Updates in Management of Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is a heterogeneous group of disorders that generally develop after trauma to soft tissue but also may develop after visceral diseases or nerve lesions, or rarely without an obvious antecedent event. This debilitating neurologic syndrome is characterized by pain and hypersensitivity, vasomotor skin changes, and functional impairment. Structural changes in both the deep and superficial tissues may occur.

The precise cause of the syndrome is not known, and treatments are not curative. However, emerging research is helping to further understanding of the pathogenesis and treatment of this challenging syndrome.

CRPS Definition

CRPS is grouped into 2 categories (CRPS type I and CRPS type II) based on the absence or presence, respectively, of peripheral nerve damage. The International Association for the Study of Pain (IASP) defines CRPS type I as “a syndrome that usually develops after an initiating noxious event, is not limited to the distribution of a single peripheral nerve, and is apparently disproportionate to the inciting event. It is associated at some point with evidence of edema, changes in skin blood flow, abnormal sudomotor activity in the region of the pain, or allodynia or hyperalgesia.”¹ CRPS type II is characterized by clinical signs of peripheral nerve injury, such as abnormalities found on nerve conduction study.²

Signs and Symptoms

CRPS is a spectrum disorder with clinical features varying in intensity and clinical presentation. The symptoms and diagnostic features of CRPS types I and II are identical. They include severe pain or uncomfortable sensations, as well as limb swelling, hair growth changes (most typically hair falling out, as well as possible development of coarser, darker hair and/or rapid hair growth), nail changes (faster growth, distorted shape), as well as muscle atrophy, increased sweating, and skin changes (thin and shiny, or skin lesions).³ Symptoms may be acute or last for many years.

In addition, patients may experience a spreading of symptoms to other parts of the body—most commonly in a contralateral or ipsilateral pattern. Diagonal spread is rare but also may occur.⁴ Spread of symptoms typically occurs spontaneously without a secondary trauma, except in the case of diagonal spread, which generally occurs in the context of a new trauma and is more common in patients with a younger age at onset of CRPS and a more severely affected phenotype.⁴ Although the cause of spreading CRPS symptoms is not clear, researchers have speculated that CRPS may spread by spinally or cortically mediated mechanisms.⁴

Patient Characteristics

A recent study examining the clinical characteristics of patients with CRPS found that approximately 73% of CRPS patients were female, and the mean age at onset of symptoms was 43 years.⁵ The investigators also found a greater predominance of left-handedness (21.8% vs 10% in the general population) and multiple limb involvement (13%, 83% of whom had contiguous spread). The median time from symptom onset to diagnosis was 6 months, but ranged up to 129 months.

Warm and Cold Subtypes

Bruehl et al recently provided evidence to support the concept of warm and cold subtypes of CRPS in an international, multicenter study.6 Their evaluation of the signs and symptoms of CRPS in 152 patients revealed a warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity, and a cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity.

Median pain duration was significantly shorter in the warm subtype than in the cold subtype (4.7 vs 20 months; P < 0.001), but pain intensity was comparable.⁶ A measure of inflammation was significantly elevated in the warm subtype (P < 0.001), but this measure decreased significantly the first year after injury (P < 0.001). The investigators suggested that inflammatory mechanisms may contribute most prominently to the acute phase of the warm subtype but diminish over time.

Mood Symptoms

Pain catastrophizing, depression, and anxiety are commonly found in patients with CRPS and are linked with poorer outcomes.^7,8 Notably, patients are at high risk for suicidal ideation (74%), underscoring the need for psychiatric evaluation and early intervention for psychiatric disorders in the overall management of CRPS.⁹ (see Patient Advocacy for Complex Regional Pain Syndrome.)

Pathophysiology of CRPS

The origins of the disease remain largely unclear. CRPS most likely is developed and maintained by both the central and peripheral nervous system. Possible contributors to CRPS include:  

• Ischemic reperfusion injury or oxidative stress^10-13  
• Peripheral and central sensitization^14-18  
• Altered sympathetic nervous system function or sympatho-afferent coupling^19-23  
• Nerve injury^24-26  
• Neurogenic inflammation and autoimmune dysfunction, including activated glial cells^27-31  
• Brain plasticity^32-35  
• Genetic and psychological factors/disuse^36-40      

The Role of Glial Cells    

Over the past decade, research on CRPS has focused on the role of glial cell activation in the perpetuation of CRPS. Increased glial cell activation has been demonstrated in patients with CRPS.^30,31 In addition, data from animal studies supports the hypothesis that limb fracture triggers afferent C-fiber substance P release, which signals chronic neuroglial activation. That glial activation, in turn, may contribute to the ongoing central nociceptive sensitization in CRPS.⁴¹ Evidence suggests that microglial activation triggers proinflammatory responses—including release of cytokines—that leads to neuronal hyperexcitability, neurotoxicity, and chronic inflammation.⁴²

This research has led to investigation of pharmacotherapies to block glial cell activation in CRPS, including use of low-dose naltrexone and minocycline.

