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9 Articles in Volume 13, Issue #3
Comprehensive Rehabilitation of the Cancer Pain Patient
Neuropathy in the Cancer Patient: Causes and Cures
The Basics of Breakthrough Pain: Transmucosal Fentanyl
The Use of Botulinum Toxin in Migraines: A Review
Complex Regional Pain Syndrome: Systemic Complications
Diagnostic Ultrasound in Carpal Tunnel Syndrome: A Helpful Additional Tool
The Homebound Adolescent Headache Patient
Editor's Memo: Neurosteroids—Gaining Ground In Pain Management Research
Ask the Expert: Monitoring Liver Function

Complex Regional Pain Syndrome: Systemic Complications

CRPS is becoming the great imitator in pain medicine. This article discusses the symptomatology of the disease, including atypical presentations.

Recent studies of neuropathic pain have helped delineate the major features of CRPS. It is now clear that most patients with CRPS have suffered either an injury to terminal twigs (peripheral fibers) of C and A-δ nociceptive afferents in soft tissue, or have a frank nerve injury, bone fracture, or have undergone a surgical procedure.2,3 Cluster analysis has revealed that the signs and symptoms of the syndrome may be separated into distinct factors (Table 1).4 The clinical diagnosis requires at least one symptom in each of the factors and one sign in at least two of the factors.5

Over time, changes occur in the central nervous system's (CNS) control of the autonomic, somatosensory, and motor systems.6 Major mechanisms underlying the pathophysiology of the disease include peripheral sensitization of the C and A-δ afferent terminal nerves in the area of injury; central sensitization of pain transmission neurons (PTNs) in all components of the pain matrix; immune mechanisms; and a maladaptive response of physiologic pain mechanisms.7-15 There are subtypes of CRPS rather than specific clinical stages through which the syndrome evolves. This review focuses on the severe subtype, which is manifested by pain that has spread from the site of original injury, is longstanding, comprises all components of the syndrome, and may be generalized to the entire body.16,17

Chest Pain in CRPS

A common cause of atypical chest pain in CRPS patients, which is more frequent in women than men, is irritation and sensitization of the intercostobrachial (ICB) nerve.16,17 The source of the ICB nerve arises from the second intercostal nerve root (T2) and has variable contributions from T3 and T4 nerve roots.18,19 It innervates the axilla, medial, and anterior arm, and contributes to the innervation of the upper anterior chest wall from its connection with the long thoracic nerves.19,20 It also contributes to the innervation of the posterior forearm from its connections with the posterior antebrachial cutaneous nerve and occasionally innervates the pectoralis major and minor muscles.20

A recent prospective study using pressure algometry to evaluate the sensitivity of the chest wall in CRPS patients and normal controls revealed that the majority of patients with upper extremity CRPS (94%) reported a history of chest pain, compared to 19% of controls.17 Of the CRPS patients with chest pain, 66% had bilateral pain; 79% reported pain that was above the breast and deep in nature; 51% of patients had pain that radiated to their jaw/head/neck; and 46% had shoulder/arm pain. In 65% of the patients, chest pain was elicited by elevation of the arms.

CRPS has developed in patients following modified radical mastectomy and other breast surgeries, as well as in patients with invasive cancers.21-23 Following mastectomy, patients have described an ever present pain in the medial and posterior arm.21 The pain is described as dull, aching, or burning, with superimposed episodes of lancinating pain. It is increased with movement and can be elicited by pressure on the second intercostal space of the anterior axillary line. Presenting symptoms of Pancoast's syndrome (lung tumors) include chest pain and allodynia in the medial upper arm and shoulder from metastatic invasion of the ICB nerve.24

Systemic Medical Complications of CRPS

It generally has been accepted that over time CRPS affects the somatosensory, autonomic, and limbic components of the pain matrix in a majority of severely affected patients.6 The systemic complications of the syndrome are not as well appreciated.25

