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Complex regional pain syndrome/Kompleks bolgesel agri sendromu.

Summary

Complex regional pain syndrome (CPRS) is a neuropathic pain disorder that can develop as a result of trauma, surgery, or nerve injury, but many times no precipitating event is known. The pain is described as severe, constant, burning and/or deep aching. The hallmark of CRPS is pain and mobility problems disproportionate to the initial injury. Clinical features can include spontaneous limb pain, changes in skin color and temperature, swelling, vasomotor instability, and autonomic dysfunction. The pathophysiology is not well understood, although progress is being made in better understanding the underlying mechanisms. The diagnosis of CRPS is generally clinical, but there are tests and procedures that may help support the diagnosis. The general awareness of CRPS is poor, and well-accepted treatment guidelines are lacking. Treatment should involve an interdisciplinary approach involving functional rehabilitation, pain management, and psychological treatment. Quality evidence supports the use of some medications. Other adjuvant therapies and more invasive treatments exist for refractory cases.

Key Words: Complex regional pain syndrome, reflex sympathetic dystrophy, causalgia, shoulder hand syndrome

Ozet

Kompleks bolgesel agri sendromu (KBAS) travma ve cerrahiden sonra ya da sinir yaralanmasini takiben baslayan, bircok olguda hastaligi baslatan nedenin bulunamadigi bir noropatik agri bozuklugudur. Agri siddetli, sabit, yanici ve/veya derin aci seklindedir. KBAS'in ayirici ozelligi, olayi ilk baslatan incinme ile orantisiz derecede agri ve mobilite sorunlari gorul-mesidir. Klinik bulgular arasinda spontan ekstremite agrisi, deri rengi ve isisinda degisiklikler, sislik, vasomotor instabilite ve otonom disfonksiyon vardir. Altta yatan mekanizmalarla ilgili bilgilerde artis olsa da patofizyo-lojisi henuz tam anlasilmamistir. KBAS tanisi genel olarak klinikle konur. Bazi testler ve yontemler ile de tani desteklenebilir. KBAS hakkinda farkin-dalik dusuktur ve tedavisinde genel kabul goren rehberler henuz yoktur. Tedavisi fonksiyonel rehabilitasyon, agrinin tedavisi ve psikolojik tedaviyi iceren interdisipliner bir yaklasimla olmalidir. Bazi ilaclarin kullanilmasi konusunda belirgin kanitlar bulunmaktadir. Refrakter vakalar icin diger yardimci tedaviler ve girisimsel yaklasimlara basvurulabilir.

Anahtar Kelimeler: Kompleks bolgesel agri sendromu, refleks sempatik distrofi, kozalji, omuz el sendromu

Introduction

Complex regional pain syndrome (CPRS) is a regional neuropathic pain disorder that can develop as a result of trauma, surgery, or nerve injury, but many times no precipitating event is known. The primary complaint is described as severe, constant, burning and/or deep aching pain. The hallmark of CRPS is pain and mobility problems out of proportion to those expected from the initial injury. Clinical features also include spontaneous limb pain, changes in skin color and temperature, swelling, vasomotor instability and autonomic dysfunction.

The condition has been previously referred to as reflex sympathetic dystrophy, causalgia, Sudeck's atrophy, post-traumatic dystrophy (minor or major), reflex neurovascular dystrophy, algodystrophy, mimo-causalgia, sympathalgia, and post-traumatic spreading neuralgia. CPRS in stroke was previously referred to as shoulder hand syndrome, which is characterized by shoulder pain, restricted shoulder range of motion, and hand swelling.

Historical

In the mid-1800s, Sir Claude Bernard, a French physiologist was the first to identify a pain syndrome that was linked to the sympathetic nervous system. In 1872, his student, Weir Mitchell, an American Civil War physician, coined the term "causalgia." It was used to describe the persistent burning pain following gunshot wounds to peripheral nerves during the American Civil War.

In 1900, Paul Sudeck described similar symptoms in a pain syndrome that developed in an extremity after distal bone fractures without affecting any peripheral nerve with radiographic signs of spotty osteopenia.

In 1916, Rene Leriche, a French surgeon, later connected the sympathetic nervous system to causalgia by noting that sympathectomy provided pain relief in many of his patients. In 1943, William K. Livingston, a second world war military doctor, expanded the Leriche theory and postulated a "vicious circle" of pain. He assumed that the activation of peripheral nociceptors would lead to an excitation of spinal interneurons and of sympathetic efferents. Inactivity serves to complicate the pain stimulus by reducing the proprioceptive input and its inhibitory effect of pain at the level of the spinal cord, resulting in unopposed hyperactivity of the sympathetic nervous system, causing further vasoconstriction, spasticity, and inactivity. In addition, he defined pain sensations as being modulated by higher cortical centers and emotional factors, thus contributing to our appreciation of chronic pain as a complex multifactorial phenomenon.

