Complex regional pain syndrome (CRPS) is a neuropathic pain disorder defined by the presence of distinct clinical features, including allodynia, hyperalgesia, sudomotor and vasomotor abnormalities, and trophic changes. The pain experienced is disproportionate to the degree of tissue injury and persists beyond the normal expected time for tissue healing. The pathophysiology is multifactorial and involves pain dysregulation in the sympathetic and central nervous systems, with likely genetic, inflammatory, and psychological contributions. There are two subtypes: type I, formerly known as reflex sympathetic dystrophy, and type II, formerly known as causalgia. Type I occurs in the absence of nerve trauma, while type II occurs in the setting of known nerve trauma. Clinically they are indistinguishable and follow a regional rather than dermatomal or peripheral nerve distribution. CPRS favors the distal extremities, though spread beyond the initially affected area commonly occurs in the proximal or contralateral limb. CRPS is further subdivided into “warm” versus “cold” and sympathetically-maintained versus sympathetically-independent, which may affect prognosis and treatment options. This activity describes the evaluation and management of complex regional pain syndrome and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Outline the typical presentation of complex regional pain syndrome.
• Describe the Budapest Criteria and their role in the diagnosis of complex regional pain syndrome.
• Review the treatment options for complex regional pain syndrome.
• Explain how careful planning and discussion amongst interprofessional team members involved in the care of patients with complex regional pain syndrome can help improve patient outcomes.

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Introduction

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder characterized by ongoing pain disproportionate to the degree of tissue injury and persists beyond the usual expected time for tissue healing. [1] Pain is accompanied by sensory, motor, and autonomic abnormalities. Such abnormalities include allodynia, hyperalgesia, sudomotor and vasomotor abnormalities, and trophic changes. Pain does not follow a particular dermatome or myotome but is rather regional. This disabling condition often develops after a trauma, fracture, or surgery.[2][3] But some spontaneous cases have also been reported.[4]

In the 16th century, Ambroise Paré reported cases with CRPS like symptoms for the first time which developed after phlebotomy.[5] In 1864, Silas Mitchell noted this syndrome after gunshot wounds. He used the term ‘causalgia’ to describe this syndrome in 1872. James A. Evans coined the term ‘reflex sympathetic dystrophy’ to describe a similar condition where he suspected sympathetically mediated pain in 1946. [6] Finally, in 1994, the International Association for the Study of Pain (IASP) named this condition ‘Complex Regional Pain Syndrome’ and proposed a diagnostic criterion. Due to low specificity, a widely accepted revised criterion was proposed in 2010 and is commonly referred to as the “Budapest Criteria.”[2][7]

CRPS has two subtypes: type I, formerly known as reflex sympathetic dystrophy, and type II, formerly known as causalgia. Type I occurs in the absence of nerve trauma, while type II occurs in the setting of known nerve trauma. Clinically they are indistinguishable and follow a regional rather than a dermatomal or peripheral nerve distribution and favor the distal extremities, though spread outside of the initially affected area commonly occurs to the proximal or contralateral limb.[6][8] CRPS is further subdivided into “warm” versus “cold,” and sympathetically-maintained (SMP) versus sympathetically-independent (SIP), which may affect prognosis and treatment options. [8]

CRPS not only impacts function, sleep, and activities of daily living but also takes a significant mental and psychosocial toll on the patient.[9][10][11] Its diverse spectrum of clinical presentation and lack of any clearly defined pathophysiology poses a challenge for optimal management of this disorder.

Evaluation

No definite pathophysiologic mechanism for CRPS has been identified yet. Therefore, no gold standard diagnostic test for CRPS exists.[8] The diagnosis is clinical and based on the widely accepted Budapest criteria. Compared to the previous IASP criteria, the Budapest criteria have similar sensitivity (0.99) but higher specificity (0.68).[7]

Budapest Criteria [6]

A. They should report continuing pain disproportionate to the inciting event.

B. They should report at least one symptom in three of the four following categories:

1. Sensory: Reports of hyperalgesia and/or allodynia,
2. Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry,
3. Sudomotor/edema: Reports of edema and/or sweating changes and/or sweating asymmetry,
4. Motor/trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, skin, nails).

C. Additionally, they must display at least one sign at the time of evaluation in two or more of the following categories:

1. Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch or deep somatic pressure),
2. Vasomotor: Evidence of temperature asymmetry and/or skin color changes and/or asymmetry,
3. Sudomotor/edema: Edema and/or sweating changes and/or sweating asymmetry,
4.  Motor/trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, skin, nails).