Neuropsychological Deficits
Cluster analysis of 500 patients with severe CRPS demonstrated 3 distinct groups: neuropsychologically normal patients (36%); patients with mild dysexecutive deficits (42%); and patients who had cognitive impairment in executive function, naming, and memory (22%).26 The memory deficits demonstrated in these latter patients suggested executive (retrieval) rather than amnestic (encoding) dysfunction. The evaluation of this large cohort of >500 patients suggests that a dysexecutive syndrome is the underlying deficit. Depression, extent, and duration of illness did not correlate with these cognitive changes.26,27

Functional magnetic resonance imaging (fMRI) studies of CRPS patients with hand involvement demonstrate activity-dependent neuroplasticity. There is clear alteration of a patient's hand representation in the primary somatosensory cortex, which reverts to normal with recovery.28-31 CRPS patients have demonstrated tactile and proprioceptive deficits and also report as if their hands feel "foreign or strange" or not belonging to their bodies.32-34 In addition to the impaired cognitive function and plastic aberrations of the body schema demonstrated in CRPS patients, there may be structural brain changes, as demonstrated in other severe neuropathic pain states.35

Constitutional Symptoms
Almost all severely affected CRPS patients complain of lethargy, tiredness, and weakness. As the illness progresses, there is an increase of proinflammatory cytokines in the serum and cerebrospinal fluid and a decline in anti-inflammatory cytokines.8,36-38 These inflammatory cytokines act both peripherally at the site of injury and centrally in the pain matrix. In patients with severe, longstanding CRPS, the extent of CD14+ and CD16+ monocyte/macrophage proinflammatory activity in the serum increases, whereas the total monocyte count remains normal.39 The initial nonspecific immune activation following injury or infection occurs within hours and is called the sickness response. The increase in inflammatory cytokines leads to brain interactions that trigger a cascade of behavioral responses, including pain facilitation.40 The severe fatigue suffered by the majority of CRPS patients at all stages of their illness may result in part from engagement of the sickness response circuitry.41

Cardiac Complications of CRPS

Approximately 2,500 CRPS patients with disease duration of longer than 2 years and at least 2 involved extremities have been evaluated at the Drexel University Pain Clinic. Of these, 800 had electrocardiogram (EKG), echocardiogram, and clinical cardiac evaluations prior to the administration of subanesthetic ketamine protocols for refractory pain. There were no specific EKG abnormalities other than a slightly higher than normal pulse rate, ranging from 80 to 100 beats per minute. The ejection fraction ranged from 50% to 65%, not differing from controls. Approximately 10% of this cohort described palpitations, syncope, or presyncope during the course of their illness.42

To evaluate complaints of syncope or presyncope, our team performed a head-up tilt test (HUTT) in 74 patients. We found that CRPS patients were 4.5 times more likely to have a positive HUTT than age- and gender-matched controls. The study demonstrated that lower-extremity CRPS involvement is more likely to precipitate vasovagal syncope and a positive HUTT than upper-extremity or total-body disease. Patients with lower-extremity CRPS also have an enhanced predisposition to neurocardiogenic syncope during HUTT compared to the vasovagal response of asymptomatic controls.43-46 Children and adolescents with CRPS demonstrate no loss of orthostasis but exhibit a higher mean heart rate during HUTT than control subjects.47

In a recent study of CRPS patients evaluated during rest, mental and orthostatic stress increased heart rate as well as decreased heart rate variability with normal baroreceptor sensitivity.48 These patients also demonstrated a drop in cardiac output and an exaggerated increase in total peripheral resistance that correlated with disease duration but not pain intensity. The authors concluded that the increased heart rate and decreased heart rate variability were measures of a generalized autonomic dysfunction that increased CRPS patients' susceptibility to sudden death.48,49

As noted above, atypical chest pain from sensitization of the ICB nerve is very common in CRPS patients with upper limb involvement.

