Introduction
Neuropathic pain comprises a wide range of heterogeneous conditions. Various types of neuropathic pain may have distinct pathophysiologic causes and different clinical signs and symptoms. Despite the diversity of conditions classified as “neuropathic pain,” many potentially share common underlying mechanisms of nociception, including neuronal hyperexcitability, but others may not. This may in part explain why certain analgesic agents are relatively effective for a wide range of neuropathic pain states but why notable exceptions exist that appear to be resistant to conventional “neuropathic” pain therapy. A group has been assembled to address the inconclusive research on “neuropathic” pain and to operationalize and specify definitions and criteria for conditions that are to be referred to as neuropathic pain ( Box 24.1 ). This work should lead to a more reductionist approach to the study of neuropathic pain and to effective therapies for specific disease processes.
IASP Definition: 1994
“pain initiated or caused by a primary lesion or dysfunction in the nervous system”
Revised Research and Clinical Definition: 2007
“pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”
IASP, International Association for the Study of Pain.
In this chapter we focus on some of the more common states of “neuropathic” pain as defined by the sensitive but nonspecific definition of the International Association for the Study of Pain (IASP). These conditions include complex regional pain syndrome (CRPS), post-herpetic neuralgia (PHN), painful diabetic peripheral neuropathy (DPN), and human immunodeficiency virus (HIV) painful sensory neuropathy.
Complex Regional Pain Syndrome
The term complex regional pain syndrome , which denotes both types 1 and 2, originated from a history of different names appointed by individuals who made particular observations. In 1864 Silas Weir Mitchell made an important observation of Civil War soldiers when he noticed that they suffered from burning pain and muscle atrophy at the sites of their injuries. He called this “causalgia,” which is derived from the Greek words kausis (burning) and algos (pain). In 1900 at a lecture in Germany, Paul Sudeck stated that this syndrome could not only extend from the initial insult but also had an inflammatory component. The name Sudeck’s dystrophy was applied in his honor. Half a century passed before the discovery that invasive procedures that block the sympathetic nervous system provide further relief of pain symptoms. Because of the success of these methods, Evans renamed the syndrome “reflex sympathetic dystrophy.” Over the years cases arose in which patients lacked a trophic component, sympathetic involvement was absent, or there was no evidence of reflex involvement. These exceptions led to a meeting in 1993 by the IASP at which the term “ complex regional pain syndrome ” was formulated and subsequently published the following year. The most commonly used clinical diagnostic criteria for CRPS types 1 and 2 are low in specificity but high in sensitivity, which has led to overdiagnosis of the pain syndrome. This in turn has made it difficult to obtain accurate epidemiologic data for CRPS or to perform rigorous studies of the pathologic state. In 2007, research criteria (also known as the Budapest criteria) were published that included objective signs of pathology characteristic of patients with CRPS ( Box 24.2 ). These criteria had good specificity and sensitivity. Although they were initially intended for research use, many physicians prefer them to the less stringent original criteria.
IASP Criteria for the Diagnosis of CRPS ∗
∗ If seen without any major nerve damage, the diagnosis is CRPS type 1; if seen with evidence of nerve damage, the diagnosis is CRPS type 2.
- 1.
Presence of an initiating noxious event or reason for immobilization
- 2.
Disproportional pain, allodynia, or hyperalgesia from a known inciting event
- 2.
Sign or symptom of any evidence showing edema, skin changes, blood flow, or abnormal sudomotor activity in the region of the pain
- 4.
No other condition that would otherwise explain the degree of pain or dysfunction
Budapest Criteria for Diagnosis of CRPS ∗
- 1.
Presence of continued disproportional pain from the known inciting event
- 2.
Must report at least one symptom in three of the following four categories:
- •
Sensory: hyperesthesia, allodynia
- •
Vasomotor: temperature asymmetry, changes in skin color
- •
Sudomotor/edema: edema, changes in sweating, sweating asymmetry
- •
Motor/trophic: decreased range of motion, motor dysfunction (tremor, weakness, dystonia), trophic changes (hair, nail, skin)
- •
- 3.
Must report at least one sign in two or more of the following categories at the time of evaluation:
- •
Sensory: hyperalgesia to pinprick, allodynia to touch or joint movement
- •
Vasomotor: temperature asymmetry, color asymmetry
- •
Sudomotor/edema: edema, asymmetrical sweating, sweating changes
- •
Motor/trophic: decreased range of motion, motor dysfunction, trophic changes
- •
- 4.
No other condition that would otherwise explain the degree of pain or dysfunction
CRPS, complex regional pain syndrome; IASP, International Association for the Study of Pain
Pathophysiology
There are two types of CRPS, known as type 1 and type 2 ( Box 24.3 ). They differ in that type 2 has evident nerve injury whereas type 1 assumes an injury to the nerve or nerves. A consistent finding in both types of CRPS is the discrepancy between the severity of the symptoms and the severity of the inciting injury. In addition, symptoms have the propensity to spread in the affected limb in a pattern not restricted to the specific nerve’s area of innervation. CRPS is characterized by intense burning pain with resultant hyperalgesia or allodynia. It may be associated with local edema and autonomic involvement, such as changes in skin color and sweating and increased or decreased skin temperature in the affected area. There may also be trophic changes in the skin, hair, and nails in the affected site (see Box 24.3 ). Although many questions concerning the pathophysiology of this syndrome are still unanswered, three main principles remain at the core of CRPS: abnormalities in both somatosensory and sensory pathways as well as sympathetic nervous system involvement.
CRPS Type 1 (Reflex Sympathetic Dystrophy) ∗
∗ Criteria 2 to 4 must be satisfied.
- 1.
The presence of an initiating noxious event or a cause of immobilization
- 2.
Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event
- 3.
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
- 4.
This diagnosis is excluded by conditions that would otherwise account for the degree of pain and dysfunction
CRPS Type 2 (Causalgia) †
† All three criteria must be satisfied.
- 1.
The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve
- 2.
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
- 3.
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.
Somatosensory Abnormalities
Inciting injury to either the upper or lower extremity is an important trigger of CRPS. Studies have shown that changes in cutaneous innervation of the injured extremities take place even when no nerve injury is found. In one recent study, skin biopsy samples were obtained from the affected limbs of patients with CRPS type 1. A lower density of C and A fibers was found in the affected limbs than in the unaffected limbs, which led to sensory deficits in the affected limbs. Brain plasticity is another important factor found to be associated with somatosensory abnormalities. Data suggest that patients with CRPS have decreased activity in the somatosensory cortex of the affected side. These patients also tend to have tactile mislocation because of somatotopic reorganization, which was found to be directly correlated with hyperalgesia. Changes occurring within the primary somatosensory (SI) cortex are dependent on pain and have been shown to be reversible after recovery from the pain.
Sensory Pathways (Central Nervous System Sensitization, Peripheral Sensitization, Inflammation)
Central sensitization occurs when pain perception increases because of constant firing of painful stimuli to the central nervous system. Neuropeptides such as substance P and bradykinin are released in response to nociceptive stimuli and activate N -methyl- d -aspartate (NMDA) receptors, which together lead to hyperalgesia and allodynia. Peripheral sensitization is the counterpart of central sensitization. When a nerve injury occurs, multiple proinflammatory factors such as glial cell activation, substance P, bradykinin, tumor necrosis factor-α, interleukin-1β, prostaglandin E 2 , and nerve growth factor are activated, which results in increased nociceptive sensitivity and a decreased threshold for firing of nociceptive stimuli. Together, central and peripheral sensitization results in the allodynia and hyperesthesia seen in patients with CRPS. There are other important factors in the inflammatory pathway, such as the role of nuclear factor NFκB upstream in the proinflammatory pathway observed in animal studies.
Altered Sympathic Nervous System Function
Involvement of the sympathetic nervous system is thought to be responsible for the limbs in patients with CRPS becoming cool, blue, and painful secondary to vasoconstriction as a result of excessive outflow from the sympathetic nervous system. In an animal study, rats with chronic postischemic pain that had norepinephrine injected into their hind paws experienced increased nociceptive firing, thus supporting the notion that pain can be sympathetically maintained. However, this provides little evidence in support of sympathetic maintenance of CRPS pain. Coupling of sympathetic neurons may occur not only to nociceptive afferents but also to non-nociceptive mechanosensitive or cold-sensitive neurons. Sympathetic afferent coupling, considered the cause of sympathetically maintained pain, occurs in cutaneous and deep somatic tissues, but during the acute event of CRPS, the deep somatic tissues are of greater importance. Although coupling occurs in some patients with CRPS, a subset of patients with clinically identical CRPS have sympathetically independent pain. These patients exhibit little to no response to sympathetic blockade either pharmacologically with phentolamine or via interventional blockade of the sympathetic ganglia.
Epidemiology
Multiple studies of CRPS type 1 have shown that the male-to-female ratio ranges between 1:2 and 1:4, thus suggesting that females are at higher risk for development of the syndrome. However, the male-to-female ratio for most other pain syndromes is similar. A retrospective, cross-sectional analysis study showed that the male-to-female ratio was 1:4 and that the most common initiating events were bone fractures, sprains, and trauma. Outcomes of the disease tended to be worse in patients with upper extremity injuries than in those with lower extremity injuries, injuries other than fractures, and “cold” (commonly chronic) CRPS rather than “warm” (acute) CRPS. Other risk factors that contribute to the development of CRPS are age, workplace, and type of injury. The average age of patients ranges between 16 and 79 (median range, 41.6), with a higher incidence in the older population. Patients with motor nerve damage were found to be at higher risk for CRPS than those with sensory nerve damage. Fracture has been reported to be the most common initiating injury. The incidence of job-related injuries leading to CRPS was as high as 76%, which may indicate a psychosocial or secondary gain component in reporting of this pain. Studies report that CRPS develops in patients with a family history of CRPS at a higher incidence and younger age, thus suggesting that CRPS may have a genetic component. Another study showed that siblings of patients in whom CRPS developed before 50 years of age had a threefold increased risk for development of the syndrome. Psychological factors such as depression, personality disorders, and anxiety have no correlation with CRPS patients, which suggests that there is no specific type of CRPS personality.
Clinical Features
The pain must be greater in proportion to the inciting event. There must be at least one symptom in three of the following four categories: sensory (hyperesthesia/allodynia), vasomotor (changes in temperature or sweating in the affected limb in comparison to the normal limb), sudomotor/edema, and motor/trophic (demonstration of weakness, decreased range of motion, or trophic changes in hair, nails, or skin). At least one sign must be present at the time of evaluation in two or more of the following four categories: sensory, vasomotor, sudomotor/edema, and motor/trophic. There must be no other diagnosis that better explains the patient’s signs and symptoms. This is different from the criteria proposed in 1993 by the IASP (see Box 24.3 ). A recent study in which the validity of CRPS was evaluated by comparing the Budapest criteria in patients with CRPS and in those with neuropathy showed that the IASP criteria had a sensitivity of 1.0 and a specificity of 0.4 and the Budapest criteria had a clinical sensitivity of 0.99 and a specificity of 0.68. The newly revised criteria are also divided into clinical and research. The research criteria contain more inclusions, which allows a specificity of 0.96.