D. Finally, there is no other diagnosis that better explains the signs and symptoms.

Various objective testing measures have been utilized to include thermography, triple-phase bone scan, and the quantitative sudomotor axon reflex test. While these studies provide further data, they are not necessary to make the diagnosis of CRPS. The diagnosis of CRPS is largely clinical and one of exclusion. The differential diagnosis includes small or large fiber sensorimotor neuropathy, cellulitis, erythromelalgia, vasculitis, vascular insufficiency, lymphedema, deep vein thrombosis, and Reynaud’s phenomenon. Diagnostic tests in CRPS are primarily aimed at screening for other potential differential diagnoses.

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Treatment / Management

Although there is a possibility that patients with CRPS may improve spontaneously, considering the debilitating nature of this syndrome, it is prudent to institute aggressive management as soon as possible as a delay may result in an unfavorable outcome. Moreover, compared to chronic CRPS, early CRPS is less resistant to treatment and therefore has a better prognosis.[49] The goal of treatment is not only improvement in pain and discomfort but also functional restoration and prevention of disability. Therefore, the most optimal management would include an interprofessional approach including physical and occupational therapy, pharmacotherapy, behavioral therapy, and interventions.[6]

Physical and Occupational Therapy

Manual therapy and exercises are not the only CRPS treatments under this section. Other therapy modalities include transcutaneous electrical nerve stimulation, ultrasound, laser, pain education, mirror therapy, and graded motor imagery (GMI). Multiple mechanisms of action of physical therapy have been proposed with no clear definitive theory. Manual therapy and exercise improve range of motion, function and reduce disability through endorphin release as well as other central and peripheral analgesic mechanisms.[3][50] Pain education influences pain perception and behavior by improving understanding of pain pathophysiology in such patients.[3] Whereas mirror therapy and GMI remediate maladaptive cortical neuroplastic changes associated with chronic pain conditions like CRPS.[51]

A 2016 Cochrane review found that among the different physiotherapy modalities, mirror therapy and GMI may improve pain as well as function in CRPS. However, the quality of evidence was poor. Two clinical trials each for GMI and mirror therapy have demonstrated improvement of pain and function at 6 months. Very low-quality evidence was also found for improvement of impairment in CRPS with multimodal physiotherapy.[3]

Pharmacotherapy

Multiple pharmacotherapeutic agents are used in the management of CRPS. The commonly used therapeutic options in this category include anti-inflammatory medications, anticonvulsants, antidepressants, transdermal lidocaine, opioids, NMDA antagonists, and bisphosphonates. Using a multimodal pharmacologic regimen that combines several different classes may lead to superior outcomes. 

Anti-inflammatory Medications

Oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been used in CRPS as inflammation is thought to play a role in disease pathogenesis. Based on three trials that compared oral corticosteroids to placebo in CRPS, a 2013 Cochrane review concluded that oral steroids do not significantly reduce pain. This was supported by very low-quality evidence. The review also found that oral corticosteroids seem to improve composite pain scores.[52] Another study found that compared to piroxicam (NSAID), oral prednisone seemed to be more effective in improving composite CRPS scores in post-stroke patients.[53] A more recent study found that 2-month treatment with low-dose oral prednisone was safe and effective in post-stroke CRPS.[54]

Bisphosphonates

This class of medication is used routinely in bone-related problems as it inhibits osteoclastic activity. Several mechanisms of action of bisphosphonates in CRPS have been proposed. The more commonly accepted mechanisms include inhibition of bone marrow cell proliferation and migration as well as inflammation modulation.[55] A 2017 meta-analysis concluded that bisphosphonates seem to reduce pain in CRPS I.[56] A Cochrane review in 2013 found that low-quality evidence also seemed to suggest the same response in CRPS, more so in those with concomitant evidence of osteopenia or osteoporosis.[52]

Anticonvulsants and Antidepressants

Gabapentin is the most widely studied medication in this class. It works by inhibiting the alpha 2-delta subunit of voltage-gated calcium channels. Despite its widespread use in treating CRPS, very low-quality evidence suggests that gabapentin is ineffective in the treatment of CRPS I.[52] In 2016, a study compared amitriptyline and gabapentin for CRPS I and pediatric neuropathic pain. Both the medications were found to reduce pain intensity and disability significantly. However, no significant difference in effect was noted between the two.[57]

Opioids

The effectiveness of opioids has not been studied in CRPS, and therefore no evidence-based conclusions can be drawn.[41]

