies performed.

  • Surgical sympathectomy should not be recommended routinely because the SMP component may resolve spontaneously over time or play a minimal role, if any, in the complicated pathogenesis of CRPS.

  • Some patients who experience complete relief for a while have a relapse.

Amputation of the affected limb as a treatment is an extreme option that is very rarely recommended. In the past, it was sometimes used with patients who had CRPS with severe hyperpathia in combination with a limb that was either nonfunctional or had severe recurrent infections. However, there is a significant risk of CRPS then developing in the stump.

Consultations

Consultation with the following may prove helpful:

  • Pain specialists (this should be the consultation of choice)

  • Physical medicine and rehabilitation

  • Neurology

  • Anesthesiology

  • Psychiatry/psychology

  • Neurosurgery

Diet

No special diet has been effective in alleviating CRPS.

Anecdotal reports suggest that vitamin C can improve outcomes.

Activity

No limitations on activity are recommended. The only restrictions should be related to what the patient cannot do because of pain or decreased range of motion, or to what the patient is not supposed to do because of associated conditions (eg, fractures, sprains, strains).

 

Medication

Medication Summary

Clinical trials strongly suggest that steroids are effective when given in the acute phase of CRPS type I. This is probably related to their effects on neurogenic inflammation. Opioids can bring relief for acute as well as chronic pain. Intranasal calcitonin has been used successfully to treat CRPS-related pain.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties. They can cause profound and varied metabolic effects and modify the body's immune response to diverse stimuli.

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Should be given in the acute phase of CRPS type I. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. After 4 wk of treatment, symptoms and signs should be decreased by 65%.

Prednisone (Sterapred)

Can be used in early phase of CRPS. Not useful in late stages. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Analgesics

Class Summary

Pain control is essential to quality patient care. Analgesics ensure patient comfort. They can have side effects such as sedation, constipation, or, rarely, respiratory depression.

Morphine (Duramorph, Astramorph, MS Contin)

The opioid used most often; many physicians are probably more comfortable with this medication than other opioids. However, other available opioids can also be used in pain control. Starting dose may depend on whether patient is already taking narcotic analgesics. Large doses required in patients who have been taking opioid analgesics for a long time. Available orally in both immediate-release and timed-release preparations. Long-acting form usually dosed q12h, but many authorities believe it loses much of its effect after 8 h. Immediate-release form may be needed for periods of pain "breakthrough." Treatment should begin at the lowest available dose in newly diagnosed patients. Available preparations of oral morphine include MSIR, MS Contin, Oramorph, RMS (Purdue Frederick), and Roxanol (Roxane).

 

Follow-up

Further Outpatient Care

Patients with CRPS type I should receive care at a pain clinic in which appropriate evaluation and treatment can minimize their discomfort and degree of disability.

Further Inpatient Care

With CRPS type I, inpatient care is typically reserved for patients with refractory pain or infections of the atrophic limb, patients requiring surgery, and sometimes patients requiring other procedures.

Transfer

Patients should be referred to a pain clinic as soon as CRPS type I is suspected on clinical grounds.

Deterrence/Prevention

The early treatment of pain appears to decrease the frequency of chronic disease and later complications.

Complications

Complications can include the following:

  • Osteoporosis

  • Limitation of active joint movement

  • Infections

  • Nodular fasciitis of the palmar or plantar skin

Prognosis

Approximately 80% of patients with CRPS type I achieve complete, spontaneous relief of signs and symptoms within 18 months; however, no diagnostic criteria have been shown to predict which patients will fall into this category. Some of the patients whose symptoms do not resolve spontaneously may still be cured by treatment.

Of the patients who develop refractory CRPS type I, 50-80% have disability secondary to pain and/or a limited range of motion. The main disabilities are limitations in their activities of daily living (ADL).

Prolonged symptoms and signs, trophic changes, and primarily cold CRPS type I are all associated with a higher chance of poor outcomes and disability.