In 1946, Boston physician Dr. James Evans introduced the term reflex sympathetic dystrophy (RSD) to distinguish patients with similar symptoms to causalgia, but who had no acute injury or visible nerve damage.

In recent years there is growing evidence that sympathetically maintained pain is still an important psychophysical response, but not obligatorily necessary for the diagnosis of these disorders. A new diagnostic criteria was introduced based entirely on elements of history, symptoms and findings on clinical examination, with no implied pathophysiological mechanism.

According to the International Association for the Study of Pain (IASP) 'Classification of Chronic Pain', reflex sympathetic dystrophy and causalgia are now called complex regional pain syndromes (1). CRPS has been divided into 2 subtypes. In CRPS type I (reflex sympathetic dystrophy), tissue injuries or lesions in remote body areas typically precede the onset of symptoms. CRPS type II (causalgia) reflects the presence of documented nerve injury.

Epidemiology

A population-based study of Olmsted County, Minnesota found that the incidence rate of CRPS was 5.46 per 100.000 person years at risk, and a prevalence of 20.57 per 100.000 (2). Females are affected more commonly than males. Average age of onset is 38-46 years (2,3). In a prospective study by Veldman and colleagues (4), which reviewed 829 patients, 628 patients were female (76%) and 201 were male (24%). CRPS can occur in children and adults, but less common in children 10 years old or younger, which may be due to underdiagnosis. In the Veldman study of 829 patients, age of diagnosis was 9-85 years (median 42 years); only 12 patients were younger than 14 years. CRPS may occur in a familial form with a higher incidence in certain HLA types (5).

Pathogenesis

The pathophysiology of CRPS is still a matter of debate. Previously, CRPS was thought to be mediated by a sympathetically maintained reflex arc. This was supported by the presence of abnormalities in skin temperature, color, and sweating in the affected extremities. However, plasma catecholamine concentrations are lower in CRPS-affected limbs (6) and most CRPS patients do not obtain significant or lasting pain relief from sympathetic blocks (7).

Three major mechanisms are proposed to encompass the underlying pathophysiology: dysfunction of the sympathetic nervous system, enhanced peripheral neurogenic inflammation, and structural reorganization of the central nervous system (8).

Sympathetic dysfunction has been demonstrated by lower catecholamine levels on the affected side (6,9). These lower epinephrine levels may imply a local sympathetic hypofunction that may be related to damage to sympathetic efferents. Reduced sympathetic function (and the resulting excessive vasodilation) in early acute CRPS is consistent with a warm, red affected limb. It is believed that the decreased sympathetic outflow in acute CRPS would be expected to lead to compensatory up-regulation of peripheral adrenergic receptors, leading to vasoconstriction and colder skin typically seen in chronic CRPS I (10).

Data support the concept of an exaggerated and persistent regional inflammatory response to injury or surgery (11,12). Two sources of inflammation have been described: classic inflammatory response and neurogenic inflammation. Classic inflammatory mechanisms can contribute through actions of immune cells such as lymphocytes and mast cells, which after tissue trauma, secrete proinflammatory cytokines, including TNF-[alpha], interleukin-1[beta], -2, and -6. These substances produce localized edema similar to that observed in CRPS. Several studies indicate that CRPS patients display significant increases in proinflammatory cytokines (TNF-[alpha], interleukin-1[beta], -2, and -6) in blister fluid, circulating plasma, and cerebrospinal fluid compared with non-CRPS pain patients (13). CRPS I patients with hyperalgesia and allodynia have significantly higher plasma levels of TNF-[alpha] than CRPS patients without hyperalgesia and allodynia (14,15).

Neurogenic inflammation can also occur in response to nerve injury. Neuropeptide mediators involved in neurogenic inflammation include substance P. calcitonin gene-related peptide (CCRP), and bradykinin. Elevated plasma levels of substance P, CGRP and bradykinin have been demonstrated in CRPS patients compared with healthy controls (16-19). These inflammatory mediators lead to the physical signs of inflammation, including warmth, swelling, and erythema characteristic of acute CRPS.

Cortical reorganization may explain some of the signs of CRPS. The pattern of motor impairment was consistent with a disturbed integration of visual and proprioceptive inputs in the posterior parietal cortex on kinematic analysis. On functional magnetic resonance imaging, CRPS patients showed a significant reorganization of central motor circuits, with an increased activation of primary motor and supplementary motor cortices. Furthermore, the ipsilateral motor cortex showed a markedly increased activation (20). Earlier studies on functional brain imaging have also demonstrated these adaptive changes and imply that chronic pain may alter central tactile and motor processing (12,21).

