Complex Regional Pain Syndrome: Pathophysiology, Diagnosis, and Treatment

Complex Regional Pain Syndrome: Pathophysiology, Diagnosis, and Treatment

Complex Regional Pain Syndrome: Pathophysiology, Diagnosis, and Treatment

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Complex regional pain syndrome (CRPS) is a chronic, predominantly neuropathic and partly musculoskeletal pain disorder often associated with autonomic disturbances. It is divided into 2 types, reflecting the absence or presence of a nerve injury.

Patients with either type may exhibit symptoms such as burning pain, hyperalgesia, and/or allodynia with an element of musculoskeletal pain. CRPS can be distinguished from other types of neuropathic pain by the presence of regional spread as opposed to a pattern more consistent with neuralgia or peripheral neuropathy. Autonomic dysfunction (such as altered sweating, changes in skin color, or changes in skin temperature); trophic changes to the skin, hair, and nails; and altered motor function (such as weakness, muscle atrophy, decreased range of motion, paralysis, tremor, or spasticity) also can be present.1,2

At least 50,000 new cases of CRPS are diagnosed in the United States annually.1 Although the incidence rate is subject to debate, a large epidemiologic study from The Netherlands involving 600,000 patients suggests an incidence of 26.2 per 100,000 individuals. The study also found that women are 3 times more likely to be affected, with postmenopausal women having the greatest risk.3


Type 1 CRPS, formerly known as reflex sympathetic dystrophy, often is triggered by a minor or major trauma—fractures account for about 60% of cases.2 Surgery is the next most common precipitating event at 20%. Other etiologies include injections, venipuncture, infections, burns, cerebrovascular accidents, or myocardial infarctions.2,4 There are no identifiable precipitating events in about 10% of patients.2

Type 2, formerly known as causalgia, often is related to high-velocity, blunt injuries, which make up more than 75% of cases. But any process that results in nerve injury, such as surgery, fractures, or injections, also can cause type 2 CRPS.4,5 More than 50% of type 2 cases involving the upper extremities often are related to injuries of the median nerve alone or in combination with another nerve of the upper extremity.5 About 60% of cases in the lower extremities are related to injury of the sciatic nerve.5 Almost all cases involve only partial nerve transection, with upper extremity involvement more prevalent than lower extremity.


Historically, CRPS has been poorly understood, and a lack of consistent diagnostic criteria often has been cited in literature. But research in recent years has provided substantial insight into the pathophysiology of the disorder.

As with many other complex conditions, the mechanisms involved in CRPS are multifactorial (Table 1) and include the peripheral and central nervous systems (Figure 1).1 Factors such as altered sympathetic and catecholaminergic function, peripheral and central sensitization, peripheral and central neurogenic inflammation, altered somatosensory representation in the brain, genetics, and psychology all affect patients to varying degrees.

Table 1. Summary of Pathophysiologic Mechanisms That May Contribute to CRPS1
Mechanism Supporting Pattern of Findings
Altered cutaneous innervation
  • Density of C- and Aδ-fibers in CRPS-affected region
  • Altered innervation of hair follicle and sweat glands in CRPS-affected limb
Central sensitization
  • Increased windup in CRPS patients
Peripheral sensitization
  • Local hyperalgesia in CRPS-affected vs unaffected extremity
  • Increased mediators of peripheral sensitization
Altered SNS function
  • Bilateral reductions in SNS vasoconstrictive function predict CRPS occurrence prospectively
  • Vasoconstriction to cold challenge is absent in acute CRPS but exaggerated in chronic CRPS
  • Sympatho-afferent coupling
Circulating catecholamines
  • Lower norepinephrine levels in CRPS-affected vs unaffected limb
  • Exaggerated catecholamine responsiveness because of receptor up-regulation related to reduced SNS outflow
Inflammatory factors
  • Increased local, systematic, and cerebrospinal fluid levels of proinflammatory cytokines, including TNF-α, IL-1β, -2, and -6
  • Decreased systemic levels of anti-inflammatory cytokines (IL-10)
  • Increased systemic levels of proinflammatory neuropeptides, including CGRP, bradykinin, and substance
  • Animal postfracture model of CRPS-1 indicates that substance P and TNF-α contribute to key CRPS features
Brain plasticity
  • Reduced representation of the CRPS-affected limb in somatosensory cortex
  • These alterations are associated with greater pain intensity and hyperalgesia, impaired tactile discrimination, and perception of sensations outside of the nerve distribution
Genetic factors
  • In the largest CRPS genetic study to date (150 CRPS patients), previously reported associations were confirmed between CRPS and HLA-related alleles
  • A TNF-α promoter gene polymorphism is associated with “warm CRPS”
Psychological factors
  • Greater preoperative anxiety prospectively predicts CRPS symptomatology after total knee arthroplasty
  • Emotional arousal has a greater effect on pain intensity in CRPS than in non-CRPS chronic pain, possibly via associations with catecholamine release
CGRP, calcitonin gene-related peptide; CRPS, complex regional pain syndrome; IL, interleukin; SNS, sympathetic nervous system; TNF, tumor necrosis factor