The current IASP taxonomy also divides CRPS into CRPS 1 (formerly known as reflex sympathetic dystrophy) and CRPS 2 (formerly known as causalgia). The distinction between CRPS 1 and 2 is the presence of a definable nerve lesion in patients with CRPS 2. The signs and symptoms for both conditions are clinically indistinguishable and include sensory changes (allodynia, hyperalgesia, and hypoalgesia), edema, temperature abnormalities, and changes in sweating (see Box 24.3 ). Pain is the principal feature in both CRPS 1 and CRPS 2. In patients with CRPS the associated clinical signs are typically out of proportion to the inciting injury. Patients describe a burning, deep-seated ache that may be shooting in nature along with associated allodynia or hyperalgesia. Pain occurs in 81.1% of patients meeting the CRPS criteria. Patients also frequently complain of sensory abnormalities such as hyperesthesia in response to the typical mechanical stimuli encountered in day-to-day activities (such as dressing) involving the affected limb.
In CRPS 2 (i.e., CRPS with associated major nerve injury), patients often report hyperesthesia around the injured nerve in addition to electric shock–like sensations, shooting pain, and allodynia. Symptoms indicative of vasomotor autonomic abnormalities (including color changes) occurred in 86.9% of patients; temperature instability occurred in 78.7%. Sudomotor symptoms of hyperhidrosis and hypohidrosis were reported in 52.9%. Trophic changes in skin, nail, or hair pattern were reported in 24.4%, 21.1%, and 18%, respectively. Edema was reported in 79.7%, with decreased range of motion in 80.3% and motor weakness in 74.6%.
Diagnosis
There is currently no “gold standard” test for the diagnosis of CRPS. A very thorough history and physical examination are essential for evaluation and diagnosis. Patients with this condition will have the signs and symptoms mentioned previously. Physical examination must be performed to establish the sensory, motor, trophic, sudomotor/edema, and autonomic changes. Sensory changes such as allodynia may be evaluated by light touch and the application of warm/cold temperature to the affected area. Autonomic dysfunction may be confirmed by the presence of asymmetry in temperature and color. Trophic changes may be manifested as changes in skin, nails, and hair in the affected limb. Motor activity may be evaluated by examining motor strength and range of motion. Sudomotor/edema changes may be assessed by dragging a smooth object over the affected and unaffected limb, with the wetter limb allowing a smoother drag than the drier limb. Common diagnostic tools used for diagnosis of CRPS include quantitative sensory testing, tests of autonomic function, and imaging for trophic changes.
Quantitative Sensory Testing
Such testing includes the use of standardized psychophysical tests of the sensory and motor systems, thermal sensation, thermal pain, and vibratory thresholds to assess the function of large-fiber, myelinated small-fiber, and unmyelinated small-fiber afferents. Patients with CRPS may have impaired paradoxical heat sensations, mechanical detection thresholds, mechanical pain thresholds to pinprick stimuli and blunt pressure, allodynia, and pain summation with the use of continuous pinprick stimuli. There is currently no definitive diagnostic sensory pattern in patients with CRPS, but this test can aid in distinguishing other neuropathies from CRPS.
Tests of Autonomic Function
Thermoregulation and sudomotor regulation are the main systems tested in patients with CRPS for disorders in autonomic function. Thermoregulation is tested by using the thermoregulatory sweat test (TST) and infrared thermography or thermometry. The TST assesses calorimetric precipitation from a specific region of the body by adding a solution that changes color when enough heat is generated to produce sweat. Infrared thermography is direct visualization of the change in temperature of the affected site, and in infrared thermometry, a device is used to measure temperature through detection of infrared energy. Changes in temperature in patients with CRPS versus those with other types of pain had a sensitivity of 76% and a specificity of 94%. Sudomotor regulation is tested by using the quantitative sudomotor axon reflex test (QSART), which measures sweat output from various regions of the skin.
Trophic Changes
Three-phase bone scintigraphy (TPBS) is a very valuable test for detection of CRPS. Although joint and bone alterations are not part of the IASP inclusion criteria, they are very important in the outcome of the syndrome. TPBS detects alterations in periarticular bone metabolism, particularly increased bone metabolism, by detecting increase uptake of a periarticular tracer, which occurs predominantly within the first year. TPBS is low in sensitivity but high in specificity. Magnetic resonance imaging of the affected limb has also been used for detection of CRPS but has high sensitivity (97%) and low specificity (17%).
Treatment
Management of CRPS has been complicated by scant knowledge of the etiology of the disease, which has resulted in few targeted therapies. Most of the medications initiated as first-line therapy have been investigated for other non-CRPS neuropathic pain conditions and then applied to the treatment of CRPS, with mixed success. The historical approach to therapy for CRPS still remains a multimodal, multidisciplinary methodology. The predominant therapeutic modalities for the care of CRPS patients include physical therapy, pharmacologic agents, and interventional procedures.
Physical and Occupational Therapy
Physical and occupational therapy for restoration of function and improvement of limbs affected by CRPS has been studied widely. Physical exercises such as isometric strengthening, active range of motion, myofascial release, and stress loading are all tools that aid in restoring functional capacity of the affected limb. Other methods of therapy are currently under study. In a large controlled study in which tactile acuity and pain on application of a tactile stimulus were measured in patients with CRPS and mirror images were used to show the reflection of the unaffected limb during the stimulus, a decreased two-point discrimination threshold and decreased pain acuity were observed. This suggests that therapies that improve functional restoration of the affected limb may improve the outcome of CRPS.
Pharmacologic Therapy
Membrane Stabilizers
Medications such as gabapentin and pregabalin have been shown to be effective in relieving neuropathic pain. CRPS is considered neuropathic pain and gabapentin is presumed to be effective in treating it, yet there are very limited studies showing its specific efficacy for CRPS. In a randomized double-blind, placebo-controlled crossover study in which patients were treated for two 3-week periods with 2 weeks in between, gabapentin had minimal effect on pain but it significantly reduced patients’ sensory deficits. Although there is no clear evidence of efficacy for gabapentin, these neuroleptic medications are the first-line therapy for neuropathic pain and are thus considered first-line therapy for CRPS.
