Complex Regional Pain Syndrome in Emergency Medicine

A French surgeon by the name of Ambroise Paré described complex regional pain syndrome (CRPS) in the mid-16th century.[1]  Paré was the physician to French King Charles IX of Valois and went on to describe the condition after the King experienced an extreme burning pain in his arm after suffering from a smallpox infection. Paré noted other symptoms, including shortened arm muscles and the inability to stretch and bend the whole arm. Paré was also said to have identified the syndrome that we now refer to as phantom limb pain during his time as a military surgeon and his experiences with limb amputations.[2]  Physicians throughout the world have described similar syndromes over the centuries and CRPS has held many names, even just within the English language. 

CRPS, an entity formally called reflex sympathetic dystrophy (RSD), has readily identifiable signs and symptoms and is treatable if recognized early; however, the syndrome may become disabling if unrecognized.[3]  Emergency medicine physicians may be the first to see the syndrome and their actions can vastly improve the quality of life and functionality of these patients if treated properly. As a medical community, the description and management of this syndrome remain incomplete, however, vast improvements have been made over the past 30 years with increased research into the field. 

With complex regional pain syndrome (CRPS) being described by many in various forms, the consensus definition is that “CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional 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 in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time.”[4]  

Schwartzman stated that a common mechanism may be injury to central or peripheral neural tissue.[5] Roberts proposed that sympathetic pain results from tonic activity in myelinated mechanoreceptor afferents. Input causes tonic firing in neurons that are part of a nociceptive pathway. Campbell et al propose a hypothesis that places the primary abnormality in the peripheral nervous system.[6] More recent articles agree that the cause is still unknown.[7] Recent interest has focused on an immune-mediated mechanism.[8]

Most authors now agree that CRPS is a neurologic disorder affecting central and peripheral nervous systems.[9, 10] Mechanisms include peripheral and central sensitization, inflammation, altered sympathetic and catecholaminergic function, altered somatosensory representation in the brain, genetic factors, and psychophysiologic interactions.[10, 11]

Other etiologic possibilities have been suggested. German research has noted the association between elevated levels of soluble tumor necrosis factor receptor 1 (sTNF-R1) and enhanced tumor necrosis factor-alpha activity in patients with polyneuropathy with allodynia.[12] Other German researchers have described autoantibodies in patients with CRPS, especially CRPS type 2.[13]

Harvard researchers Oaklander and Fields have proposed that distal degeneration of small-diameter peripheral axons may be responsible for the pain, vasomotor instability, edema, osteopenia, and skin hypersensitivity of CRPS-1.[14]

The recent association between the use of ACE inhibitors and CRPS has caused some to consider a neuroinflammatory pathogenesis.[15]

Research has demonstrated cortical changes, suggesting a possible role in pathophysiology.[16]

This complex syndrome has been further classified into two subtypes: 

• Type I: No evidence of peripheral nerve injury (formerly reflex sympathetic dystrophy) 

• Type II: Peripheral nerve injury present (formerly “causalgia”) 

Frequency

CRPS occurs in approximately 1–15% of peripheral nerve injury cases. Schwartzman states that CRPS usually occurs secondary to fractures, sprains, and trivial soft tissue injury.[5] The incidence after fractures and contusions ranges from 10% to 30%. While some cases are associated with an identifiable nerve injury, many are not. Even "microtrauma" as might occur with an immunization may be responsible. The upper extremities are more likely to be involved than the lower.

Entities that have led to RSDS include the following:

• Head injury

• Stroke

• Polio

• Amyotrophic lateral sclerosis (ALS)

• Myocardial infarction

• Polymyalgia rheumatica

• Operative procedures (eg, carpal tunnel release)

• Brachial plexopathy

• Cast/splint immobilization

• Minor extremity injury

• Prolonged bedrest

A retrospective epidemiologic analysis of CRPS patients compared to patients with other pain disorders found an incidence of 13.6 per 100,000 per year.[17]

Mortality/Morbidity

In and of itself, CRPS is not fatal. Morbidity of CRPS is associated with disease progress through a series of stages (see Physical).

Schwartzman et al reviewed questionnaires from 656 patients with CRPS. Once patients had experienced symptoms for more than one year, the majority of signs and symptoms were developed. No one reported spontaneous remission of symptoms.[18]

Race

In a retrospective study of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States, Elsharydah et al found that the patient population was primarily White.[19]  

Sex

Stanton-Hicks and others note that women predominate in a range of 60–80% of cases.[20]  Elsharydah et al also found that women continued to be the predominant sex affected by CRPS.[19]  It should be noted that CRPS can affect both sexes and occur at any age.

