Complex regional pain syndrome (CRPS) was first described by Claude Bernard in 1851 as a pain syndrome linked to sympathetic nervous system dysfunction (1). Soon after, Silas Weir-Mitchell coined the term causalgia to describe a pain syndrome seen in civil war veterans. There are a number of names of historical significance, but reflex sympathetic dystrophy was the most commonly used diagnostic phrase in the late 20th century. The current nomenclature for this condition is complex regional pain syndrome. Research on CRPS has been plagued by varied diagnostic criteria over the years. The current diagnostic criteria, from the Budapest consensus conference in 2003 (2) strived to incorporate the findings from the validation studies done since the Orlando consensus conference in 1994.
CRPS is defined as a syndrome characterized by a continuing pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional, not dermatomal, and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time (1,3).
The clinical diagnostic criteria are grouped into four distinct areas of signs and symptoms (Table 1). Patients with this condition must report symptoms in three of the four categories of symptoms and at least one of the signs in two or more categories at the time of diagnosis.
These diagnostic criteria achieve a sensitivity of 0.85 and a specificity of 0.69. For research purposes, the consensus was to require signs in two of four categories and symptoms in four of four categories. This decreased sensitivity to 0.70 but increased specificity to 0.90 (1).
CRPS is divided into different categories based on whether or not a primary nerve lesion is present. Type I is historically consistent with what was termed reflex sympathetic dystrophy when no identifiable major nerve damage was present and type II, historically consistent with causalgia, where a nerve lesion is present. The authors of the 2013 treatment guidelines also created a CRPS not otherwise specified category where the diagnostic criteria are not completely met, but the presentation cannot be explained by any other diagnosis or entity (1). These categories may have little clinical significance because the treatment algorithms are consistent despite categorization.
Since the precipitating event in CRPS is often an injury, such as a distal radius fracture or ankle sprain, the condition is relevant to the athletic population. No studies to date have addressed activity level as a risk factor or positive influence for the development of CRPS, but numerous case reports exist about this condition in athletes (4–6).
The incidence of CRPS after injury varies by study but has been reported in two prospective studies to be 3.8% to 7% within 4 months after fracture (7,8). In a study that looked at inpatient data from 2007 to 2011 in the United States, risk factors for developing or having CRPS type 1 included age between 45 and 55 years, female sex, white race, higher median household income, and a history of headache, depression, and drug abuse (9,10). Another study, published in 2007 from an outpatient database from the Netherlands, also showed that women were approximately three times more likely to be diagnosed and that upper extremity fractures were the most common inciting event (11). Patients with a prior history of a psychiatric disorder can have a greater incidence of developing CRPS. In one retrospective study, patients with a prior history of a psychiatric disorder of any type had a six-fold increase in risk of developing CRPS (9). The mechanism of injury also may be important. Higher impact injuries, falls from height, and immobilization greater than 8 wk also appear to be risk factors. The presence of a secondary gain, such as disability or lawsuit also seems to elevate the risk of developing CRPS (12).
It is now generally accepted that the pathophysiology of CRPS is a multifactorial process with both peripheral and central components (12). There is an initial inflammatory response with elevated proinflammatory neuropeptides and cytokines. These factors increase plasma extravasation and produce vasodilation, which is seen clinically as the warm, red edematous skin. There also is evidence of peripheral and central nociceptive sensitization (13). This is mediated primarily by substance P and bradykinin and is in part responsible for the hyperalgesia and allodynia (14). Altered sympathetic nervous system functioning contributes to the cool, clammy skin that also is seen. Historically, sympathetic ganglion blocks were used to treat CRPS, but more recent literature suggests that nociceptive fibers in the injured tissue actually develop catecholamine receptors and show increased firing in the presence of circulating catecholamines. Clinically, the sympathetic nervous system dysfunction presents as a cold, sweaty limb with alterations in color. There also are genetic factors that seem to be at play, but these are very poorly understood. One study found an association between HLA-DQ8 and HLA-B62 in patients with CRPS and a fixed dystonia (15).
Psychological factors have long been felt to play a major role in CRPS. While comorbid axis 1 diagnoses are common in patients with CRPS, it is no more prevalent than in other chronic pain conditions (16). Generalized anxiety and the elevated catecholamine levels associated with it may worsen the pain experienced (16). Avoidance behaviors to limit pain also may be considered a psychological factor. In addition, a study published in 2015 did show that higher levels of anxiety, pain-related fear, and disability were associated with a poorer outcome (17).