Trauma (often minor) is the leading provocative event. A population based study found fracture to be the most common trigger occurring in 46% of the cases (2). In 2 prospective studies of patients with Colles fracture, 28-37% developed signs and symptoms consistent with CRPS (22,23). Another prospective study of unilateral tibial shaft fractures found that 30% showed signs of CRPS (24).

Other precipitating factors include ischemic heart disease and myocardial infarction, cervical spine or spinal cord disorders, cerebral lesions, infections, surgery, and repetitive motion or cumulative trauma disorders. CRPS has been found to be an infrequent complication of various surgical procedures including carpal tunnel release (25,26), Dupuytren contracture release (27), knee arthroplasty (28), lower extremity amputation (29), total hip replacement (30), and arthroscopy (31). However, in some patients a definite precipitating event cannot be identified.

Clinical Features

CRPS is distinguished by significant autonomic features and typically develops in an extremity after acute tissue trauma. In addition to classic neuropathic pain characteristics, CRPS is associated with local edema and changes suggestive of autonomic involvement. Trophic changes and altered motor function may also occur (32-35). An important feature of CRPS is that the severity of symptoms is disproportionate to the severity of trauma. CRPS is subdivided into CRPS I (reflex sympathetic dystrophy) and CRPS II (causalgia), reflecting, respectively, the absence of presence of documented nerve injury. Signs and symptoms of the two CRPS subtypes are similar, and there is no evidence that they differ in terms of pathophysiologic mechanisms or treatment options.

Sensory, autonomic, and motor abnormalities are variably present. All tactile stimulation of the skin may be perceived as painful. Stimulus-evoked pains such as mechanical and thermal allodynia and/or hyperalgesia may be present. Sensory abnormalities often appear early, are most pronounced distally, and have no consistent spatial relationship to individual nerve territories or to the site of the inciting lesion. Autonomic abnormalities include skin temperature of the affected extremity being either warmer or colder. Sweating abnormalities include either hypohidrosis or, more frequently, hyperhidrosis. Trophic changes to the skin, hair and nails may also occur.

Motor dysfunction is often present. This includes weakness, tremor, exaggerated tendon reflexes, dystonia, and incoordination (4,20,36). Almost all patients are found to have weakness of the affected distal extremity (37).

Initially, CRPS symptoms are generally localized to the site of injury. The upper limb is affected twice as often as the lower limb (2). As time progresses, the pain and symptoms tend to become more diffuse. Three patterns of spreading symptoms in CRPS have been described:

i) "Continuity type" of spread where the symptoms spread upward from the initial site, e.g. from the hand to the shoulder,

ii) "Mirror-image type" where the spread is to the opposite limb, and

iii) "Independent type" where symptoms spread to a separate, distant region of the body. This type of spread may be spontaneous or related to a second trauma.

Patterns of spread remain controversial. Perceived spreading may be due to compensatory mechanisms and myofascial pain. Maladaptive changes in the body and supporting muscles can occur from compensating for the injured limb over time. These overused and deconditioned muscle groups are more likely to develop myofascial pain. Myofascial trigger points in the neck and shoulder can cause pain to radiate to the head or to the same or opposite limb. These painful and sometimes disabling symptoms may be perceived by the patient as "spreading."

Historically, three stages of CRPS have been cited to identify progression of the syndrome, but were based on certain authors' experience rather than an outcome of empirical scientific study. These stages of CRPS were no longer found to be accurate or useful and therefore the concept of staging CRPS has lost its significance.

Classically CPRS is divided into 3 stages: Stage 1 is characterized by persistent pain in the extremity. The pain is frequently described as burning or aching and is aggravated by movement. Blood flow to the extremity is increased. Onset of severe pain is limited to the site of injury. There is increased sensitivity of the skin to touch and light pressure (hyperesthesia), stiffness and limited mobility. At onset, the skin is usually warm, red and dry, and then it may change to blue (cyanotic) in appearance and become cold and sweaty. There is increased sweating (hyperhidrosis).

If CRPS progresses to stage 2 or 3, functional recovery of the affected limb is considerably limited. Stage 2 is characterized by pain that becomes even more severe and more diffuse. Early dystrophic changes in the limb develop. Swelling tends to spread and it may change from a soft to hard (brawny) type. Hair may become coarse then scant. Nails may grow faster, and then grow slower and become brittle, cracked and heavily grooved. Spotty osteoporosis occurs early but may become severe and diffuse.

Stage 3 is characterized by marked wasting of tissue, soft-tissue dystrophy, and contractures. Pain becomes intractable and may involve the entire limb. A small percentage of patients develop generalized CRPS affecting the entire body. However, severe chronic CRPS is uncommon with a low prevalence (<2%) in retrospective series (38).

The course of the disease seems to be so unpredictable that staging is not helpful in the diagnosis of CRPS. Not all of the clinical features listed for the various stages of CRPS may be present. The speed of progression also varies greatly in different individuals. Some patients do not even progress to Stage III. Thus the concept of staging of CRPS has lost its significance.

