Complex Regional Pain Syndrome (CRPS)

CRPS is divided into 2 types. CRPS type I accounts for a majority of cases and is defined as CRPS without known nerve injury.

CRPS type II is similar to type I but involves overt damage to a peripheral nerve.

The distinction between CRPS subtypes I and II is based on changes in skin temperature and is characterized as either warm or cold, respectively. However, the distinction of subtypes based on skin temperature and the concept that CRPS is "sympathetically maintained pain" remain unproven. Some experts describe central, peripheral, and mixed phenotypes based on symptom patterns, but the clinical relevance of these classifications remain unclear (1).

Pathophysiology is unclear, but peripheral nociceptor and central sensitization and release of neuropeptides (substance P, calcitonin gene-related peptide) help maintain pain and inflammation. The sympathetic nervous system is more involved in CRPS than in other neuropathic pain syndromes. Central sympathetic activity is increased, and peripheral nociceptors are sensitized to Pathophysiology is unclear, but peripheral nociceptor and central sensitization and release of neuropeptides (substance P, calcitonin gene-related peptide) help maintain pain and inflammation. The sympathetic nervous system is more involved in CRPS than in other neuropathic pain syndromes. Central sympathetic activity is increased, and peripheral nociceptors are sensitized tonorepinephrine (a sympathetic neurotransmitter); these changes may lead to sweating abnormalities and poor blood flow due to vasoconstriction. Nonetheless, only some patients respond to sympathetic manipulation (ie, central or peripheral sympathetic blockade).

Symptoms of complex regional pain syndrome vary greatly and do not follow a pattern; they may include sensory, focal autonomic (vasomotor or sudomotor), and motor abnormalities. Symptoms are unilateral; bilateral symptoms at onset suggest a different diagnosis.

Pain—usually burning or aching—is a core diagnostic feature and tends to be out of proportion to physical examination findings. It need not follow the distribution of a single peripheral nerve; it is regional, even when caused by injury to a specific nerve, as occurs in CRPS type II. It may worsen with changes in the environment or emotional stress. Allodynia and/or hyperalgesia are usually present, indicating central sensitization. Pain often causes patients to limit use of an extremity.

Cutaneous vasomotor changes (eg, red, mottled, or ashen color; increased or decreased temperature) and sudomotor abnormalities (dry or hyperhidrotic skin) may be present. Edema may be considerable and locally confined.

Other symptoms include trophic abnormalities (eg, shiny, atrophic skin; cracking or excess growth of nails; bone atrophy; hair loss) and motor abnormalities (weakness, tremors, spasm, dystonia with fingers fixed in flexion or equinovarus position of foot). Range of motion is often limited, sometimes leading to joint contractures. Symptoms may interfere with fitting a prosthesis after amputation.

Psychological distress (eg, depression, anxiety, anger) is common, fostered by the poorly understood cause, lack of effective therapy, and prolonged course.

• History and physical examination

Complex regional pain syndrome is diagnosed when the following are present (1) :

• Patients have continuing pain beyond that explained by dysfunction of a single nerve and that is disproportionate to any original tissue damage.

• Certain clinical criteria (Budapest criteria) are met.

The Budapest criteria have 4 categories. According to the criteria, the patient must report at least 1 symptom in 3 of the 4 categories listed below, and the clinician must detect at least 1 sign in 2 of the same 4 categories (symptoms and signs overlap) (1):

• Sensory: Hyperesthesia (as a sign, to pinprick) or allodynia (as a sign, to light touch, deep somatic pressure, and/or joint movement)

• Vasomotor: Temperature asymmetry (> 1° C as a sign) or asymmetric skin color changes

• Sudomotor or edema: Sweating changes, sweating asymmetry, or edema

• Motor or trophic: Trophic changes in skin, hair, or nails, decreased range of motion, or motor dysfunction (weakness, tremor, dystonia)

Also, there must be no evidence of another disorder that could explain the symptoms. If another disorder is present, CRPS should be considered possible or probable.

Bone changes (eg, demineralization on radiograph, increased uptake on a triple-phase radionuclide bone scan) may be detected. Imaging is not usually performed unless the diagnosis is equivocal. However, on imaging tests, bone may also look abnormal after trauma in patients without CRPS, making abnormalities detected by radiographs and bone scans nonspecific.

• Multimodal therapy (eg, medications, physical therapy, sympathetic blockade, psychological treatments, neuromodulation, mirror therapy)

Treatment of CRPS is complex and often does not result in complete relief of symptoms, particularly if begun later. It includes medications, physical therapy, interventions, and psychological treatments (1). The primary goal of all treatments for complex regional pain syndrome is to increase the mobility and use of the affected limb. As such, patient education in CRPS is crucial. Clinicians should emphasize that, while the pain is likely due to neuropathic and central mechanisms rather than tissue damage, participation in physical and occupational therapy is important for regaining limb function despite the challenges posed by ongoing pain.