While it is considered a diagnosis of exclusion, the diagnosis of CRPS needs to be entertained whenever a patient presents with pain out of proportion to an inciting event or identifiable pathology. The pain experienced will typically be deep aching or burning and worsened by movement. The literature describes the exaggerated pain response as either hyperalgesia — an increased response to a painful stimulus or allodynia — a perception of pain to a stimulus that would typically not be painful. In addition, patients will have temperature and color changes in the affected limb when compared with the contralateral limb. Often, the affected limb will have a darker red or purple appearance and may be either colder or warmer than the other extremities. Sudomotor changes refer to unexplained sweating or edema that can occur in the affected limb. Motor changes include decreased range of motion, weakness, tremor, or dystonia in the affected limb with or without trophic changes to the skin, hair, and nails. Often, there is exaggerated growth of hair and nails and a shiny, smooth texture to the skin.
There is a distinction made between “warm CRPS” where the affected extremity is warm, red, and edematous and “cold CRPS” where the extremity is cool, dusky, and sweaty. Acute CRPS is more commonly warm while chronic CRPS is cold. Patients may exhibit both presentations at different points in their disease progression, however, and both types can be seen in the same patient (3).
The diagnosis of CRPS is made on clinical examination and history only. It needs to exist in the list of possible diagnoses whenever a provider sees a patient with pain out of proportion to expectations, but it really must be a diagnosis of exclusion. A number of other conditions can mimic CRPS, however, and testing is necessary to rule out other causes. Table 2 shows an incomplete list of diagnoses to consider when you see a patient with pain out of proportion to injury. Laboratory and imaging test to exclude these other diagnoses is prudent because treatment options will be altered dramatically.
There have been multiple imaging modalities used to further aid the diagnosis of CRPS. Plain film radiography, triple phase bone scans (TPBS), dual-energy x-ray absorptiometry scans, and magnetic resonance imaging (MRI) may all be used to exclude other possible diagnoses. Imaging is not required to establish the diagnosis of CRPS, but each of these imaging modalities has findings that are indicative of the condition. Plain film radiography findings include osteopenia, soft tissue swelling, subperiosteal bone resorption, and joint space preservation. Triple-phase bone scans show increased uptake of radionucleotide matter in all three phases in the affected extremity. MRI can display bone marrow edema, skin edema, and joint effusions (18). In a meta-analysis published in 2012, TPBS showed significant statistical advantage over plain film and MRI in terms of sensitivity and negative predicative value (19).
To reiterate, history and physical examinations are key for the diagnosis and any other laboratory or imaging test done are to rule out other disease processes.
There are very few randomized controlled trials of treatment for CRPS. The fourth edition of the Practical Diagnostic and Treatment Guidelines from the Reflex Sympathetic Dystrophy Syndrome Association published in 2013 summarized the treatment options available at the time with the focus primarily on recovery of functional status with medications, physical and occupational therapy and psychological interventions (1). Interventional or invasive procedures, such as regional sympathetic blocks, may be used for both diagnostic and therapeutic indications.
Treatments can be divided into the following categories:
Many medications have been used to treat CRPS, with varying and somewhat unpredictable results. Gabapentin, pregabalin, and tricyclic antidepressants are used with some efficacy (20). Both topical and intravenous (IV) ketamine in subanesthetic doses has been used to treat intractable pain (21,22). Oral steroids in high doses with a taper over several weeks has been shown to be effective in the initial acute inflammatory phase (23,24). Opioid medications are not typically effective, and the high risk of addiction makes this class of medication quite problematic and should be prescribed with extreme caution.
Vasospastic symptoms can be addressed with oral Nifedipine at a dose of 60 mg·d−1 (25). Short-term use of the PDE5 inhibitors, such as sildenafil or tadalafil, also may be of benefit. Transdermal clonidine also has shown some efficacy (26).
Medications to inhibit bone resorption also have shown promise. Calcitonin at 100 IU three times a day and IV alendronate at 7.5 mg for 3 d or oral dose at 40 mg·d−1 for 8 wk may improve immobility, osteopenia, and trophic changes (26).
The dystonia of CRPS is typically responsive most to baclofen. Often, doses high enough to treat the dystonia cause such profound sedation that it is not practical. If the oral formulation is poorly tolerated, an intrathecal route can be considered (27).