NMDA Antagonists

NMDA receptor antagonists like ketamine have been hypothesized to reverse central sensitization and maladaptive cortical neuroplastic changes in CRPS.[24] Low-quality evidence suggests that intravenous ketamine infusion may improve pain in CRPS for up to 4-11 weeks. [52][52] However, side effects and psychomimetic properties of ketamine have prevented widespread use.[24]

Behavioral Therapy

Elevated levels of catecholamines associated with depression can worsen CRPS by inducing central sensitization through adrenergic mechanisms. Reversal of this effect is one of the proposed mechanisms of action of psychotherapy in CRPS. Apart from case reports and case series, only one small trial has been done evaluating the efficacy of behavioral interventions in CRPS. Despite the lack of clear evidence supporting their use in CRPS, behavioral therapy has been recommended part of comprehensive treatment.[58]

Interventions

Sympathetic Blocks

Sympathetic hyperactivity is believed to be an underlying pathophysiologic mechanism of CRPS.[41] Therefore, lumbar sympathetic nerve blocks are routinely used in the treatment of lower extremity symptoms, and stellate ganglion sympathetic blocks are used for the management of upper extremity symptoms of this syndrome. A 2013 Cochrane review found that sympathetic blocks with local anesthetic were ineffective at reducing CRPS related pain, but the quality of evidence was low.[52] A more recent Cochrane review in 2016 failed to draw any definitive conclusions on the efficacy of such treatment in CRPS due to paucity of evidence.[59]

Spinal Cord Stimulation

Spinal cord stimulation (SCS) involves delivering electric stimulation to the dorsal column of the spinal cord by the placement of electrodes in the epidural space. The electrodes are usually connected to an implanted pulse generator to power the electrode, but some devices use an external pulse generator. Multiple mechanisms of action of SCS have been proposed, which include inhibition of nociceptive neural conduction in the spinal cord, adrenergic inhibition, vasodilation, and reversal of cortical maladaptive neuroplastic changes. A systematic review in 2017 studied the effectiveness of SCS in CRPS. The authors concluded that a high level of evidence supports the use of SCS for improvement of pain scores, quality of life as well as the perception of pain relief in CRPS.[59]

Dorsal Root Ganglion Stimulation

Targeting the dorsal root ganglion (DRG) instead of the spinal cord is a relatively new and novel neuromodulation modality for the management of chronic pain. This enables a more focused application of neurostimulation than traditional SCS. DRG stimulation was approved by United States Food and Drug Administration in 2016 for treatment of lower extremity pain in CRPS. A recent pooled analysis study concluded that DRG stimulation was safe and effective for CRPS with a 4.9-point mean reduction of pain intensity in CRPS-I.[60] The ACCURATE study compared SCS and DRG stimulation in 152 subjects with CRPS, and study results were published in 2017. This multicenter randomized trial found that DRG stimulation was more effective than traditional SCS in reducing pain and improving quality of life in CRPS.[61]

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Differential Diagnosis

• Arterial insufficiency
• Gillian Barre syndrome
• Hysteria
• Monometric amyotrophy
• Multiple sclerosis
• Peripheral atherosclerotic disease
• Phlebothrombosis
• Porphyria
• Poliomyelitis
• Tabes dorsalis

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Staging

Bonica, in 1990 had proposed 3 stages of CRPS. Bruehl et al. studied the validity of stages in a series of 113 patients and found no significant difference in duration of symptoms among the stages. This research suggested that clear generalized disease stages don’t exist in CRPS.[62]

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Prognosis

The prognosis of CRPS can be variable. Both spontaneous remission and refractory clinical presentation have been seen. But early treatment may improve the prognosis.

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Complications

Dystonia, cognitive executive dysfunction, adrenal insufficiency, gastroparesis, and irritable bowel syndrome are a few of the complications associated with long-standing CRPS.

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Deterrence and Patient Education

Oral supplementation of vitamin C has been hypothesized to lower the risk of development of CRPS after fractures due to its antioxidant properties. A meta-analysis of 3 trials in 2015 found that available evidence failed to demonstrate a definitive preventive role of vitamin C in CRPS development after distal radial fractures, although the level of evidence was low.[63] Another meta-analysis and systemic review in 2017 evaluated the efficacy of vitamin C in the prevention of CRPS development after wrist fractures. 500 mg vitamin C daily therapy for 50 days seemed to reduce the risk of CRPS at 1 year in this study.[64]

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Enhancing Healthcare Team Outcomes

An interdisciplinary team approach to this problem is required to maximize recovery and limit disability. Social service, pharmacology, nursing, and physical therapy, along with early advanced pain management, are key to improved outcomes. 

Source: PubMED