Corticosteroids
A large part of the pathophysiology in CRPS is the acute inflammatory process that occurs after an inciting event (see “Pathophysiology”). Because of this inflammatory course, corticosteroids have been used for treatment. In a recent randomized controlled trial comparing prednisolone with piroxicam, patients were given either medication for 1 month, and their shoulder-hand syndrome scores (measuring pain, distal edema, passive humeral abduction, and external rotation) were determined. In the prednisolone group, 83.3% showed improvement, and in the piroxicam group, only 16.7% improved. The shoulder-hand syndrome score in the steroid group was significantly lower than that in the piroxicam group.
Antidepressants
These drugs have not been studied for use specifically with CRPS, but they have been widely studied for the control of neuropathic pain, and because CRPS is considered neuropathic pain, they are used in pain management. Antidepressants such as tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) have been used to control neuropathic pain effectively. In a recent Cochrane review, TCAs were found to be effective in treating neuropathy, with a number needed to treat (NNT) of 3.6 and a relative risk (RR) of 2.1. Venlafaxine, an SSNRI, was also found to be effective, with an NNT of 3.1 and RR of 2.2. Further studies to investigate the drugs’ ability to specifically target CRPS are warranted. A recent study showed that the combination of gabapentin and nortriptyline was a more effective therapy than either medication alone for neuropathic pain (including CRPS).
Opioids
Studies on the effects of opioids directly on CRPS are lacking, although some have shown opioids to improve neuropathic pain when used in high doses. However, a double-blind, placebo-controlled trial studying the efficacy of sustained-release morphine in CRPS patients for a total treatment of 8 days showed that it was ineffective in decreasing pain, but the study had many limitations. Substantial challenges to using opioid therapy for nonmalignant pain include nausea, constipation, cognitive impairment, tolerance, and hyperalgesia, and therefore it should be used only until other therapies can be initiated. Studies of these medications in the CRPS population are lacking, and more are needed to demonstrate the efficacy of opioids.
Ketamine
Ketamine is an NMDA receptor antagonist. The NMDA receptor is a major part of the central sensitization that occurs in patients with CRPS (see “Pathophysiology”). Ketamine can be administered topically, orally, intranasally, or parentally in subanesthetic (analgesic) doses or in high doses to produce ketamine coma. A double-blind, randomized, placebo-controlled, parallel-group trial studying the effects of subanesthetic intravenous dosing of ketamine for 4 days in CRPS patients showed decreased levels of pain, but the pain progressively increased from the 1st week after infusion to the 12th week. In patients undergoing ketamine infusion, minor and rare side effects such as nausea, vomiting, and psychomimetic effects developed. In another nonrandomized open-label trial in which chronic CRPS patients refractory to standard therapies were treated with anesthetic doses of ketamine for 5 days, the pain improved significantly for 6 months, but 79.3% relapsed back to baseline after the 6-month period. The topical form of ketamine has also been shown to decrease allodynia and hyperalgesia in response to pinprick stimuli, but this has not been well validated.
Bisphosphonates
Bone resorption at the site of inflammation in the affected limb contributes to the pain in CRPS. The use of bisphosphonates to decrease osteoclast overactivity has shown promise in its pain-reducing effects. In an 8-week randomized, double-blind, placebo-controlled study, alendronate was used in patients with post-traumatic CRPS type 1. This drug improved spontaneous pain, tolerance to pressure, and extremity range of motion. However, other trials have shown no reduction in CRPS-related pain.
Interventional Treatment
Sympathetic Nerve Block
The most common sympathetic nerve blocks are the stellate ganglion and lumbar sympathetic blocks for treatment of CRPS of the upper and lower extremities, respectively. Multiple modalities have been studied for their ability to disrupt the sympathetic pathway through these nerve plexuses, including local anesthetics, chemical neurolysis, and radiofrequency ablation. In a study in which both stellate ganglion and lumbar sympathetic blocks were performed with local anesthetic and normal saline on each subject, it was observed that the decreased pain that each experienced was almost identical, but the duration of decreased pain was longer when patients received the local anesthetic block. In a small randomized study in which radiofrequency neurolysis was compared with chemical neurolysis, the pain decreased from baseline, but no significant difference was seen between the two methods. Although sympathetic blocks provide a significant reduction in pain by blocking the sympathetic pathway of the pathophysiologic stages in CRPS, their greatest limitation is that they provide only short-term relief in the vast majority of treated patients. This means that patients must continue to frequently undergo sympathetic blocks, which most often places them on maintenance therapy. This form of therapy should be performed to provide enough pain relief so that patients are able to perform physical therapy exercises for functional restoration and multidisciplinary therapy, but not as a sole therapeutic modality.
Spinal Cord Stimulation
A spinal cord stimulator is a generator containing leads that are placed in the dorsal aspect of the spinal cord within the level that innervates the area causing pain. Most patients have been managed with standard medical therapy and some treated surgically before undergoing spinal cord stimulation (SCS). In a randomized trial, patients with CRPS were separated into two groups: SCS with physical therapy and physical therapy only. This study showed that SCS provided significant improvement in pain for the first 2 years. Unfortunately, there was no amelioration in quality of life or functionality in the group undergoing SCS with physical therapy, although this study was seriously flawed because of excessive patient dropout. SCS has been used widely for the control of intractable pain, but further research is needed to verify its impact on CRPS.