The goal of pharmacologic therapy is to allow patients to engage in rehabilitation techniques. Many of the medications used for neuropathic pain, including tricyclic antidepressants and antiepileptic agents, may be tried; none is known to be superior. NSAIDs are commonly used as an initial treatment for CRPS, though their effectiveness has not been well studied; they are typically prescribed for short-term use and may be combined with other treatments, with selective COX-2 inhibitors as an alternative for those who cannot tolerate nonselective NSAIDs. Neuraxial infusion ziconotide, and/or clonidine may help, and intrathecal baclofen may reduce dystonia. is to allow patients to engage in rehabilitation techniques. Many of the medications used for neuropathic pain, including tricyclic antidepressants and antiepileptic agents, may be tried; none is known to be superior. NSAIDs are commonly used as an initial treatment for CRPS, though their effectiveness has not been well studied; they are typically prescribed for short-term use and may be combined with other treatments, with selective COX-2 inhibitors as an alternative for those who cannot tolerate nonselective NSAIDs. Neuraxial infusion ziconotide, and/or clonidine may help, and intrathecal baclofen may reduce dystonia.

Bisphosphonates may be considered for pain reduction in early CRPS, especially in patients with abnormal bone scans, although the exact mechanism of action is unclear and likely unrelated to their antiresorptive properties. Several small randomized trials have shown that bisphosphonates such as alendronate, neridronate, and clodronate can reduce pain in CRPS (Bisphosphonates may be considered for pain reduction in early CRPS, especially in patients with abnormal bone scans, although the exact mechanism of action is unclear and likely unrelated to their antiresorptive properties. Several small randomized trials have shown that bisphosphonates such as alendronate, neridronate, and clodronate can reduce pain in CRPS (2), with side effects generally being mild, but serious risks such as osteonecrosis of the jaw and esophageal ulceration need to be considered. Topical lidocaine or capsaicin creams may be used for treating neuropathic pain in early CRPS with mild to moderate symptoms, though evidence of their efficacy is limited, and local side effects like burning and irritation may restrict their use.), with side effects generally being mild, but serious risks such as osteonecrosis of the jaw and esophageal ulceration need to be considered. Topical lidocaine or capsaicin creams may be used for treating neuropathic pain in early CRPS with mild to moderate symptoms, though evidence of their efficacy is limited, and local side effects like burning and irritation may restrict their use.

Evidence for the efficacy of opioids, calcitonin, and oral glucocorticoids is generally weak. Calcitonin may carry a lower risk of adverse effects than glucocorticoids.Evidence for the efficacy of opioids, calcitonin, and oral glucocorticoids is generally weak. Calcitonin may carry a lower risk of adverse effects than glucocorticoids.

The goals of physical therapy include desensitization, strengthening, increased range of motion, and vocational rehabilitation. In some patients with sympathetically maintained pain, regional sympathetic blockade relieves pain, making physical therapy possible.

Desensitization of an allodynic limb involves first applying stimuli that are relatively nonirritating (eg, silk) and, then over time, increasing to more irritating stimuli (eg, denim). Desensitization can also involve thermal contrast baths, in which the affected limb is placed in a cool water bath, then placed in a warm water bath.

Mirror therapy has been reported to benefit patients with CRPS type 1 due to phantom limb pain or stroke. Patients sit with a large mirror facing their unaffected limb and hiding the affected (painful or missing) limb, giving patients the impression that they have 2 normal limbs. Patients are instructed to move the normal limb while viewing its reflected image in the mirror. This exercise tricks the brain into thinking that the affected or absent limb is moving without pain. Most patients who do this exercise for 30 minutes a day for 4 weeks report a substantial reduction in pain (3).

Other interventions for CRPS include sympathetic blockade, neuromodulation, and trigger point injections, though evidence in their favor is limited and of lower quality (4). Trigger-point injections using local anesthetics, with or without glucocorticoids, are sometimes effective for early CRPS, particularly in the shoulder area, and are considered safer than more invasive treatments. Sympathetic nerve blocks, used for patients unresponsive to standard treatments, involve anesthetic infiltration near the sympathetic ganglia though evidence of their efficacy is conflicting.

For neuromodulation, implanted spinal cord stimulators are commonly used; in severe cases with significant functional impairment, they should be considered early. Dorsal root ganglion stimulation may target localized symptoms. Peripheral nerve stimulation is being used more frequently in the management of CRPS with favorable results (5).

Transcutaneous electrical nerve stimulation (TENS), which is applied at multiple locations with different stimulation parameters, may be effective. However, TENS requires a long trial before its efficacy can be determined. Scrambler therapy, which uses surface electrodes to stimulate nerves, is another option. However, the data for its efficacy in CRPS are limited, and it is used more widely to treat neuropathic pain (5).

Acupuncture may help relieve the pain.

In patients with complex regional pain syndrome, psychotherapy may be used to treat depression and anxiety; it may also help patients successfully improve function and their control over their life despite the chronic pain disorder.

Prognosis varies and is difficult to predict. CRPS may remit or remain stable for years; in a few patients, it progresses, spreading to other areas of the body.

Vitamin C has been suggested as a low-risk preventive measure for CRPS, particularly in older patients with distal radius fractures. Its potential antioxidant effects may aid in fracture healing and reduce soft tissue injury, though evidence to support this claim is inconsistent (1, 2). Early mobilization and physical therapy have been shown to be important in preventing the progression of suspected cases of early CRPS (2).