Age

Persons of all ages are affected. Stanton-Hicks reports that in contrast to adults, 90% of pediatric cases occur in female children aged 8-16 years, with the youngest being 3 years. That author and others report that CRPS is treated most effectively in pediatric patients, with a remission rate of 97%.[21, 22]

An Israeli group suggested that CRPS in children and adolescents is underdiagnosed. They emphasize the importance of early recognition and multidisciplinary treatment.[23]

Several have looked into the possibility that there may be an increased risk of CRPS development in siblings. de Rooij et al showed that, although the overall risk is not increased, the risk in siblings younger than 50 years is significantly increased.[24, 25]

Prognosis of complex regional pain syndrome (CRPS) depends largely on timely diagnosis and use of early aggressive therapy. The ultimate outcome relies heavily on the severity of the original injury, age at onset or inciting event, and comorbidities such as smoking and diabetes. Some patients will continue to have disability, but this is becoming less common as the recognition of the disease is better understood. 

Patients should be encouraged to seek out complex regional pain syndrome (CRPS) support groups. The Reflex Sympathetic Dystrophy Syndrome Association has produced a user-friendly guideline document that may be helpful to both clinicians and patients.[9] ​

• Reflex Sympathetic Dystrophy Syndrome Association (RSDSA) 

• International Research Foundation for RSD/CRPS 

• NeuropathyCommons.org 

The most widely accepted criteria for the diagnosis of complex regional pain syndrome (CRPS) were published by the International Association for the Study of Pain (IASP). It lists the diagnostic criteria for CRPS I as follows:[26, 27]

1. The presence of an initiating noxious event or a cause of immobilization

2. Continuing pain, allodynia (perception of pain from a nonpainful stimulus), or hyperalgesia disproportionate to the inciting event

3. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the area of pain

4. The diagnosis is excluded by the existence of any condition that would otherwise account for the degree of pain and dysfunction.

According to the IASP, CRPS II (also known as causalgia) is diagnosed as follows:

1. The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve

2. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain

3. The diagnosis is excluded by the existence of any condition that would otherwise account for the degree of pain and dysfunction.

The IASP CRPS Special Interest Group conducted a review in 2019 to evaluate ambiguities and diagnostic pitfalls of the criteria. The group was able to update assessment instructions without text alterations to maintain the validity of the IASP criteria. The outcome was the addition of four additional requirements as follows:[14]

A. The patient has continuing pain which is disproportionate to any inciting event

B. The patient reports at least one symptom in 3 or more of the categories

C. The patient displays at least one sign in 2 or more of the categories

D. No other diagnosis can better explain the signs and symptoms

The major difference between the original IASP criteria and the updates is that the above-listed criteria must be met to diagnose CRPS. Validation of the criteria was proposed by Harden et al in 2010 secondary to high sensitivity and lower specificity, leading to overdiagnosis of false-positive cases for CRPS.[28]  The above criteria is summarized into a table below. 

While the IASP has published and updated their guidelines, others have developed a slightly different methodology to include follow-up metrics. Brunner et al performed a Delphi survey among international experts.[29] The survey asked those experts to list and grade diagnostic and follow-up parameters for CRPS I. Although there was some disagreement about weighting, the consensus follows.

The three diagnostic parameters, each with a subcategory, are listed below.

• Pain

  • Hyperesthesia

  • Hyperalgesia

  • Allodynia

• Signs

  • Edema

  • Color

• Mobility

  • Motor change

  • Range of motion

  • Strength

The one follow-up parameter is clinical course. The subcategories are as follows:

• Decrease in pain

• Decrease in hyperalgesia

• Decreased edema

• Improvement in motor function

• Improvement in strength

The expert consensus was that the diagnosis can and should be established without additional studies (radiography, scintigraphy).[29] Other authors believe likewise.[30] Much of the older CRPS literature notes a predisposing personality of depression. However, many other studies have demonstrated that, while most patients are depressed, they are depressed because of their pain. (See causes below.)

Many patients with CRPS will exhibit some type of movement disorder ranging from strength reduction (78%) to tremor (25-60%) to myoclonus and dystonia. Although some authors believe these are pain-induced findings, others believe they are primary abnormalities.[31]

The physical findings for complex regional pain syndrome (CRPS) have been listed as part of the "History" section because the criteria sets include both signs and symptoms. Three stages have been classified. Although a consensus panel recommended that staging be eliminated, it is important that the emergency physician has an awareness of potential disease progress. Disease progress is very variable.