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Figure 1. Speculative model of interacting CRPS mechanisms.

CGRP, calcitonin gene-related peptide; CRPS, complex regional pain syndrome; IL, interleukin; TNF, tumor necrosis factor

Central Sensitization

Central sensitization is an increased firing of nociceptive fibers in response to intense or persistent noxious stimuli. It is mediated by the nociception-induced release of neuropeptides such as bradykinin, glutamate, and substance P. This phenomenon is part of the reason patients experience allodynia and hyperalgesia. It is not known whether central sensitization precedes, occurs with, or follows development of other CRPS signs and symptoms.1,4,6

Peripheral Sensitization

Peripheral sensitization occurs when an initial tissue trauma causes proinflammatory neuropeptides to be released from primary afferent fibers. These neuropeptides increase background firing of nociceptors, decrease the firing threshold for thermal and mechanical stimuli, and increase firing in response to nociceptive stimuli. This decrease in firing threshold contributes to patients experiencing allodynia and hyperalgesia.1,4,6

Sympathetic Nervous System

Several human studies demonstrated expression of adrenergic receptors on nociceptive fibers after nerve injury. Given that there is likely some sort of nerve damage in type 1 CRPS, this explains why sympathetic outflow has an important effect on pain in patients with this condition. Manipulations with whole-body cooling and heating have supported the theory of sympatho-afferent coupling, although it would not be correct to imply that altered sympathetic function is solely responsible for the development of CRPS. Vascular abnormalities seen in CRPS also are mediated by altered levels of endothelin-1, nitric oxide synthase, nitric oxide, and impaired endothelial-related vasodilatory function. During the progression from acute to chronic CRPS, patients have intense vasoconstriction response in the setting of lowered levels of norepinephrine, implying altered local sympathetic outflow. This is believed to occur due to up-regulation of noradrenergic receptors as a response to low levels of catecholamines. When patients experience pain or regular life stress, these sensitive receptors respond intensely to the release of catecholamines, resulting in a cold, blue, and sweaty appearance.1


The inflammatory process is involved in at least the acute phase of CRPS. There are 2 potential sources of inflammation:

  1. Classic mechanisms through actions of immune cells, which, after tissue trauma, secrete proinflammatory cytokines, including interleukin-1, -2, and -6, and tumor necrosis factor-α.
  2. Neurogenic inflammation, which occurs through the release of proinflammatory mediators directly from injured nociceptive fibers in response to various stimuli. These neuropeptides include substance P, calcitonin gene-related peptide, and bradykinin, which promotes plasma extravasation and local tissue edema.1

A subset of patients with CRPS has been found to have low levels of anti-inflammatory and high levels of proinflammatory cytokines.4


It has been suggested that autoantibodies may play a role in CRPS. Autoantibodies found in the plasma of patients with CRPS are active at the muscarinic cholinergic and β2 adrenoceptors. Transfer of serum immunoglobulin G to mice from patients with CRPS elicited symptoms of CRPS in recipient mice.7


Although there is no clear evidence of genetic predisposition to developing CRPS, it would be prudent to further investigate genetic factors that influence inflammatory and other mechanisms contributing to the syndrome. The largest study of 150 CRPS patients has found a link between CRPS and HLA-related alleles.1,4

Psychological Factors

To date, no evidence has suggested a purely psychological form of CRPS. However, poor coping and emotional stress can certainly raise levels of circulating catecholamines, which could exacerbate vasomotor signs of CRPS, cause pain, and maintain central sensitization.1,4

Brain Plasticity

Functional magnetic resonance imaging scans have shown that there is significant cortical reorganization of somatosensory cortex, which may underlie various manifestations of CRPS. Functional disturbances in posterior parietal cortex responsible for integrating various external stimuli and constructing real-time body schema in space, also may contribute to chronification of pain.1,4,7


The diagnosis of CRPS is clinical and depends on patient history, physical examination, and findings of musculoskeletal degeneration and secondary pain that develops as a result of persistence of the disease state. CRPS is a diagnosis of exclusion and cannot be made in the presence of other diagnoses that can be responsible for the presentation. Chronic CRPS needs to have symptoms and signs consistent with time-dependent effect of CRPS (ie, atrophy, dystrophy, contractions, and secondary pain).