Respiratory Complications

Many patients with CRPS complain of not being able to take a deep breath. Dystonia of the chest wall muscles is common in CRPS patients, but no epidemiologic studies have been done to determine its incidence and prevalence. In our experience, dystonia in CRPS occurs in younger patients with long duration of disease, but it may precede other disease manifestations of the disease.50 One patient with chest wall dystonia affecting respiratory muscles and causing restrictive lung disease recently was reported by our group.51 Another cause of shortness of breath in CRPS patients is sensitization of the ICB nerve. Inspiration activates the nerve, causing a nocifensive guarding reflex of the pectoral and intercostal muscles.17

A longitudinal retrospective study of 270 patients with moderate-tosevere CRPS (involvement of 2 or more extremities) revealed shortness of breath in 16% (42/270), subsegmental atelectasis in 33%, and low lung volumes in 17%.2 Only 1 patient (0.5%) had evidence of chronic obstructive lung disease.

Autonomic Dysregulation

The peripheral autonomic manifestations of CRPS are frequently misdiagnosed as Raynaud's disease, particularly if the affected extremity is minimally painful. In older patients, CRPS is confused with fibromyalgia or vascular insufficiency. Often a warm extremity is thought to be infected. Syncope or presyncope from failure of the compensatory reflexinduced increase in heart rate when blood pressure falls is seen in approximately 25% of CRPS patients.2

Early in the course of the illness (<4 months of illness), the affected extremities are often warm and demonstrate higher skin perfusion than unaffected extremities.52,53 In patients who have had CRPS for longer than 2 years, the extremity is usually cold.53 It is believed that early in the disease there is CNS autonomic dysregulation. Over time, however, there is upregulation of noradrenergic receptors or an increase in their sensitivity on blood vessels that may increase their responsiveness (vasoconstriction) to circulating norepinephrine from the adrenal gland.54-57 Sympathetic innervation of arterioles is the major innervation that controls blood flow to capillaries in the extremities. Vasomotion—the normal environmentally driven, sympathetically mediated wavelike fluctuations in veins—are reduced or absent in CRPS patients (manifested as dilated veins).57 Sympathetic dysfunction is often a component of post-traumatic neuropathy and immobilization, and may induce temperature changes in an injured extremity. These changes may increase the risk for the subsequent development of CRPS.53,58-61.

Inflammation/Neurogenic Edema

An aberrant inflammatory response to tissue or nerve injury that does not abate with healing is an important aspect of CRPS. In a longitudinal study of more than 600 patients with CRPS of at least 1 year's duration, 75% of the patients exhibited neurogenic edema. As the duration of the disease increased, the percentage rose to 90% after 15 years.2 Edema may be generalized and massive. For example, the average weight loss of patients with moderate to severe CRPS when they undergo ketamine treatment, which reduces edema, is 10 to 15 pounds.62 The swollen body parts are concomitantly erythematous. Experiments in neuropathic pain models have revealed that C and A-δ terminal afferent fibers, when activated, induce an axon reflex that releases vasoactive neuropeptides—the best studied of which are substance P (SP), calcitonin gene-related peptide (CGRP), and neurokinin A (NKA). SP and NKA cause endothelial disruption and protein extravasation from the blood vessels, and CGRP causes paralysis of vasculature smooth muscle with consequent vasodilation.63-68

This process is maintained at the site of injury, where an "inflammatory soup" develops. It consists of brainderived neurotrophic factor, bradykinin, epinephrine, neurotrophin-3, adenosine, proinflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor-α) from invading neutrophils/macrophages, lipoxygenase, and prostaglandins.69,70 This neurogenic inflammation often is mistaken for thrombophlebitis or infection, which may occur concomitantly.