Patient Education

Patients should be informed that, even while wearing a cast, their treatment will include mild, passive range-of-motion exercises. After the cast is removed, physical and occupational therapy should be started immediately, and some ADLs should be resumed as soon as possible in accordance with the recommendations of the physical and occupational therapists.

 

Online Patient Education Resources

There are a number of online resources that patients may find to be helpful. Four sites are listed below. Patients should be mindful of the fact that not all online information is reliable. Disparities can be found between information on different sites or even between information on different parts of the same site. These online resources should be view as a starting point for discussion between the patient and her or his healthcare provider.

American Chronic Pain Association

https://theacpa.org/

American RSDHope

http://www.rsdhope.org/crps.html

International Research Foundation for RSD/CRPS

http://www.rsdfoundation.org/

Reflex Sympathetic Dystrophy Syndrome Association (RSDSA)

http://www.rsds.org

 

Many patients inquire about clinical trials of new treatment methods.

The website www.clinicaltrials.gov  is a good source of information about clinical trials on CRPS (and most other disease). The specific link within this site to CRPS is https://clinicaltrials.gov/ct2/results?term=Complex%20Regional%20Pain%20Syndrome

One can also use the site’s own search function.

 

Questions & Answers

Overview

How are complex regional pain syndrome (CRPS) type I and type II defined?

How is complex regional pain syndrome not otherwise specified (CRPS-NOS) defined?

What are the clinical diagnostic criteria for complex regional pain syndrome (CRPS)?

What is the pathophysiology of complex regional pain syndrome (CRPS)?

What is the role of peripheral and central sensitization in the pathophysiology of complex regional pain syndrome (CRPS)?

Which brain structure factors may have a role in the pathophysiology of complex regional pain syndrome (CRPS)?

What is the role of sympathetically maintained pain (SMP) in the pathogenesis of complex regional pain syndrome (CRPS)?

What is the role of sensory and motor dysfunction in the pathophysiology of complex regional pain syndrome (CRPS)?

What is the role of aberrant healing and inflammation in the pathophysiology of complex regional pain syndrome (CRPS)?

What is the role of protective disuse in the development of complex regional pain syndrome (CRPS)?

What is the incidence of complex regional pain syndrome (CRPS) in the US?

What is the morbidity associated with complex regional pain syndrome (CRPS)?

Which patient groups have the highest incidence of complex regional pain syndrome (CRPS)?

Presentation

Which clinical history findings are characteristic of complex regional pain syndrome (CRPS) type I?

What are the signs and symptoms of complex regional pain syndrome (CRPS) type I?

Which physical findings are characteristic of complex regional pain syndrome (CRPS)?

What causes complex regional pain syndrome (CRPS)?

DDX

How is neuropathy differentiated from complex regional pain syndrome (CRPS)?

How is posttraumatic neuralgia differentiated from complex regional pain syndrome (CRPS)?

Which conditions should be included in the differential diagnoses of complex regional pain syndrome (CRPS)?

Workup

What is the role of lab testing in the workup of complex regional pain syndrome (CRPS)?

What is the role of imaging studies in the workup of complex regional pain syndrome (CRPS)?

What is the role of radiography in the workup of complex regional pain syndrome (CRPS)?

What is the role of bone scintigraphy in the workup of complex regional pain syndrome (CRPS)?

What is the role of MRI in the workup of complex regional pain syndrome (CRPS)?

What is the role of quantitative sensory testing in the workup of complex regional pain syndrome (CRPS)?

What is the role of autonomic function testing (AFT) in the workup of complex regional pain syndrome (CRPS)?

Which biomarkers are used in the evaluation of complex regional pain syndrome (CRPS)?

What is the role of skin biopsy in the evaluation of complex regional pain syndrome (CRPS)?

What is the role of muscle biopsy in the evaluation of complex regional pain syndrome (CRPS)?

What is the role of peripheral nerve biopsy in the evaluation of complex regional pain syndrome (CRPS)?