In the initial several months of CRPS, hypoesthesia and hyperalgesia are common, whereas ongoing disease anesthesia dolorosa can be seen.2 The pain present in later cases when compared with the acute phase is more often present at rest and resistant to treatment. One of the hallmarks of persistent CRPS is the accumulation of orthopedic and neuropathic findings due to altered biomechanics of the affected area and tissue dystrophy and atrophy in superficial and deeper tissues, as well as development of secondary pain in the contralateral limb and other parts of the body as the patient attempts to compensate.

A main reason why CRPS is difficult to diagnose and treat is because the majority of patients do not have classic “warm” (acute) or “cold” (cold) affected limbs—they fall somewhere along the spectrum.1,4 Veldman et al described more patients as having the “cold” type as the duration of CRPS increases, however, some patients with CRPS for more than 10 years still have “warm” limbs.2 And despite being classified as 2 types, there is no evidence that pathophysiologic mechanisms or treatment responsiveness differ in any appreciable way except that type 2 and underlying nerve injury may need to be addressed directly, sometimes surgically (Figure 2).

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Figure 2. Schematic representation of treatment modalities based on pathophysiologic mechanisms.7

Skin biopsies of patients with type I CRPS show a significantly decreased amount of C and Aδ-fibers after tissue injury, possibly indicating nerve damage may be present in type 1.1 However, there is no clear evidence as to whether this is a cause or effect of CRPS. Animal models support an increased nociceptive firing in response to norepinephrine, providing evidence that there is sympatho-afferent coupling, which has been suggested by human studies.1 There is further suggestion in animal models that a transcription factor, nuclear factor-β, could play a role in CRPS. This may provide an upstream link between increased proinflammatory neuropeptides and increased proinflammatory cytokines in CRPS.1,4

It also has been shown that patients with CRPS and people with prolonged immobilization, from things like casts for limb fractures, show similar signs of edema, skin color changes, limited range of motion, and altered sensation. This suggests that patients with CRPS experience derangement of normal physiologic responses, making it difficult to identify when these physiologic changes becomes pathologic CRPS and not another diagnosis.4

Diagnostic Tools

During a consensus workshop in 1994, the International Association for Study of Pain (IASP) proposed diagnostic criteria based on clinical symptomatology (Table 2).8 Criticisms of the IASP criteria included a lack of specificity and misdiagnosing other types of neuropathic pain conditions as CRPS. The false diagnosis was thought to stem from the IASP criteria being met solely by self-reported symptoms uncovered by the history without physical signs and symptoms.7

Table 2. IASP CRPS Diagnostic Criteria8
2-4 of the following with 2, 3, and 4 being mandatory:

  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 the existence of conditions that would otherwise account for the degree of pain and dysfunction.
All of the following:

  • The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve.
  • Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain.
  • 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; IASP, International Association for the Study of Pain

In an aim to improve the IASP criteria, an international consensus meeting was held in Budapest in 2003. The results were based on the previously published Harden/Bruehl criteria (Table 3).9 A 2010 study showed the IASP criteria of being 100% sensitive but only 41% specific in 113 CRPS type 1 patients and 47 non-CRPS neuropathic pain patients. The new Budapest criteria revealed 99% sensitivity with 68% specificity.10 Veldman’s criteria includes physical signs in combination with symptoms and was derived from a cross-sectional cohort study of 829 patients (Table 4).2