Intrathecal Treatments
Baclofen and ziconotide administered intrathecally have been examined for the treatment of CRPS. Baclofen is a γ-aminobutyric acid receptor agonist. It is currently used as a muscle relaxant and has been indicated for muscle spasticity and dystonia. A single-blind, placebo run-in, dose escalation study of CRPS patients with dystonia showed that intrathecal baclofen was very effective in decreasing dystonia and pain, as well as in improving quality of life, as indicated in a 12-month follow-up. Ziconotide is a very potent drug made from the toxin of sea snail venom and works by blocking chemicals that transmit pain signals. Intrathecal administration of this drug has great potential in reducing edema, trophic changes, and pain in these patients. However, it is associated with a nearly 100% side effect profile.
Complex Regional Pain Syndrome
The term complex regional pain syndrome , which denotes both types 1 and 2, originated from a history of different names appointed by individuals who made particular observations. In 1864 Silas Weir Mitchell made an important observation of Civil War soldiers when he noticed that they suffered from burning pain and muscle atrophy at the sites of their injuries. He called this “causalgia,” which is derived from the Greek words kausis (burning) and algos (pain). In 1900 at a lecture in Germany, Paul Sudeck stated that this syndrome could not only extend from the initial insult but also had an inflammatory component. The name Sudeck’s dystrophy was applied in his honor. Half a century passed before the discovery that invasive procedures that block the sympathetic nervous system provide further relief of pain symptoms. Because of the success of these methods, Evans renamed the syndrome “reflex sympathetic dystrophy.” Over the years cases arose in which patients lacked a trophic component, sympathetic involvement was absent, or there was no evidence of reflex involvement. These exceptions led to a meeting in 1993 by the IASP at which the term “ complex regional pain syndrome ” was formulated and subsequently published the following year. The most commonly used clinical diagnostic criteria for CRPS types 1 and 2 are low in specificity but high in sensitivity, which has led to overdiagnosis of the pain syndrome. This in turn has made it difficult to obtain accurate epidemiologic data for CRPS or to perform rigorous studies of the pathologic state. In 2007, research criteria (also known as the Budapest criteria) were published that included objective signs of pathology characteristic of patients with CRPS ( Box 24.2 ). These criteria had good specificity and sensitivity. Although they were initially intended for research use, many physicians prefer them to the less stringent original criteria.
IASP Criteria for the Diagnosis of CRPS ∗
∗ If seen without any major nerve damage, the diagnosis is CRPS type 1; if seen with evidence of nerve damage, the diagnosis is CRPS type 2.
- 1.
Presence of an initiating noxious event or reason for immobilization
- 2.
Disproportional pain, allodynia, or hyperalgesia from a known inciting event
- 2.
Sign or symptom of any evidence showing edema, skin changes, blood flow, or abnormal sudomotor activity in the region of the pain
- 4.
No other condition that would otherwise explain the degree of pain or dysfunction
Budapest Criteria for Diagnosis of CRPS ∗
- 1.
Presence of continued disproportional pain from the known inciting event
- 2.
Must report at least one symptom in three of the following four categories:
- •
Sensory: hyperesthesia, allodynia
- •
Vasomotor: temperature asymmetry, changes in skin color
- •
Sudomotor/edema: edema, changes in sweating, sweating asymmetry
- •
Motor/trophic: decreased range of motion, motor dysfunction (tremor, weakness, dystonia), trophic changes (hair, nail, skin)
- •
- 3.
Must report at least one sign in two or more of the following categories at the time of evaluation:
- •
Sensory: hyperalgesia to pinprick, allodynia to touch or joint movement
- •
Vasomotor: temperature asymmetry, color asymmetry
- •
Sudomotor/edema: edema, asymmetrical sweating, sweating changes
- •
Motor/trophic: decreased range of motion, motor dysfunction, trophic changes
- •
- 4.
No other condition that would otherwise explain the degree of pain or dysfunction
CRPS, complex regional pain syndrome; IASP, International Association for the Study of Pain
Pathophysiology
There are two types of CRPS, known as type 1 and type 2 ( Box 24.3 ). They differ in that type 2 has evident nerve injury whereas type 1 assumes an injury to the nerve or nerves. A consistent finding in both types of CRPS is the discrepancy between the severity of the symptoms and the severity of the inciting injury. In addition, symptoms have the propensity to spread in the affected limb in a pattern not restricted to the specific nerve’s area of innervation. CRPS is characterized by intense burning pain with resultant hyperalgesia or allodynia. It may be associated with local edema and autonomic involvement, such as changes in skin color and sweating and increased or decreased skin temperature in the affected area. There may also be trophic changes in the skin, hair, and nails in the affected site (see Box 24.3 ). Although many questions concerning the pathophysiology of this syndrome are still unanswered, three main principles remain at the core of CRPS: abnormalities in both somatosensory and sensory pathways as well as sympathetic nervous system involvement.
CRPS Type 1 (Reflex Sympathetic Dystrophy) ∗
∗ Criteria 2 to 4 must be satisfied.
- 1.
The presence of an initiating noxious event or a cause of immobilization
- 2.
Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event
- 3.
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
- 4.
This diagnosis is excluded by conditions that would otherwise account for the degree of pain and dysfunction
CRPS Type 2 (Causalgia) †
† All three criteria must be satisfied.
- 1.
The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve
- 2.
Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain
- 3.
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.
Somatosensory Abnormalities
Inciting injury to either the upper or lower extremity is an important trigger of CRPS. Studies have shown that changes in cutaneous innervation of the injured extremities take place even when no nerve injury is found. In one recent study, skin biopsy samples were obtained from the affected limbs of patients with CRPS type 1. A lower density of C and A fibers was found in the affected limbs than in the unaffected limbs, which led to sensory deficits in the affected limbs. Brain plasticity is another important factor found to be associated with somatosensory abnormalities. Data suggest that patients with CRPS have decreased activity in the somatosensory cortex of the affected side. These patients also tend to have tactile mislocation because of somatotopic reorganization, which was found to be directly correlated with hyperalgesia. Changes occurring within the primary somatosensory (SI) cortex are dependent on pain and have been shown to be reversible after recovery from the pain.