Diagnosis

The diagnosis of CRPS is generally clinical. The current IASP criteria permits a diagnosis based solely on patient-reported historical symptoms (1). There are four criteria that must be satisfied for a diagnosis of CRPS:

i) an initiating trigger or event,

ii) pain symptoms out of proportion to the inciting event,

iii) sudomotor, blood flow, or edema changes at some point in time, and

iv) no other diagnosis can account for this condition.

The 1994 IASP diagnostic criteria for CRPS have low specificity, potentially leading to over diagnosis. A validation study compared the IASP diagnostic criteria for CRPS to proposed new diagnostic criteria referred to as the "Budapest Criteria". The Budapest clinical criteria demonstrated exceptional sensitivity of the IASP criteria when 2 of 4 sign categories and 3 of 4 symptom categories were present. With improved sensitivity and specificity, as many patients with CRPS were identified and there was a reduction in the high level of false-positive diagnoses associated with the 1994 IASP criteria. An even higher specificity was required to meet the Budapest research criteria, so the researchers recommended that 2 of 4 sign categories and all 4 symptom categories must be positive for the diagnosis of CRPS to be made (39). To make a diagnosis of CRPS there are several criteria that should be present:

i) persistent pain disproportionate to the initial trigger,

ii) there must be symptoms in all four categories, a. sensory function

b. vasomotor dysfunction

c. sudomotor dysfunction or edema

d. trophic changes, motor dysfunction, or restricted range of motion

iii) there must be at least one sign in at least two of the categories at the time of evaluation:

a. Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)

b. Vasomotor: evidence of temperature asymmetry and/or skin color changes and/or asymmetry

c. Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating asymmetry

d. Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

iv) there should be no other diagnosis to explain the condition.

There is no laboratory test or objective modality that is diagnostic of CRPS. However, sympathetic blocks, bone scans, and thermography have been useful in providing evidence of CRPS.

Sympathetic Blocks: Sympathetic blocks may be utilized for diagnostic and/or therapeutic purposes for patients with sympathetically maintained pain. These involve injection of local anesthetic around the sympathetic paravertebral ganglia. Cervical ("stellate") blocks are performed for upper extremity symptoms, whereas lumbar blocks are performed for lower extremity symptoms. Regional intravenous sympathetic blocks to an extremity blocked with a tourniquet are performed infrequently. The evidence-based literature with regards to sympathetic, stellate, and lumbar blocks in CRPS is overall not of high quality. The majority of the literature involves retrospective case series, very small sample sizes, lack of control groups, inadequate assessment of response including pain reduction, duration of response not typically reported, and possible complications ignored (40-42). Despite the lack of supporting evidence, sympathetic blocks have been used for many years in the diagnosis and management of CRPS.

Plain Radiography: Though it is not diagnostic of CRPS, plain X-rays are useful to identify radiological abnormalities, such as diffuse osteoporosis and spotty demineralization, particularly in the periarticular regions, combined with subperiostal bone resorption in CRPS patients.

Three-phase Bone Scintigraphy: Three-phase bone scintigraphy is highly sensitive and specific for CRPS. Furthermore, bone scintigraphy detects osseous changes earlier than plain radiographs (43,44). Findings include increased periarticular uptake throughout the three phases, indicating increased bone metabolism. These findings are not expected until at least 6 months after the onset of CRPS (45). Bone scan is not only useful as a diagnostic tool but may also provide a quantitative indication of the severity of the condition (46).

Thermography: Stress infrared thermography is a diagnostic imaging procedure that detects and records body surface temperatures by detecting the heat emitted from the skin. This safe, noninvasive, nonionizing physiologic procedure accurately assesses the integrity of the vasomotor component of the peripheral autonomic nervous system. This procedure has demonstrated to be a highly specific and sensitive indicator of the CRPS-I (47).

Plain radiographs, bone densitometry, and magnetic resonance imaging have not been shown to be sensitive or specific in diagnosing CRPS (48,49).

Treatment

The general awareness of CRPS is still poor. As a result, an average of thirty months elapses until patients are admitted to a pain center for adequate therapy (3). Multiple pharmacologic and nonpharmacologic interventions usually fail. A well-accepted treatment algorithm and guideline for pharmacotherapy in CRPS is lacking (50). However, an expert panel encourages an interdisciplinary approach involving rehabilitation, pain management, and psychological treatment (51). Other adjuvant therapies may include relaxation techniques, biofeedback, and cognitive behavioral therapy. Interdisciplinary treatment is thought to be most effective early in the disease process. The goals of interdisciplinary treatment are pain reduction and preserving and/or reestablishing limb function.