Table 3. Harden/Bruehl CRPS Diagnostic Criteria9
  1. Continuing pain, which is disproportionate to any inciting event
  2. Must report ≤1 symptom in 3 of the following 4 categories:
    • Sensory:
      Reports of hyperesthesia and/or allodynia
    • Vasomotor:
      Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
    • Sudomotor/Edema:
      Reports of edema and/or sweating changes and/or sweating asymmetry
    • Motor/Trophic:
      Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin)
  3. Must display ≤1 sign at time of evaluation in ≥2 of the following categories:
    • Sensory:
      Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
    • Vasomotor:
      Evidence of temperature asymmetry (>1∞C) and/or skin color changes and/or asymmetry
    • Sudomotor/Edema:
      Evidence of edema and/or sweating changes and/or sweating asymmetry
    • Motor/Trophic:
      Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin)
  4. There is no other diagnosis that better explains the signs and symptoms
Same as CRPS I but with the evidence of a peripheral or central nerve injury
Patients who do not fully meet the clinical criteria, but whose signs and symptoms cannot be better explained by another diagnosis
CRPS, complex regional pain syndrome; NOS, not otherwise specified
Table 4. Veldman2 CRPS Diagnostic Criteria
  1. Presence of 4 or 5 of the following:
    • Unexplained diffuse pain
    • Difference in skin color relative to other limb
    • Diffuse edema
    • Difference in skin temperature relative to other limb
    • Limited active range of motion
  2. Occurrence or increase of above signs and symptoms after use.
  3. Above signs and symptoms are present in an area larger than the area of primary injury or operation and include the area distal to the primary injury.
CRPS, complex regional pain syndrome


Although the majority of CRPS symptoms resolve within an approximate 12-month period, an estimated 25% of patients still fulfill IASP diagnostic criteria at 12 months and may suffer from CRPS chronicity. CRPS following fracture has a better resolution rate; “cold” CRPS or upper-limb involvement has the worst outcome. Because CRPS is a multifactorial disease with poorly understood mechanisms, the mainstay of treatment remains physical and occupational therapy aimed at return and preservation of function, prevention of loss of range of motion, and prevention of contractures and atrophy.4

Pharmacologic Treatment

IV Ketamine has proven to be very effective in the treatment of CRPS /RSD

At the Florida Spine Institute, treatment protocols are individually planned depending on the nature of pain and the patient’s responsiveness to initial sessions. Infusion cocktails are prepared in house so that they can be tailored to each patient’s therapeutic needs.  A variety of medications are often used:

  • Lidocaine
  • Ketamine
  • Bisphophonates
  • Magenesium

These medications are typically mixed with saline in an IV bag and infused slowly over several hours, depending on the medication and/or protocol being used.  Usually, a series of treatments will be recommended daily for a period of a week or more. The duration of pain relief following one or more ketamine infusions cannot be predicted. The goal is to achieve lasting relief as measured in weeks or months following the last treatment. Most patients who enjoy prolonged pain relief will need to return on occasion for a booster infusion, or continue to take low dose intranasal ketamine at home.

There is also convincing results with regard to IV bisphosphonates—most recently neridronate in patients with disease duration of less than 6 months. At 1-year follow-up, neridronate showed improved pain control. Multiple neuropathic medications such as gabapentin, tricyclic antidepressants, and opioids have been used through their extrapolated benefit in neuropathic conditions other than CRPS. Oral steroids continue to be used in acute CRPS, although the evidence is poor and sympatholytic drugs are used by clinicians with low success rates.7,11,12 But a recent small trial using low-dose oral phenoxybenzamine showed significant functional improvement in patients with CRPS.13 Taking everything above into consideration, we can conclude that the majority of pharmacologic treatments used by clinicians are quite empirical and largely based on personal preferences and experiences.

Interventional and Surgical Techniques

The main utility of interventional pain medicine in CRPS is to enable proper physical or occupational therapy and break the cycle of peripheral and/or central pain. Moderate evidence shows that sympathetic blockade is effective. Spinal cord stimulators appear to provide significant improvement of function in type 1 CRPS, and are more cost-effective over a patient’s lifetime compared with physical therapy and medical management.4,14 Although there is great resistance to surgery for CRPS patients, significant pain resolution may be achieved through nerve decompression or denervation procedures, neuroma resection, and neurolysis once patients are properly identified by nerve blocks. In many patients, the noxious stimulus is maintained through nerve compression; osteophytes; fibrosis; neuroma; arteriovenous malformation; or anything that entraps, compresses, or distorts the nerve. Surgery may be indicated in these cases.

Psychological Interventions

Psychological factors play a role in the treatment of CRPS. There is likely benefit in cognitive-behavioral therapy. Correcting body image also may help in CRPS affected patients.4,7


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