Treatment

What is the role of IV phentolamine in the treatment of complex regional pain syndrome (CRPS)?

What is the role of drug treatment for complex regional pain syndrome (CRPS)?

What is the role of corticosteroids in the treatment of complex regional pain syndrome (CRPS)?

What is the role of calcium-regulating drugs in the treatment of complex regional pain syndrome (CRPS)?

What is the role of opioids in the treatment of complex regional pain syndrome (CRPS)?

What is the role of NSAIDs in the treatment of complex regional pain syndrome (CRPS)?

What is the role of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in the treatment of complex regional pain syndrome (CRPS)?

What is the role of sodium channel blocking agents in the treatment of complex regional pain syndrome (CRPS)?

What is the role of gamma-aminobutyric acid (GABA) agonists in the treatment of complex regional pain syndrome (CRPS)?

What is the role of gabapentin in the treatment of complex regional pain syndrome (CRPS)?

What is the role of calcium channel blockers in the treatment of complex regional pain syndrome (CRPS)?

What is the role of beta-blockers in the management of complex regional pain syndrome (CRPS)?

What is the role of oral sympatholytic agents in the treatment of complex regional pain syndrome (CRPS)?

What is the role of clonidine in the treatment of complex regional pain syndrome (CRPS)?

Which techniques are used to block sympathetic activity in the treatment of complex regional pain syndrome (CRPS)?

What is the efficacy of sympathetic interventions in the treatment of complex regional pain syndrome (CRPS)?

What is the role of selective sympathetic ganglion nerve blocks in the treatment of complex regional pain syndrome (CRPS)?

What is the role of IV regional sympathetic blocks in the treatment of complex regional pain syndrome (CRPS)?

What is the role of ketamine in the treatment of complex regional pain syndrome (CRPS)?

How is ketamine administered in the treatment of complex regional pain syndrome (CRPS)?

What are the possible adverse effects of ketamine for the treatment of complex regional pain syndrome (CRPS)?

What is the role of IV immunoglobulin in the treatment of complex regional pain syndrome (CRPS)?

What is the role of epidural clonidine in the treatment of complex regional pain syndrome (CRPS)?

What is the role of surgical sympathectomy in the treatment of complex regional pain syndrome (CRPS)?

What is the role of spinal cord stimulation (neuromodulation) in the treatment of complex regional pain syndrome (CRPS)?

What is the role of magnetic stimulation in the treatment of complex regional pain syndrome (CRPS)?

What is the role of physical and occupational therapy in the treatment of complex regional pain syndrome (CRPS)?

What is the role of CBT in the treatment of complex regional pain syndrome (CRPS)?

What is the goal of treatment for complex regional pain syndrome (CRPS)?

What are therapeutic guidelines for complex regional pain syndrome (CRPS)?

What is the role of surgery in the treatment of complex regional pain syndrome (CRPS)?

Which specialists should be consulted for the treatment of complex regional pain syndrome (CRPS)?

Which dietary modifications are used in the treatment of complex regional pain syndrome (CRPS)?

Which activity modifications are advisable for patients with complex regional pain syndrome (CRPS)?

Medications

What is the role of medications in the treatment of complex regional pain syndrome (CRPS)?

Which medications in the drug class Analgesics are used in the treatment of Complex Regional Pain Syndromes?

Which medications in the drug class Corticosteroids are used in the treatment of Complex Regional Pain Syndromes?

Follow-up

How is pain managed in patients with complex regional pain syndrome (CRPS)?

When is inpatient care indicated for patients with complex regional pain syndrome (CRPS)?

When is transfer indicated for patients with complex regional pain syndrome (CRPS)?

How is complex regional pain syndrome (CRPS) prevented?

What are possible complications of complex regional pain syndrome (CRPS)?

What is the prognosis of complex regional pain syndrome (CRPS)?

What is included in patient education about complex regional pain syndrome (CRPS)?

Where can patient resources about complex regional pain syndrome (CRPS) be found?