Musculoskeletal System

Loss of strength, difficulty initiating movements, and atrophy of the affected extremity are seen in 70% of CRPS patients.2 This is seen in hand and foot muscles as well as the gastrocnemius muscles (calf muscles). Pathological evaluation of muscle from amputated limbs of 14 longstanding CRPS patients revealed fatty degeneration, type I (oxidative) and type II (glycolytic) fiber atrophy, neural degeneration, and reinnervation.71 Occasionally, muscles distant from the involved site can be atrophied as well. Magnetic resonance spectroscopy demonstrates that muscle in CRPS patients is hypoxic and, consequently, fails to maintain a normal redox state. This, in turn, increases the production of reactive oxygen species, with consequent muscle cell injury.72,73 Biochemical analysis of the muscles of patients with severe CRPS also reveals decreased activity of mitochondrial complex II (succinate dehydrogenase), with consequent decreased energy production and increased free radical production.74 Dysfunctional mitochondria appear to be mechanistically involved in the muscle pathology of CRPS.

The majority of patients with CRPS suffer deep bone and joint pain. X-ray evaluations of affected extremities reveal intracortical excavation (bone lakes); periarticular, trabecular, and periosteal demineralization; and bone resorption.75 These changes occur from activated osteoclasts, possibly due to the nociceptor release of SP.76 This postulated pathophysiology would decrease pH enough to depolarize the dense nociceptive innervation of bone.75 Bone formation and maintenance are dependent on a small fiber innervation, which may be deficient in CRPS.3,77-79 Pathologic fractures occur during the usual activities of daily living, or with minimal trauma, and heal poorly. Frequent sites of pathologic fracture are the fifth metatarsal of the foot and the distal ulna. Further demonstrations of bone involvement in CRPS are MRI evidence of bone marrow edema and pooling of blood in the late phase of the triple-phase bone scan.75,76,80

Endocrine System

In a longitudinal study of 270 patients from the Drexel University CRPS database, 69% of patients described overwhelming fatigue. Virtually all patients with moderate-to-severe CRPS suffer severe stress due to pain and disruption of all activities of life. Twenty-six patients with generalized CRPS underwent extensive testing to rule out the usual causes of excessive fatigue. Ten of the 26 patients (38%) were found to have low baseline cortisol levels. The adrenocorticotrophic hormone stimulation test demonstrated significant increase serum cortisol within 1 hour, which implied normal adrenal gland function but an impaired hypothalamic-pituitaryadrenal axis81 and demonstrated tertiary adrenal insufficiency82 in this subset of patients. Approximately 30% of CRPS patients at all stages of illness suffer hypothyroidism.2 The effects of severe stress and the use of opioids in a majority of CRPS patients contribute to endocrine dysfunction.83-85

Dermatologic Manifestations

Approximately 71% of patients with CRPS of at least 5 year's duration suffer skin manifestations. This number increases with disease duration, with more than 80% of patients who have CRPS at least 15 years exhibiting dermatologic manifestations.2 These signs usually are a combination of an erythematous malar rash (often mistaken for systemic lupus erythematosus), mottling, cyanosis, and erythema (misdiagnosed as Raynaud's phenomenon), and a 1- to 3-mm punched-out circular lesion.2,86 Neurogenic edema at some point during the illness is almost universal. A peculiar finding is the "ligature sign," which looks as if the patient had tied a single or multiple strings around the edematous extremity. The indentations persist even as edema subsides.

The punched-out lesion is the second most common skin manifestation. It is pruritic and often thought to be an insect bite. Within a week the center of the lesion excavates and its outer margin becomes slightly elevated. The lesion may scar and characteristically heals with an atrophic thin center and erythematous margins. Skin biopsy of one patient with recurrent bullae in a chronically edematous leg revealed basement membrane and anchoring fibril pathology.86

Several patients have been described as presenting with Gardner-Diamond syndrome.87,88 In these patients, lesions appear as spontaneous bruises. Several patients have had an acute onset of marked erythema in chronically edematous extremities similar to pigmented purpura. They presented with the acute-onset erythema in their chronically edematous extremities. On biopsy, the pathological changes resembled Schamberg's disease, with lymphocytes and histiocytes surrounding blood vessels.89 During the course of the illness, the skin becomes atrophic and shiny; nails are ridged, thin, and break; and there is muscle and integument atrophy. In addition to CRPS-specific changes, patients often have concomitant venous stasis, cellulitis, and ulceration.