• Stage I or early CRPS: Pain is more severe than would be expected from the injury, and it has a burning or aching quality. It may be increased by dependency of the limb, physical contact, or emotional upset. The affected area becomes edematous, may be hyperthermic or hypothermic, and shows increased nail and hair growth. Radiographs may show early bony changes. Duration is usually 3 months from onset of symptoms. Some patients remain in one stage or another for many months or even years. They may never progress or they may progress quickly to late stage. Remember that physical findings may be minimal, especially in those who remain in stage I or progress slowly.

• Stage II or established CRPS: Edematous tissue becomes indurated. Skin becomes cool and hyperhidrotic with livedo reticularis or cyanosis. Hair may be lost, and nails become ridged, cracked, and brittle. Hand dryness becomes prominent, and atrophy of skin and subcutaneous tissues becomes noticeable. Pain remains the dominant feature. It usually is constant and is increased by any stimulus to the affected area. Stiffness develops at this stage. Radiographs may show diffuse osteoporosis. The 3-phase bone scan is usually positive. Duration is 3-12 months from onset.

• Stage III or late CRPS: Pain spreads proximally. Although it may diminish in intensity, pain remains a prominent feature. Flare-ups may occur spontaneously. Irreversible tissue damage occurs. Skin is thin and shiny. Edema is absent. Contractures may occur. Radiographs indicate marked demineralization.

Extensive changes are present in the muscles of patients with long-standing disease.[32]

Many hypotheses exist, but a definite cause for complex regional pain syndrome (CRPS) has not been identified. The most frequently associated inciting events that lead to a diagnosis include trauma, extremity fractures, surgery, and carpal tunnel syndrome. 

Older literature suggested that development of CRPS required a triad of conditions: an injury, an abnormal sympathetic response, and a predisposing personality. Most current literature disputes the need for an underlying personality disorder. In August 2000, Schwartzman stated, "There is no evidence that affected patients have a personality disorder, but the severity of pain and the disruption of the patient's life can lead to anxiety and depression."[33] Beerthuizen et al reviewed 31 articles that addressed an association between psychiatric illness and CRPS-1. Almost all the studies showed no causal relationship.[34]

Peterlin et al suggested that migraine may be a risk factor for the development of CRPS, but this is the only paper suggesting an association.[35]

ACE inhibitors have been suggested as a possible cause for the development of CRPS.[15, 36]

Evidence now shows that CRPS may have a genetic predisposition.[10, 11]

Once refractory to neural blockade, pain is probably lifelong and may be severe enough to be debilitating. 

A single, reliable, sensitive, and specific diagnostic test for complex regional pain syndrome (CRPS) is not available.

Quantitative sensory testing and quantitative sudomotor axon reflex test (QSART) may be performed to look for sensory and sweating abnormalities.[37]

And as noted above, experts agree that diagnostic studies are not necessary to make the diagnosis.[29, 30]

Although not required for diagnosis, these studies have been advocated for a variety of reasons.

• Three-phase bone scan and gadolinium magnetic resonance imaging (MRI) have been used to diagnose and stage the disease.

• Standard radiographic findings are normal in as many as 30% of patients. However, they may show osteoporosis as soon as 3-5 weeks of onset.

• Laser Doppler flow studies have been used to monitor background vasomotor control.

• A cold pressor test performed in conjunction with thermographic imaging observes vasoconstrictor response.

• Functional MRI (fMRI) has been used to demonstrate that allodynic stimulation produces objective findings.[37]

• Magnetic resonance neurography (MRN) can be used to evaluate specific areas of nerve damage. 

• Structural MRI may be useful for the measurement of gray matter volume, which was directly correlated to pain intensity in one study[38]

• Triple-phase bone scans with dye can evaluate excess bone resorption

Some authors believe that the best diagnostic approach for complex regional pain syndrome (CRPS) involves use of differential neural blockade. In those with sympathetically mediated pain (as opposed to those whose pain is sympathetically independent), response to neural blockade may help guide medical therapy.

• For cases involving an upper extremity, a stellate ganglion block may aid the diagnostic process and may be therapeutic. However, failure to relieve pain does not eliminate the diagnosis.[5, 33]

• Differential blockade has been performed using Bier blocks with a variety of agents, including local anesthetics, bretylium, steroids, ketorolac, reserpine, and guanethidine and clonidine.[33, 39]

• The rationale for selective neural blockade is to interrupt stimulation to the sympathetic nervous system. Again, this is effective only in those whose pain is sympathetically dependent.[33]

It is in the best interest of patients with complex regional pain syndrome (CRPS) to have a physician knowledgeable about this entity orchestrate all care. Appropriate referral is important.