Brain Imaging Findings

Brain imaging research had vastly improved our understanding of CRPS and has demonstrated that CRPS is associated with abnormal brain system morphology. These morphologic changes result in dysregulation of pain processing in motor, sensory, affective pain, and autonomic systems.

For example, a 2014 study by Barad et al illustrated that patients with CRPS have a decreased volume of gray matter in pain-related affect regions in the brain including the dorsal insula, left orbitofrontal cortex, and several areas of the cingulate cortex.³² Patients also had a greater volume of gray matter in the bilateral dorsal putamen and right hypothalamus.

Barad et al³² found that pain duration was associated with decreased gray matter in the left dorsolateral prefrontal cortex, whereas pain intensity was associated with increased volume in the left posterior hippocampus and left amygdala and decreased volume in the bilateral dorsolateral prefrontal cortex. They hypothesized that the findings may reflect a neurobiological predisposition for central sensitization or plasticity changes resulting from ongoing neuropathic afferent input.

Diagnosis

CRPS is diagnosed based on clinical signs and symptoms. Table 1 shows what is commonly referred to as the “Budapest Criteria” for CRPS diagnosis, which was adopted as the official IASP diagnostic criteria for CRPS in 2012.³

Treatment of CRPS

Four general treatment guidelines have been published since 2010.^43-46 Given the regional differences in the guidelines, this review primarily discusses the 2013 RSDSA guidelines by Harden et al,⁴⁴ which also were published most recently.

As with patients with other chronic pain conditions, patients with CRPS appear to derive the greatest improvement in physical function, mood, and ability to cope with pain when they are treated with an interdisciplinary pain management approach.^47-49 Such an approach incorporates physical therapy (PT), occupational therapy (OT), pharmacotherapy, psychotherapy, interventional and neurostimulation techniques, as well as complementary and alternative approaches.

Functional Restoration

The RSDSA guidelines⁴⁴ noted that pain management techniques that focus on functional restoration (ie, PT/OT) are an important aspect of CRPS treatment, with the goal being gradual desensitization and steady progression to increase strength and improve flexibility.⁴⁴ Harden et al suggest a staged approach to PT/OT as shown in the Figure.⁴⁴ As part of this algorithm, medications, interventional techniques, and more intense psychotherapies should be reserved for patients who fail to progress using functional restoration techniques or who cannot initiate these programs because of high pain levels.⁴⁴

Evidence-Based Treatments

Formulating an evidence-based approach to CRPS management is difficult given the lack of high-quality evidence supporting efficacy of most available therapies. Cochrane reviews^50,51 found low-quality evidence to support the following:

• PT or OT therapy
• Bisphosphonates, calcitonin, or subanesthestic intravenous ketamine
• Graded motor imagery (laterality training, motor imagery, mirror therapy for visual feedback)

Mirror therapy (use of a mirror box to watch the reflection of the unaffected limb move as if it were the affected limb). Table 2 presents current evidence on treatments proposed for CRPS.^2,52-90 Notably, many of the commonly used treatments for CRPS (eg, antidepressants, opioids, and anticonvulsants) have not been evaluated in randomized controlled trials (RCTs) or have shown equivocal findings.²

Download pdf of Table 2

In addition, some treatments, such as sympathetic nerve blocks, have shown negative findings in RCTs. Future, larger RCTs of these treatments, as well as results from emerging therapies, such as minocycline, transcranial magnetic stimulation, real-time neurofeedback, and high-frequency neurostimulation, are eagerly anticipated.

Conclusion

The most significant way to improve the care of patients with CRPS is to attain early diagnosis, typically using the Budapest Criteria. Some physicians may choose to use sympathetic nerve blocks to try to establish the diagnosis and/or confirm the clinical diagnosis. However, no more than 1 to 3 injections should be used, as per this author’s protocol. Also, it is important to remember that the “soft tissue trauma” that may have precipitated the problem may be so insignificant that the patient may not remember it.

Treatment with pharmacotherapy by itself is helpful but is not adequate. Without question, patients are best treated in an interdisciplinary neurorehabilitation center. A combination of PT/OT along with appropriate pharmacotherapy can allow patients to achieve improvement in pain and functioning; however, achieving health insurance coverage may be an arduous process.

Although significant gains in knowledge have been achieved in the past decade, more research into the diagnosis and treatment of CRPS is needed urgently. It is the author’s opinion that experimental studies on the use of minocycline to decrease glial cell activity is an important avenue of research, and the new research on low-dose oral naltrexone is extremely exciting.