Physical Therapy

Physical therapy has been shown to improve outcomes in CRPS patients in case reports and randomized control trials. Improvements from physical therapy include faster improvement in pain, skin temperature changes, and active mobility. In a multi-center, randomized controlled study, patients with CRPS of one upper extremity that were treated with adjuvant physical therapy had a significant and faster improvement in impairment compared to patients who only had medical therapy. Therefore, physical therapy started at an early stage should be considered as a significant component of the therapeutic process (52).

Functional recovery through a measured pace should be the ultimate goal of treatment. Initially, desensitization and overcoming fear of movement is important, allowing the limbs to be touched and the patient to start moving. First steps are to manage edema, initiate gentle active movements, and institute preliminary desensitization techniques. Edema is managed using specialized garments and manual edema mobilization techniques. All other treatments are to aid therapy and improve function. Desensitization, edema control and active motor control are the hallmarks of PT and OT for CRPS (52-54).

The Evidence Based Guidelines Development (EBGD) Guidelines on Complex Regional Pain Syndrome type I (CRPS-I) dealing with the diagnosis and treatment of CRPS-I were published in 2006. The principal objective of the physiotherapeutic treatment protocol as developed by the physiotherapy department of St. Radboud University Medical Centre (Nijmegen, the Netherlands) is to enable the patient to gain the greatest possible degree of control over his or her symptoms (55).

The key components of this protocol are:

i) Increasing the degree of control over the pain and improving the way the patient copes with the syndrome, for instance by giving him or her information and support (recording and discussing a program of daily activities) or relaxation exercises (55).

ii) Extinguishing the source of pain and treating any dysregulation, for example by performing exercises to attenuate pain, desensitization, or the use of a sling or splint (55).

iii) Improving skills, for example by practicing compensatory skills, training skills, and posture and movement instruction. The patient's need for (and interest in) help will determine the specific exercises carried out at a later stage (55).

Efforts to improve mobility can start as soon as the pain is 'under control'. The emphasis here will be on active and functional movement. Attention needs to be paid throughout the entire course of treatment to maintaining as normal a posture and movement pattern as possible and to preventing changes to adjacent joints and muscles (for example, changes brought about by contraction) (55).

Occupational Therapy

A general occupational therapy protocol when treating patients with upper-limb CRPS-I are:

i) to reduce clinical symptoms, and protect and support the affected limb in the most functional and comfortable position by means of a splint, and explanation and advice.

The practitioner will decide whether the patient should be measured for a supportive splint. This could be a resting splint for the entire hand and forearm, or for part thereof (wrist or thumb, for instance). Patients are instructed individually on how to wear the splint. The aim of wearing an orthotic device is to minimize symptoms and prevent overstrain (55);

ii) to normalize sensitivity by carrying out an extensive desensitization program (55);

iii) to encourage the functional use of the limb within the pain threshold. Various play activities, dexterity techniques and/or everyday activities are carried out for this purpose (55);

iv) to encourage independence, particularly with regard to self-care, productivity and relaxation. The strategies can be targeted at restoring the necessary skills, at learning to do things in another way (with one hand, for instance), or at advising the patient on devices he or she could use or sources of additional support and care that are available (55).

Mirror Box Therapy. The affected limb is placed within a mirror box, such that the unaffected limb is reflected in a way to make the patient think they are looking at the affected limb. Using the mirror, a visual illusion can be created of a normal and pain-free movement of the affected limb. Mirror box therapy is thought to work by providing visual feedback by moving the unaffected limb in front of the mirror resulting in cortical reorganization (56). Studies showed that altered or absent sensory feedback results in cortical reorganization of body representations in the primary somatosensory and motor cortex, and that the amount of reorganization is correlated with the severity of the experienced pain. This cortical reorganization in pathological conditions may be influenced by providing alternative sensory input using a visual illusion, thereby reducing pain (57,58). Mirror box therapy in patients with CRPS-I existing for less than 2 years has shown to cause some regain of functionality and mobility and to reduce pain (59).

Complementary Therapies: A small double-blind, placebo-controlled prospective trial of acupuncture was performed on patients diagnosed with CRPS of the upper limb with less than 6 months duration. Patients were randomly assigned subjects to either the classical acupuncture or sham acupuncture. Both groups received 30 minutes of treatment five times a week for three weeks. During therapy clinical parameters, as well as pain, improved in both groups and reached nearly normal levels after 6 months. No differences between sham and treatment group could be recognized (60).

Acupressure is an ancient healing art skillfully pressing key points on specific locations on the body. In a case study, improvement was found in a patient that previously received various treatments including repeated lumbar sympathetic blockade and multiple medications (61).

Hyperbaric Oxygen (HBO): In a double blind, randomized, placebo-controlled study of 71 patients, 37 were assigned to the HBO group and 34 to the control (normal air) group. Both groups received 15 therapy sessions in a hyperbaric chamber. The HBO group showed a significant decrease in pain and edema and a significant increase in ROM (62).