Pathological studies of the amputated limbs of patients with longstanding severe CRPS demonstrated muscle atrophy, thickened capillaries, and C-fiber degeneration.90 Altered neuropeptide profiles in small nociceptive fiber afferents that had innervated hair follicles, superficial arterioles, and sweat glands also have been described in studies of moderate to severely affected CRPS patients.91,92 However, a recent study of patients with less severe CRPS demonstrated only a 20% alteration of nociceptive skin innervation.93,94

Although early in the course of the illness, when the pain may be sympathetically maintained, the hair becomes thicker, curlier, and grows more rapidly—however, as the disease progresses, hair often is lost.58

Sweating abnormalities are reported in approximately 30% of patients during the course of the illness.95 Denervated or abnormal sweat glands were seen in autopsies reviewed by Oaklander et al.3 Sweat glands may respond to circulating norepinephrine, although their usual ligand is acetylcholine96; this may be a mechanism for hyperhidrosis in some patients. Another mechanism for severe body temperature fluctuations seen in a majority of CRPS patients is abnormality of the sympathetic innervation of the arteriovenous shunts at the fingertips, which are thermoregulatory. Sympathetic innervation of these arterioles tonically constricts their smooth muscle, which occludes these arteriovenous shunts. As the illness progresses, there is nervi vasorum degeneration (1-μ sympathetic fibers), which allows blood to bypass nutritive capillaries in favor of thermoregulatory ones. This results in hypoxia of skin, connective tissue, and muscle and may be a contributing factor for the atrophy and dystrophy seen in the integument of these patients.97

Urological System

Urological symptoms and signs are encountered in approximately 25% of CRPS patients.2 These symptoms include increases in frequency and/ or urgency, as well as the inability to initiate micturition or incontinence. Cystometrogram analysis of a small series of 20 urological patients uncovered detrusor hyperreflexia in 8 patients, detrusor areflexia in 8 patients, and sensory urgency in 3 patients.97 One patient had detrusor hyperreflexia associated with external sphincter dysnergia.98 Pelvic, penile, and perineal pain is prominent in CRPS patients, particularly if both lower extremities are affected.58,99

Gastrointestinal System

In a prospective study of 270 CRPS patients, the most common gastrointestinal (GI) symptoms were constipation (41%), nausea (23.3%), vomiting (11.5%), intermittent diarrhea (18.5%), and indigestion (18.5%).2 Irritable bowel syndrome (IBS) was diagnosed in 17% of patients and dysphagia in 18%. All patients with dysphasia demonstrated difficulty with bolus formation and control. There was poor clearance with deglutition from the hypopharynx. Patients also had diminished sensation of the bolus associated with pooling within the vallecula, delayed swallowing, and significant residual material within the piriform sinus. Gastroesophageal reflux disease was seen in 73% of the patients.


Gastroparesis frequently occurs in patients with longstanding CRPS (usually longer than 5 year's duration). Most often, these patients with gastroparesis have pain over much of their body (generalized CRPS) where the pain affects the lower extremities more so than the upper extremities. Urological symptoms are frequently associated with gastroparesis. The most frequently associated complaints are early satiety, bloating, constipation, and diarrhea.100 IBS, functional dyspepsia, and cyclic vomiting also have been noted in CRPS patients.101-104 There is accumulating evidence that C fibers and thinly myelinated A-δ fibers, which are involved in the somatic manifestations of CRPS, also may involve internal organs such as the GI tract—similar to that which occurs in diabetic gastroparesis.105


CRPS is becoming a great imitator in pain medicine. It is clear that while there is a gamut of CRPSassociated problems for the various subtypes of patients, one particular sign or symptom may predominate certain patients' conditions. The process spreads, and in a significant proportion of patients, becomes generalized over time. The visceral and internal organ involvement may be the most troubling aspect of the disease.


The author would like to acknowledge the support given to research over the years by the Tilly Family Foundation for the study of CRPS, and the Emily Sunstein Foundation for the study of neuropathic pain.

Last updated on: October 27, 2014
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