Sensory Pathways (Central Nervous System Sensitization, Peripheral Sensitization, Inflammation)
Central sensitization occurs when pain perception increases because of constant firing of painful stimuli to the central nervous system. Neuropeptides such as substance P and bradykinin are released in response to nociceptive stimuli and activate N -methyl- d -aspartate (NMDA) receptors, which together lead to hyperalgesia and allodynia. Peripheral sensitization is the counterpart of central sensitization. When a nerve injury occurs, multiple proinflammatory factors such as glial cell activation, substance P, bradykinin, tumor necrosis factor-α, interleukin-1β, prostaglandin E 2 , and nerve growth factor are activated, which results in increased nociceptive sensitivity and a decreased threshold for firing of nociceptive stimuli. Together, central and peripheral sensitization results in the allodynia and hyperesthesia seen in patients with CRPS. There are other important factors in the inflammatory pathway, such as the role of nuclear factor NFκB upstream in the proinflammatory pathway observed in animal studies.
Altered Sympathic Nervous System Function
Involvement of the sympathetic nervous system is thought to be responsible for the limbs in patients with CRPS becoming cool, blue, and painful secondary to vasoconstriction as a result of excessive outflow from the sympathetic nervous system. In an animal study, rats with chronic postischemic pain that had norepinephrine injected into their hind paws experienced increased nociceptive firing, thus supporting the notion that pain can be sympathetically maintained. However, this provides little evidence in support of sympathetic maintenance of CRPS pain. Coupling of sympathetic neurons may occur not only to nociceptive afferents but also to non-nociceptive mechanosensitive or cold-sensitive neurons. Sympathetic afferent coupling, considered the cause of sympathetically maintained pain, occurs in cutaneous and deep somatic tissues, but during the acute event of CRPS, the deep somatic tissues are of greater importance. Although coupling occurs in some patients with CRPS, a subset of patients with clinically identical CRPS have sympathetically independent pain. These patients exhibit little to no response to sympathetic blockade either pharmacologically with phentolamine or via interventional blockade of the sympathetic ganglia.
Epidemiology
Multiple studies of CRPS type 1 have shown that the male-to-female ratio ranges between 1:2 and 1:4, thus suggesting that females are at higher risk for development of the syndrome. However, the male-to-female ratio for most other pain syndromes is similar. A retrospective, cross-sectional analysis study showed that the male-to-female ratio was 1:4 and that the most common initiating events were bone fractures, sprains, and trauma. Outcomes of the disease tended to be worse in patients with upper extremity injuries than in those with lower extremity injuries, injuries other than fractures, and “cold” (commonly chronic) CRPS rather than “warm” (acute) CRPS. Other risk factors that contribute to the development of CRPS are age, workplace, and type of injury. The average age of patients ranges between 16 and 79 (median range, 41.6), with a higher incidence in the older population. Patients with motor nerve damage were found to be at higher risk for CRPS than those with sensory nerve damage. Fracture has been reported to be the most common initiating injury. The incidence of job-related injuries leading to CRPS was as high as 76%, which may indicate a psychosocial or secondary gain component in reporting of this pain. Studies report that CRPS develops in patients with a family history of CRPS at a higher incidence and younger age, thus suggesting that CRPS may have a genetic component. Another study showed that siblings of patients in whom CRPS developed before 50 years of age had a threefold increased risk for development of the syndrome. Psychological factors such as depression, personality disorders, and anxiety have no correlation with CRPS patients, which suggests that there is no specific type of CRPS personality.
Clinical Features
The pain must be greater in proportion to the inciting event. There must be at least one symptom in three of the following four categories: sensory (hyperesthesia/allodynia), vasomotor (changes in temperature or sweating in the affected limb in comparison to the normal limb), sudomotor/edema, and motor/trophic (demonstration of weakness, decreased range of motion, or trophic changes in hair, nails, or skin). At least one sign must be present at the time of evaluation in two or more of the following four categories: sensory, vasomotor, sudomotor/edema, and motor/trophic. There must be no other diagnosis that better explains the patient’s signs and symptoms. This is different from the criteria proposed in 1993 by the IASP (see Box 24.3 ). A recent study in which the validity of CRPS was evaluated by comparing the Budapest criteria in patients with CRPS and in those with neuropathy showed that the IASP criteria had a sensitivity of 1.0 and a specificity of 0.4 and the Budapest criteria had a clinical sensitivity of 0.99 and a specificity of 0.68. The newly revised criteria are also divided into clinical and research. The research criteria contain more inclusions, which allows a specificity of 0.96.
The current IASP taxonomy also divides CRPS into CRPS 1 (formerly known as reflex sympathetic dystrophy) and CRPS 2 (formerly known as causalgia). The distinction between CRPS 1 and 2 is the presence of a definable nerve lesion in patients with CRPS 2. The signs and symptoms for both conditions are clinically indistinguishable and include sensory changes (allodynia, hyperalgesia, and hypoalgesia), edema, temperature abnormalities, and changes in sweating (see Box 24.3 ). Pain is the principal feature in both CRPS 1 and CRPS 2. In patients with CRPS the associated clinical signs are typically out of proportion to the inciting injury. Patients describe a burning, deep-seated ache that may be shooting in nature along with associated allodynia or hyperalgesia. Pain occurs in 81.1% of patients meeting the CRPS criteria. Patients also frequently complain of sensory abnormalities such as hyperesthesia in response to the typical mechanical stimuli encountered in day-to-day activities (such as dressing) involving the affected limb.