Electroconvulsive Therapy (ECT): In a case study, a 42-year-old female patient underwent a series of 12 standard bitemporal ECT sessions for medically refractory depression. The treatment completely resolved the patient's depressive symptoms and the patient's CRPS symptoms were also reversed (63). In another small study, 3 cases presented in which ECT for depression led to the relief of co morbid CRPS as well as depression (64).

Hypnosis: A patient who was unresponsive to multiple medical treatments for CRPS was assessed using a sodium pentothal hypnosis interview. The hypnosis interview suggested pain was centrally generated. The patient's pain symptoms resolved with hypnotherapeutic treatment (65).

Pharmacological Therapies

A limited number of randomized controlled trials of oral pharmacotherapy have been performed in CRPS patients. The presence of unsettled disability or liability claims, a common issue in CRPS patients, is usually an exclusion for entry into pharmaceutical industry-sponsored studies (66). Further it is difficult to perform clinical trials on pharmacotherapy due to controversy in objective diagnostic criteria (67). Quality evidence does exist that supports the use bisphosphonates, glucocorticosteroids, calcitonin, and gabapentin.

NSAIDs: Non-steroidal anti-inflammatory (NSAIDs) drugs are often first line agents in various painful conditions. In several clinical trials of neuropathic pain, NSAIDs have shown mixed results (68). There is no quality evidence that oral NSAIDs are beneficial in decreasing pain due to CRPS.

Antiepileptic Drugs: Gabapentin is a gamma aminobutyric acid (GABA) analog that has no action on the GABA receptor, but binds to the 2- voltage-regulated calcium channel. It may be beneficial for treatment of CRPS. A randomized double blind placebo controlled crossover study with two 3-weeks treatment periods with gabapentin and placebo separated by a 2-weeks washout period was performed. This high quality study found significant pain relief in favor of gabapentin in the first period. Therapy effect in the second period was less. CRPS patients had sensory deficits at baseline that were significantly reversed in gabapentin users in comparison to placebo users. Overall, the benefits of gabapentin in CRPS are considered mild and short term (69).

Bisphosphonates: It is postulated that osteoclast hyperactivity is the dominant mechanism involved in the localized osteoporosis present in CRPS. Bisphosphonates reduce osteoclastic activity in bone. Bisphosphonates have significant analgesic efficacy in a number of bone-related pathologies suggesting additional analgesic mechanisms. They may play a role in modifying inflammatory cytokines (e.g., interleukin-1) and other systemic factors (e.g., prostaglandin E2) involved in sensitizing painful nociceptors and low-threshold mechanoreceptors (70).

Bisphosphonates are pyrophosphate analogues that appear to offer clear benefits for patients with CRPS. A study evaluated the efficacy of intravenous clodronate in patients with reflex sympathetic dystrophy syndrome. The conclusion was that a 10 day intravenous clodronate course is better than placebo and effective in the treatment of RSD (71). A randomized, blinded, placebo-controlled study demonstrated that patients treated with oral alendronate 40 mg daily exhibited a marked and sustained improvement in levels of spontaneous pain, pressure tolerance, and joint mobility (72). Another study using alendronate found patients treated with alendronate experienced significant improvement in motion, diminution in spontaneous pain, tenderness, and swelling (70). These studies have demonstrated the substantial benefit of bisphosphonates in the treatment of CRPS.

Calcitonin: Calcitonin is a hormone secreted by the parafollicular cells of the thyroid gland. It retards bone loss and is thought to have anti-nociceptive effects (73). The mechanism of this anti-nociceptive effect is uncertain. A meta-analysis of a limited number of controlled studies indicates efficacy of calcitonin in the treatment of CRPS at intranasal doses of 100-300 units per day (74).

Corticosteroids: Short courses of corticosteroids have meaningful benefits in the treatment of CRPS. Two prospective, randomized, controlled trials utilizing a course of oral corticosteroids (approximately 30 mg/day for 2-12 wks, followed by a tapering period) reported significant improvements compared with placebo in patients with early acute CRPS (75,76). In another study, 31 subjects with CRPS were treated with corticosteroids. Low risk of side effects was noted. Improvement persisted at one-year follow-up (77).

Phenoxybenzamine: Phenoxybenzamine is a non-specific alpha antagonist. In cases of causalgia due to nerve injuries from missile or shrapnel wounds, oral phenoxybenzamine in gradually increasing increments until a maximum daily dose of 40 to 120 mg was studied. Duration of treatment was usually 6 to 8 weeks. Total resolution of pain was achieved in all cases. The follow-up period ranged between 6 months and 6 years. Side effects were primarily that of orthostatic hypotension and ejaculatory problems. The study concluded that oral phenoxybenzamine is a simple, safe, and effective treatment of causalgia (78).