Both occupational and physical therapy play an important role in the treatment of CRPS. Two therapy types are usually utilized. Mirror visual feedback therapy is initiated in which patients describe their limbs with their eyes closed followed by monitoring the limb via mirror and trying to overcome their initial symptoms (28). Usually, the sessions would last 5 min and be performed approximately six times during the day. Graded Motor Imagery is another potentially useful technique. The treatment starts with recognizing the limb in pictures, trying to then imagine moving it and finally seeing the movement being reflected in a mirror (28,29). After this, desensitization and edema management can be started. Carrying objects of increasing weight in the hand and scrubbing to increase the stress loading are then implemented. Finally, when these have been achieved, the patient can be progressed to functional range of motion (30). An individualized program that focuses on regaining use of the extremity and tolerating the pain is a standard approach. This progression can take some time and should not be aggressive. In addition, patients must be guided to find a balance in their pain threshold. They should be guided in working on their coping skills while meeting their functional activities through flexibility and strengthening exercises. Studies have determined that a graded exposure to activities that the patient feared led to reduction of pain and disability in the long term (30,31). Aquatic therapy, myofascial release, and massage also can help (1).
Often, in addition to other treatments, cognitive behavioral therapy with a psychologist or psychiatrist is thought to be beneficial (1). Using psychological interventions to help frame pain response can help patients tolerate their therapy and improve outcomes (1). A history of anxiety or depression prior to surgery increases the likelihood of disease development. An emphasis on relaxation techniques, exposure therapy, biofeedback treatments along with management of stressors were the cornerstone of this treatment modality (16).
The 2013 guidelines referenced earlier make a strong recommendation that early in the treatment process, the patient and their family receive detailed information about the negative effects of disuse, the importance of reactivation and the need for an active self-management approach to treatment. Giving patients the tools that give them some control over their pain is likely to be beneficial (1).
Several interventional therapies, including sympathetic nerve blocks, drug infusions, and implantable pain devices, have been and are used to treat CRPS. A local anesthetic block of the sympathetic chain at the stellate ganglion for upper-extremity CRPS or at the lumbar sympathetic chain for lower-extremity CRPS is a common part of the evaluation and treatment algorithm. Historically, response to this block was felt to confirm the diagnosis of CRPS with sympathetically mediated pain. When there was no response, then the pain was felt to be sympathetically independent pain. Current evaluation guidelines do not include this procedure for diagnosis, but it is still widely used and may have a role in temporary pain control to allow for rehabilitation techniques (1).
IV regional anesthesia also has been used historically with infusions of guanethidine. An analysis of randomized controlled trials undertaken by Perez et al. (22) published in 2001 showed no benefit over placebo for any substance other than calcitonin.
The use of epidural infusion also has shown success in the short-term treatment of CRPS. A study published in 1993 by Rauck et al. showed a significant decrease in pain with an epidural infusion of clonidine for an average of 43 d. Catheter infection was the most common complication (32). Surgical sympathectomy also is performed with varying success (1). Other procedures used to treat refractory cases include radiofrequency or chemical ablation of the sympathetic nerves, spinal cord stimulation, and intrathecal baclofen infusion (1,26,29).
Prevention of CRPS, if possible, is obviously preferable to any of the treatment options available. Vitamin C taken post injury or post procedure may have some benefit (22). The rationale is that the antioxidant properties of vitamin C will stop the acute inflammatory response brought on by the oxidative stress of the trauma or surgery. A meta-analysis of four randomized controlled trials showed a significant risk reduction when 500 mg of vitamin C was taken for at least 45 d after surgery (33). Another study, published in 2014, however, showed no difference in the incidence of CRPS in 336 patients with distal radius fractures (34). The efficacy of this preventative intervention remains unclear.
The outcome of CRPS is remarkably variable. In a review published in 2014, Bean et al. (35) reviewed the available literature on outcomes of CRPS. A total of 18 studies were included, 3 with prospective data. They found that vasomotor and sudomotor changes typically appeared early and were more likely to resolve but functional outcomes, such as weakness, stiffness, and limited range of motion, persisted in a majority of patients for more than 1 year.
Complex regional pain syndrome is seen infrequently as a consequence of trauma to or surgery on an extremity. It has a variable presentation but is characterized by an exaggerated pain response with vasomotor, sudomotor, and dystonic components. Treatment is multimodal and directed at restoration of function. Medications are used to control symptoms while therapy is performed. Physical and occupational therapy that promotes desensitization and functional improvement along with cognitive behavioral therapy to assist with coping seems to improve outcomes. When the symptoms of CRPS have lasted for longer than 1 year, complete recovery becomes less likely.
The authors declare no conflict of interest and do not have any financial disclosures.
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