In CRPS 2 (i.e., CRPS with associated major nerve injury), patients often report hyperesthesia around the injured nerve in addition to electric shock–like sensations, shooting pain, and allodynia. Symptoms indicative of vasomotor autonomic abnormalities (including color changes) occurred in 86.9% of patients; temperature instability occurred in 78.7%. Sudomotor symptoms of hyperhidrosis and hypohidrosis were reported in 52.9%. Trophic changes in skin, nail, or hair pattern were reported in 24.4%, 21.1%, and 18%, respectively. Edema was reported in 79.7%, with decreased range of motion in 80.3% and motor weakness in 74.6%.
Diagnosis
There is currently no “gold standard” test for the diagnosis of CRPS. A very thorough history and physical examination are essential for evaluation and diagnosis. Patients with this condition will have the signs and symptoms mentioned previously. Physical examination must be performed to establish the sensory, motor, trophic, sudomotor/edema, and autonomic changes. Sensory changes such as allodynia may be evaluated by light touch and the application of warm/cold temperature to the affected area. Autonomic dysfunction may be confirmed by the presence of asymmetry in temperature and color. Trophic changes may be manifested as changes in skin, nails, and hair in the affected limb. Motor activity may be evaluated by examining motor strength and range of motion. Sudomotor/edema changes may be assessed by dragging a smooth object over the affected and unaffected limb, with the wetter limb allowing a smoother drag than the drier limb. Common diagnostic tools used for diagnosis of CRPS include quantitative sensory testing, tests of autonomic function, and imaging for trophic changes.
Quantitative Sensory Testing
Such testing includes the use of standardized psychophysical tests of the sensory and motor systems, thermal sensation, thermal pain, and vibratory thresholds to assess the function of large-fiber, myelinated small-fiber, and unmyelinated small-fiber afferents. Patients with CRPS may have impaired paradoxical heat sensations, mechanical detection thresholds, mechanical pain thresholds to pinprick stimuli and blunt pressure, allodynia, and pain summation with the use of continuous pinprick stimuli. There is currently no definitive diagnostic sensory pattern in patients with CRPS, but this test can aid in distinguishing other neuropathies from CRPS.
Tests of Autonomic Function
Thermoregulation and sudomotor regulation are the main systems tested in patients with CRPS for disorders in autonomic function. Thermoregulation is tested by using the thermoregulatory sweat test (TST) and infrared thermography or thermometry. The TST assesses calorimetric precipitation from a specific region of the body by adding a solution that changes color when enough heat is generated to produce sweat. Infrared thermography is direct visualization of the change in temperature of the affected site, and in infrared thermometry, a device is used to measure temperature through detection of infrared energy. Changes in temperature in patients with CRPS versus those with other types of pain had a sensitivity of 76% and a specificity of 94%. Sudomotor regulation is tested by using the quantitative sudomotor axon reflex test (QSART), which measures sweat output from various regions of the skin.
Trophic Changes
Three-phase bone scintigraphy (TPBS) is a very valuable test for detection of CRPS. Although joint and bone alterations are not part of the IASP inclusion criteria, they are very important in the outcome of the syndrome. TPBS detects alterations in periarticular bone metabolism, particularly increased bone metabolism, by detecting increase uptake of a periarticular tracer, which occurs predominantly within the first year. TPBS is low in sensitivity but high in specificity. Magnetic resonance imaging of the affected limb has also been used for detection of CRPS but has high sensitivity (97%) and low specificity (17%).
Treatment
Management of CRPS has been complicated by scant knowledge of the etiology of the disease, which has resulted in few targeted therapies. Most of the medications initiated as first-line therapy have been investigated for other non-CRPS neuropathic pain conditions and then applied to the treatment of CRPS, with mixed success. The historical approach to therapy for CRPS still remains a multimodal, multidisciplinary methodology. The predominant therapeutic modalities for the care of CRPS patients include physical therapy, pharmacologic agents, and interventional procedures.
Physical and Occupational Therapy
Physical and occupational therapy for restoration of function and improvement of limbs affected by CRPS has been studied widely. Physical exercises such as isometric strengthening, active range of motion, myofascial release, and stress loading are all tools that aid in restoring functional capacity of the affected limb. Other methods of therapy are currently under study. In a large controlled study in which tactile acuity and pain on application of a tactile stimulus were measured in patients with CRPS and mirror images were used to show the reflection of the unaffected limb during the stimulus, a decreased two-point discrimination threshold and decreased pain acuity were observed. This suggests that therapies that improve functional restoration of the affected limb may improve the outcome of CRPS.
Pharmacologic Therapy
Membrane Stabilizers
Medications such as gabapentin and pregabalin have been shown to be effective in relieving neuropathic pain. CRPS is considered neuropathic pain and gabapentin is presumed to be effective in treating it, yet there are very limited studies showing its specific efficacy for CRPS. In a randomized double-blind, placebo-controlled crossover study in which patients were treated for two 3-week periods with 2 weeks in between, gabapentin had minimal effect on pain but it significantly reduced patients’ sensory deficits. Although there is no clear evidence of efficacy for gabapentin, these neuroleptic medications are the first-line therapy for neuropathic pain and are thus considered first-line therapy for CRPS.
Corticosteroids
A large part of the pathophysiology in CRPS is the acute inflammatory process that occurs after an inciting event (see “Pathophysiology”). Because of this inflammatory course, corticosteroids have been used for treatment. In a recent randomized controlled trial comparing prednisolone with piroxicam, patients were given either medication for 1 month, and their shoulder-hand syndrome scores (measuring pain, distal edema, passive humeral abduction, and external rotation) were determined. In the prednisolone group, 83.3% showed improvement, and in the piroxicam group, only 16.7% improved. The shoulder-hand syndrome score in the steroid group was significantly lower than that in the piroxicam group.