Nifedipine: Nifedipine, a calcium channel blocker, was initially studied as a potential treatment for CRPS due to its benefit in Raynaud's phenomenon. This syndrome was considered similar to RSD in being characterized by vasospasm and cold intolerance. The drug was found effective in the treatment of CRPS in two uncontrolled case series at doses of up to 60 mg/day (79,80).

Free Radical Scavengers: Vitamin C reduces lipid peroxidation, scavenges hydroxyl radicals, protects the capillary endothelium, and inhibits vascular permeability (81). There is evidence that Vitamin C taken after a wrist fracture decreases the incidence of CRPS 1. A double-blind study of 127 wrist fractures treated with placebo or vitamin C found that oral administration of 500 mg of vitamin C per day for 50 days from the date of the injury reduced the incidence of CRPS 1 in patients with wrist fractures (82). A cohort study of patients with wrist fractures treated by surgery demonstrated a decreased incidence of reflex sympathetic dystrophy in patients given vitamin C 1000 mg/day for 45 days starting on the day of the fracture versus placebo (83).

Opioids: Opioids are frequently used in CRPS when other measures fail to adequately control pain. One randomized, controlled trial with the use of sustained-release morphine reported no difference in pain reduction compared with placebo after 8 days of use. Patients with peripheral neuropathic pain, exclusively pain reduced by spinal cord stimulation (SCS), were enrolled. A painful state was obtained after SCS inactivation. Patients subsequently received either sustained release morphine (90 mg/d) or placebo for 8 days (84). Morphine may require larger individually titrated dosages than those used in this study for results to be adequately interpreted. There is a lack of evidence supporting the use of oral opioids in patients with CRPS 1.

Topical Agents: A number of topical applications have been tried for CRPS. Capsaicin cream is used for treating other neuropathic pain conditions. Capsaicin is a selective neurotoxin, and long-term treatment causes selective epidermal C fibers loss and resulting in less substance P released. Repeated topical application of capsaicin prevents the antero- and retrograde release of neuropeptides and glutamate (85). In a case report a multi-trauma patient who developed CRPS 1 in the left foreleg, which hindered mobilization was treated with topical capsaicin 0.075% twice daily and stress-loading mobilization. After 6 weeks, no signs or symptoms of CRPS I were present and capsaicin was discontinued (86). Many patients with CRPS may not tolerate capsaicin due to the burning sensation.

Transdermal lidocaine patches may be better tolerated. In a case report a 10-year-old girl developed CRPS 1 after arthroscopic surgery for a sprained ankle obtained a good response to topical lidocaine (87). A small open label study of topical lidocaine showed benefits in all 5 patients enrolled (88).

Isosorbide dinitrate, a vasodilator, might be effective in the renormalization of the disturbed balance between endothelin-1 and nitric oxide levels and the diminished microcirculation, thereby reducing tissue acidosis and the resulting pain (89). In a pilot study, 5 patients with CRPS 1 in one hand were treated with topical isorbide dinitrate ointment 4 times daily for 10 weeks. Results demonstrated an increase in mean skin temperature of the cold CRPS 1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks (90). The authors concluded its topical application seemed to be beneficial in improving symptoms for patients with cold type CRPS1.

In a case series, the alpha 2-adrenergic agonist clonidine was delivered topically to the patients with hyperalgesic skin due sympathetically maintained pain. The transdermal clonidine was found to be effective in reducing or eliminating local CRPS-induced hyperalgesia and allodynia (91).

Ketamine: Several case and open label studies reported the effectiveness of ketamine infusions in the treatment of CPRS (92-98). A small double blinded placebo controlled study by Schwartzman showed that intravenous ketamine administered in an outpatient setting resulted in reductions in many pain parameters (99). A larger double-blinded randomized placebo-controlled trial involving 60 patients with mostly chronic CPRS 1 found a multiple day intravenous ketamine infusion resulted in significant pain improvement but without functional improvement (100). Furthermore, this evolving course of treatment has been questioned due to lack of safety data and potential treatment costs of repeated intravenous ketamine infusions (101). Due to the undesirable side effects of parental ketamine, Finch et al. (102) investigated the sensory effects of topical ketamine 10% in CRPS, particularly on allodynia. The study found ketamine applied to the symptomatic limb inhibited allodynia to light brushing and hyperalgesia to punctate stimulation but did not result in pain reduction. The systemic effects of the ketamine were determined to be unlikely to account for the improvement in allodynia because the plasma levels were below detectable limits.