There is nothing for prehospital providers to do in cases of complex regional pain syndrome (CRPS) except transport. Most state guidelines do not include chronic pain syndromes as an indication for narcotic administration.

Definitive care for complex regional pain syndrome (CRPS) is really beyond the purview of the ED physician. An emergency physician's primary role with patients who have CPRS is to recognize the possibility of the diagnosis and refer such patients to clinical services utilizing treatment modalities listed below. Early breaking of the pain cycle increases the likelihood of a better outcome.

The 3 basic modes of therapy include pain management, rehabilitation (including physical therapy), and psychological therapy.[40]

Once the diagnosis is established, a number of treatment modalities are available. The most effective treatment involves differential neural blockade. Children may also benefit from neural blockade.[39]

CRPS experts and researchers have looked at many treatment possibilities. Some have proven beneficial, others less so. The list below includes most of the possibilities that have been considered. Some of the oral medications may be prescribed in the ED after discussion with the primary care physician or pain specialist. Neural blockade may be an option for ED providers, based on location of pain. Although none of the other modalities will be used in the ED, the clinician should have an overview of the available options.

• The anesthesia literature provides good evidence that spinal stimulation is effective.[41, 42]

• Most patients, especially children, can benefit from physical therapy.[21, 43, 44, 45] A new physical modality—graded motor imagery—has recently received a great deal of attention.[46, 47]

• Tricyclic antidepressants have been used to decrease burning. Gabapentin (Neurontin) and systemic steroids have also been used with varying degrees of success. Other agents include the alpha-1 adrenoreceptor antagonists terazosin and phenoxybenzamine; the alpha-2 adrenoreceptor agonist clonidine; and the NDMA receptor antagonists ketamine, dextromethorphan, and calcitonin. When treatment reaches a plateau, invasive interventions to be considered include tunneled epidural catheters and neuroaugmentation.

• Dadure et al recently described a series of pediatric patients with recurrent CRPS who benefited from continuous peripheral nerve blocks given at home.[39]

• Sympathetic nerve block as well as ketamine infusions have become widely used in CRPS. Cohen et al conducted a multi-center retrospective study that found improved effects of ketamine infusion after successful use of sympathetic nerve block.[48]  

• Acupuncture has been reported to have some value, especially in children.[49]

• Topical and intravenous lidocaine have been reported to be effective in some cases.[50] Most of the literature appeared several years ago, but the group at Drexel University College of Medicine in Philadelphia reported favorable results for a 5-day lidocaine infusion.[51]

• Eckmann et al performed a randomized, controlled trial that looked at several parameters with the use of IV regional block with ketorolac and lidocaine for treating CRPS. This small study of10 patients with lower extremity CPRS type I showed short-term (1 week) pain relief. No improvement was shown in the primary outcome of overall pain numeric rating scale or secondary outcomes of pain in motion, allodynia, joint pain score, edema, range of ankle motion, and skin temperature.[52]

• A Turkish group performed a randomized controlled trial using a Bier block containing methylprednisolone and lidocaine in patients with CRPS type I patients. The group concluded that the therapy did not provide long-term benefit, and the short-term benefit was no better than with placebo.[53]

• Case reports and small number studies have reported good efficacy for topical and IV infusion of ketamine. As a dissociative anesthetic, the logic is to try to "erase the memory" of the pain stimulation.[54, 55, 56] Several more recent studies also discuss the value of this therapy.[57, 58, 59]

• A group in the Netherlands reported significant pain decrease in 8 patients treated with an IV infusion of magnesium.[60]

• Work that is looking at the efficacy of bisphosphonates has begun.[11, 61]

• Intravenous immunoglobulin has been studied.[8]

• Case reports describe some promise for the injection of botulinum toxin.[62, 63]

• The use of hyperbaric oxygen chambers has been evaluated and found to decrease edema when compared to regular air, however, this treatment option requires further investigations to become a true treatment strategy.[64]  

• For patients who cannot be seen in the ED or cannot be treated in an expeditious fashion with neural blockade, the primary care physician who knows the patient best should arrange for narcotic analgesia, recognizing that neuropathic pain may be very resistant to standard analgesics, even potent ones. Patients who fail neural blockade very well may have disease that has progressed to the sympathetic-independent stage, and they are likely to have a lifelong problem. In this group, treatment by specialists in pain management, who have access to more sophisticated and experimental therapies, is mandatory.