Antidepressants
These drugs have not been studied for use specifically with CRPS, but they have been widely studied for the control of neuropathic pain, and because CRPS is considered neuropathic pain, they are used in pain management. Antidepressants such as tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) have been used to control neuropathic pain effectively. In a recent Cochrane review, TCAs were found to be effective in treating neuropathy, with a number needed to treat (NNT) of 3.6 and a relative risk (RR) of 2.1. Venlafaxine, an SSNRI, was also found to be effective, with an NNT of 3.1 and RR of 2.2. Further studies to investigate the drugs’ ability to specifically target CRPS are warranted. A recent study showed that the combination of gabapentin and nortriptyline was a more effective therapy than either medication alone for neuropathic pain (including CRPS).
Opioids
Studies on the effects of opioids directly on CRPS are lacking, although some have shown opioids to improve neuropathic pain when used in high doses. However, a double-blind, placebo-controlled trial studying the efficacy of sustained-release morphine in CRPS patients for a total treatment of 8 days showed that it was ineffective in decreasing pain, but the study had many limitations. Substantial challenges to using opioid therapy for nonmalignant pain include nausea, constipation, cognitive impairment, tolerance, and hyperalgesia, and therefore it should be used only until other therapies can be initiated. Studies of these medications in the CRPS population are lacking, and more are needed to demonstrate the efficacy of opioids.
Ketamine
Ketamine is an NMDA receptor antagonist. The NMDA receptor is a major part of the central sensitization that occurs in patients with CRPS (see “Pathophysiology”). Ketamine can be administered topically, orally, intranasally, or parentally in subanesthetic (analgesic) doses or in high doses to produce ketamine coma. A double-blind, randomized, placebo-controlled, parallel-group trial studying the effects of subanesthetic intravenous dosing of ketamine for 4 days in CRPS patients showed decreased levels of pain, but the pain progressively increased from the 1st week after infusion to the 12th week. In patients undergoing ketamine infusion, minor and rare side effects such as nausea, vomiting, and psychomimetic effects developed. In another nonrandomized open-label trial in which chronic CRPS patients refractory to standard therapies were treated with anesthetic doses of ketamine for 5 days, the pain improved significantly for 6 months, but 79.3% relapsed back to baseline after the 6-month period. The topical form of ketamine has also been shown to decrease allodynia and hyperalgesia in response to pinprick stimuli, but this has not been well validated.
Bisphosphonates
Bone resorption at the site of inflammation in the affected limb contributes to the pain in CRPS. The use of bisphosphonates to decrease osteoclast overactivity has shown promise in its pain-reducing effects. In an 8-week randomized, double-blind, placebo-controlled study, alendronate was used in patients with post-traumatic CRPS type 1. This drug improved spontaneous pain, tolerance to pressure, and extremity range of motion. However, other trials have shown no reduction in CRPS-related pain.
Interventional Treatment
Sympathetic Nerve Block
The most common sympathetic nerve blocks are the stellate ganglion and lumbar sympathetic blocks for treatment of CRPS of the upper and lower extremities, respectively. Multiple modalities have been studied for their ability to disrupt the sympathetic pathway through these nerve plexuses, including local anesthetics, chemical neurolysis, and radiofrequency ablation. In a study in which both stellate ganglion and lumbar sympathetic blocks were performed with local anesthetic and normal saline on each subject, it was observed that the decreased pain that each experienced was almost identical, but the duration of decreased pain was longer when patients received the local anesthetic block. In a small randomized study in which radiofrequency neurolysis was compared with chemical neurolysis, the pain decreased from baseline, but no significant difference was seen between the two methods. Although sympathetic blocks provide a significant reduction in pain by blocking the sympathetic pathway of the pathophysiologic stages in CRPS, their greatest limitation is that they provide only short-term relief in the vast majority of treated patients. This means that patients must continue to frequently undergo sympathetic blocks, which most often places them on maintenance therapy. This form of therapy should be performed to provide enough pain relief so that patients are able to perform physical therapy exercises for functional restoration and multidisciplinary therapy, but not as a sole therapeutic modality.
Spinal Cord Stimulation
A spinal cord stimulator is a generator containing leads that are placed in the dorsal aspect of the spinal cord within the level that innervates the area causing pain. Most patients have been managed with standard medical therapy and some treated surgically before undergoing spinal cord stimulation (SCS). In a randomized trial, patients with CRPS were separated into two groups: SCS with physical therapy and physical therapy only. This study showed that SCS provided significant improvement in pain for the first 2 years. Unfortunately, there was no amelioration in quality of life or functionality in the group undergoing SCS with physical therapy, although this study was seriously flawed because of excessive patient dropout. SCS has been used widely for the control of intractable pain, but further research is needed to verify its impact on CRPS.
Intrathecal Treatments
Baclofen and ziconotide administered intrathecally have been examined for the treatment of CRPS. Baclofen is a γ-aminobutyric acid receptor agonist. It is currently used as a muscle relaxant and has been indicated for muscle spasticity and dystonia. A single-blind, placebo run-in, dose escalation study of CRPS patients with dystonia showed that intrathecal baclofen was very effective in decreasing dystonia and pain, as well as in improving quality of life, as indicated in a 12-month follow-up. Ziconotide is a very potent drug made from the toxin of sea snail venom and works by blocking chemicals that transmit pain signals. Intrathecal administration of this drug has great potential in reducing edema, trophic changes, and pain in these patients. However, it is associated with a nearly 100% side effect profile.
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