Intravenous Immunoglobulin: Evidence suggests that an immune response is activated in the affected limb, blood, and cerebrospinal fluid of CRPS patients (13,16,103). Intravenous immunoglobulin (IVIC) interferes with the cytokines and pro-inflammatory markers produced in the activated immune response. An open-label study of patients who suffered from a variety of chronic pain syndromes demonstrated that low dose IVIG provided a new, effective treatment for patients with chronic pain syndromes (104). IVIC has been shown to reduce pain in refractory CRPS in randomized controlled conditions (105). This study was limited by the involvement of a single study center, small number of participants, short observation period, and lacked objective measures. Some consider IVIG an unrealistic treatment option for CRPS because it is available in limited quantities and expense (106).

Interventional Therapies

Sympathetic Blocks: The quality of published reports on lumbar sympathetic and stellate ganglion blocks is poor (107). The majority of the literature involves retrospective case series, very small sample sizes, lack of control groups, inadequate assessment of response including pain reduction, duration of response not typically reported, and possible complications ignored. A systematic review concluded that less than one third of patients obtained full pain relief; which the authors noted is consistent with placebo response (107).

Patients with mechanical allodynia with burning pain accompanied by temperature and color changes might be reasonable candidates for sympathetic blockade. Sympathetic blocks may be helpful if pain is limiting participation in physical and occupational therapy despite adequate trials of oral medications. Sympathetic blocks are a treatment consideration early in the course of treatment particularly when allodynia and temperature and color changes are present (108). However, the presence of autonomic abnormalities does not guarantee a positive response (107).

There does not appear to be convincing evidence to support an extended series of blocks unless there is clear observation that the blocks are facilitating increased ROM, pain reduction, and increased tolerance of activity and touch in physical and occupational therapy. Further, response to repeated blocks may lessen in effectiveness over time.

Sympathectomy: If patients obtain significant symptomatic temporary relief from sympathetic blocks, then a more permanent sympathetic block may be considered. This may be done by either surgical, chemical, or radiofrequency techniques (108-110). Several open studies report a beneficial effect on pain reduction in patients with CRPS (114-117). However, a Cochrane Database review concluded that the practice of surgical and chemical sympathectomy is based on poor quality evidence, uncontrolled studies and personal experience. It further reported that significant complications may occur, in terms of either worsening pain or producing a new pain syndrome (115). The most important factor in determining satisfactory outcomes of sympathectomy was the time between injury and sympathectomy (111-113).

Spinal cord stimulation: Retrospective, uncontrolled case series show that spinal cord stimulation (SCS) can reduce intensity of neuropathic pain. Biases in existing literature (lack of blinding, heterogeneity of interventions/assessments, small numbers) confound its interpretation. Unfortunately, the methodologic quality of published reports remains generally weak (116).

Reports of success with relatively small samples of patients with CRPS mixed among patients with other chronic pain conditions have suggested potential benefit. One randomized controlled trial in patients receiving spinal cord stimulation and physical therapy experienced significant reduction in pain intensity relative to those only receiving physical therapy (117). A 2 year follow up suggested that with careful selection of patients and successful test stimulation, SCS is safe, reduces pain and improves quality of life in chronic RSD. However, there was no clinically important improvement of functional status (118).

Continuous Spinal Infusion Catheter: Implantable pumps can be used to deliver medications directly into the cerebrospinal fluid. Two case series found benefit from the use of intraspinal opioid therapy for the management of intractable pain from nonmalignant origin in carefully selected patients (119,120). The use of continuous spinal infusion systems is generally not recommended. Continuous spinal infusion catheters might be considered for patients with markedly decreased ROM, poor pain control, and intolerance of activity or touch as long as it is combined with aggressive PT and OT.

Conclusion

CRPS is a perplexing neurological disorder with potentially devastating consequences. Its pathophysiology is not well understood. This poor understanding has led to the lack of well-accepted treatment guidelines. Further insight into its underlying mechanisms may lead to better treatments for those suffering from CRPS. There should be an interdisciplinary approach to the treatment of patients diagnosed with CRPS with an emphasis on pain relief and improving function.

DOI: 10.4274/tftr.09327

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Stephen KISHNER, Brett J. ROTHAERMEL, Satvik B. MUNSHI, Jacinthe V. MALALIS, Osman Hakan GUNDUZ *

Louisiana State University School of Medicine, Section of Physical Medicine and Rehabilitation, New Orleans, USA

* Marmara University School of Medicine,

Department of Physical Medicine and Rehabilitation, Istanbul, Turkey

Address for Corresponctence:/Yazisma Adresi: Stephen Kishner MD, Louisiana State University Medical Center, Section of PM&R, Touro Rehabilitation Center, Touro Infirmary, 1401 Foucher Street, Suite 10012, New Orleans, Louisiana 70115 USA Phone: +1 504 897 8948 Fax: +1 504 897 7145 E-mail: skishn@lsuhsc.edu

Received/Gelis Tarihi: May/Mayis 2011 Accepted/Kabul Tarihi: Auqust/Aqustos 2011
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