• In the ED, narcotics often are required to provide temporary relief while waiting for definitive treatment to begin. Patients with refractory disease may present to the ED with flare-ups that require narcotics. Although distinguishing between those who are truly in pain and those who are malingering is very difficult, the clinician must not assume that all who present without an obvious painful problem are drug seekers. Those with CRPS/RSDS may have a paucity of objective findings. Many are under the care of a knowledgeable pain expert and do not allow themselves to run out of analgesia.

Consultations with the following in cases of complex regional pain syndrome (CRPS) may include the following:

• anesthesiologist or other qualified pain management specialist

• physical medicine personnel regarding rehabilitation

• occupational, physical, and vocational rehabilitation specialists

• hand surgeon

• psychiatry for coping mechanisms as well as secondary psychological problems from the disease course 

Although not FDA approved in the United States, in some countries, patients with complex regional pain syndrome (CRPS) are hospitalized and placed on continuous intravenous infusions of medications such as lidocaine or ketamine. As a dissociative anesthetic, the latter is intended to "erase" the memory of dysfunctioning neurons. Results have been variable.

Unfortunately, the syndrome cannot be prevented entirely, given the variety of injuries and inciting events that may result in CRPS.

It has been well documented that those with CRPS who are diagnosed earliest do the best. Once the disease is well established, it probably cannot be reversed.

Specialists in pain management (usually an anesthesiologist or physiatrist) commonly perform neural blockade. Use of pain modifying agents, such as cyclic antidepressants and gabapentin, usually is left to the primary care physician or pain management team.

The ED physician's primary responsibilities are to recognize the complex regional pain syndrome (CRPS) and refer patients to an appropriate specialist. However, these patients experience severe pain and should be given sufficient analgesia to provide relief. Narcotics usually are required.

Discussion of available agents has been limited to morphine and hydromorphone. ED physicians choose the agent with which they are most familiar and comfortable. Clinicians who choose to use meperidine should remember that it provides some euphoria and also has an active metabolite that may accumulate.

Agents with a short duration of action (eg, fentanyl) are not usually appropriate.

Some pain specialists prefer methadone for its long duration of action and mechanism of action benefit. This agent is an NMDA antagonist and may therefore be more effective in neuropathic pain syndromes. Conversion from other opioids to methadone should be done by a qualified pain management professional.[65] Other long-acting agents include sustained-release forms of oxycodone and morphine.

One meta-analysis from 1950 to 2017 evaluated the use of ketamine infusions for CRPS.[66]  The primary outcome was pain relief, which was found to be improved but only in short-term use (~3 months' treatment duration). Due to publication bias and study heterogenicity, there should be more trials conducted to evaluate ketamine efficacy, especially for long-term pain relief in CRPS patients.  

Class Summary

Breaking the pain cycle is high priority. Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties. Note that controversy exists among authors about the appropriateness of chronic narcotic analgesia. Some are opposed. Others note that, when more specific measures fail, patients must have pain relief in order to live their lives. The latter believe that patients with CRPS have a true chronic pain syndrome.

Morphine sulphate (Duramorph, MS Contin)

DOC for analgesia because of reliable and predictable effects, safety profile, and ease of reversibility with naloxone.

Initial dose dependent on whether patient already is taking narcotic analgesics. For patients not using long-term agents, as little as 2 mg IV/SC may be sufficient, though higher doses are often needed. Larger doses may be required in patients taking long-term narcotic analgesics.

Also available in oral form in immediate-release and timed-release preparations. Long-acting form usually is administered q12h, but many believe that it loses much of its effect after 8 h; immediate-release form may be needed for periods of pain "break-through," dose dependent on previous use. ED physician should begin at lowest available dose in newly diagnosed patients.

No intrinsic limit to the amount that can be given exists, as long as patient is observed for signs of adverse effects, especially respiratory depression. Various IV doses are used, commonly titrated until desired effect obtained.

Hydromorphone (Dilaudid)

Hydromorphone is a potent semisynthetic opiate agonist similar in structure to morphine. It is approximately 7-8 times as potent as morphine on mg-to-mg basis, with a shorter or similar duration of action. Used to manage moderate to severe pain. Available IV and PO.

Class Summary

Agents with effects on muscle contractions appear to be effective. 

Ketamine (Ketalar)

While ketamine infusions are unlikely to be initiated by Emergency Medicine providers, there is growing evidence for its use in neuropathic syndromes, to include CRPS. Ketmaine has been evaluated for infusion therapy as well as topical.