Learning Objectives/Outcomes:After participating in this CME/CNE activity, the provider should be better able to:

1. Identify at least 3 signs and symptoms of complex regional pain syndrome.

2. Outline the pathophysiology of complex regional pain syndrome.

3. Evaluate therapeutic strategies for treatment of complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a pain condition characterized by chronic spontaneous and/or evoked regional pain that typically affects an extremity with a distal to proximal gradient.1 The regional nature of CRPS means that it does not follow a specific nerve distribution or dermatome.

CRPS type I, which was once referred to as regional sympathetic dystrophy, usually develops after traumatic injury to an extremity, such as fracture. Type II CRPS, previously referred to as causalgia, can develop after major nerve damage. Although an inciting event is almost always present, CRPS can occur spontaneously, and has been reported to have begun that way in up to 11% of cases.2

Individuals affected by CRPS report that motor and sensory symptoms significantly impair quality of life, such as through mood disturbance, difficulties with mobility, and social, recreational, and work-related disability.3 The following article reviews the clinical signs and symptoms of CRPS and underlying pathophysiology and treatment strategies to reduce pain and related disability.

Overview of Complex Regional Pain Syndromes

CRPS has an estimated rate of 26.2/100,000 person-years, with 50,000 new cases reported annually in the United States.4,5 Although the incidence is relatively rare, the disabling consequences of this condition make it a clinically significant topic. CRPS affects individuals across age groups but has a peak incidence in the fourth decade of life, and women are affected 3 times more often than men.4,6 In adults, the upper extremity is more often involved compared with the lower extremity, and bone fracture is the most frequent precipitating event.7 Other initiating events can involve sprain, crush injuries, surgery, and immobilization.5 Common risk factors for CRPS type I are as follows:

* Female;

* White;

* Comorbid depression;

* Menopause;

* Osteoporosis;

* Autoimmune conditions (asthma);

* Immobilization;

* Comorbid headache disorder;

* History of drug abuse;

* History of angiotensin-converting enzyme inhibitory therapy; and

* Higher median household income.

Although CRPS was once thought to be rare in children, several recent reports have surfaced describing the presentation and differences compared with CRPS in adults.8,9 Most cases of childhood CRPS involve girls between 8 and 16 years of age, with the lower limb most often affected-particularly the foot. Neurologic and sympathetic symptoms are less pronounced and there is less edema. However, the most common symptoms at presentation are cooler skin temperature, intense burning pain, cold and mechanical allodynia, dysesthesia, and paresthesia. Of concern, there seems to be a much higher relapse rate of CRPS in children-20% to 30% as compared with 1% to 2% in adults.8

Signs and Symptoms

Signs and symptoms of CRPS are listed in Table 1. These typically evolve within a month after the inciting event. The location of pain is most often distal, typically with a glove or stocking distribution in the distal extremity, although it can also occur in the knee or the shoulder. The most common signs can be grouped into the categories of sensory, vasomotor, sudomotor/edema, and motor/trophic. Standardization of diagnostic criteria was proposed by the Budapest Consensus Workshop and later validated.10 For clinical diagnosis, patients must report 1 symptom in 3 out of the 4 categories, and 1 sign must be present in 2 or more of the categories at the time of evaluation.5,10 In the research setting, the patient must report 1 symptom in each of the 4 categories. These criteria in the clinical setting produce a sensitivity of 0.94 and a specificity of 0.36, whereas the research criterion has a sensitivity of 0.85 and a specificity of 0.69.10,11

Table 1. Signs and Symptoms of Complex Regional Pain Syndrome

Clinical examination findings may identify allodynia, hyperalgesia, or hypoalgesia.12 Edema and pain may impair movement, and fibrotic contractions can limit movement further in the chronic stage. Due to autonomic dysfunction, vasodilation or constriction can cause hyperhidrosis or hypohidrosis with color changes.

CRPS can be categorized based on the symptoms of being "warm" or "cold."13 Warm CRPS, which often occurs in the acute phase, is characterized by a warm, red, and swollen limb, whereas cold CRPS is associated with a cold, dark, and pale limb. Approximately 30% of patients present with cold CRPS.12 The patient's fingernails or toenails may grow at an unusual speed (faster or slower than other limbs) and the patient's hair might also grow faster or slower.

Atrophy of the skin can occur in the chronic stage, giving the skin a shiny appearance. In some cases, central motor symptoms can develop, including tremors, dystonia-like postures, and irregular myoclonus.14 Abnormal limb perception in relation to the size of the limb, neglect-like phenomena, and altered proprioception may be present.15 Patients with severe pain may be expected to have a greater degree of the latter symptoms, as it has been demonstrated that the degree of cortical reorganization is related to the intensity of CRPS pain. Cortical representation of the affected limb is smaller than the unaffected limb, and can produce a perception as though it is an abnormal shape and size and, in some cases, as though the limb is no longer their own.

Quantitative changes in skin temperature, blood flow, sensation, and edema may be determined by the use of a thermometer, Doppler ultrasonography, mechanical and thermal testing equipment, and extremity circumference measurements.16 Diagnostic testing with electromyography may be used to detect peripheral nerve injury. Plain films may reveal advanced osteoporosis or fracture. MRI may demonstrate soft tissue injury or bone edema.

Differential diagnosis should include inflammatory arthritis, local pathology such as fracture, sprain/strain, cellulitis, Raynaud disease, traumatic vasospasm, thromboangiitis obliterans, thrombosis, neuropathy, and erythromelalgia.

CRPS may or may not have a sympathetic component. To evaluate the contribution of sympathetic input to the reported symptoms, a fluoroscopically guided stellate ganglion block (SGB) may be used for the upper extremity or a lumbar paravertebral block for the lower extremity.

Spontaneous spread of the pain occurs at the level of the spinal cord and can involve contiguous spread, spread to another site, and mirror-image spread.17,18 In a small study that included 27 patients with CRPS, all of the patients demonstrated contiguous spread, whereas 70% also had spread to another site, 15% had mirror-image spread, and 19% had contiguous spread alone.16 Allodynia, swelling, and loss of strength, and functional movement have been reported in patients with CRPS up to 15 years after the initiation of symptoms.19,20 In addition, there are several studies that suggest an association between CRPS diagnosis and development of comorbid pain disorders, including chronic widespread pain and migraines.21,22 Early identification and treatment for CRPS are thought to reduce the risk of persistent symptoms and may increase functional recovery.

Pathophysiology

At one time, CRPS was thought to progress in severity through 3 stages defined by the occurrence of specific symptoms.23 Due to the lack of empirical evidence supporting the existence of stages of CRPS, this concept has been abandoned. However, there are classic signs and symptoms of inflammation involved in the presentation of CRPS. After tissue trauma, lymphocytes and mast cells secrete proinflammatory cytokines, such as interleukin (IL)-1[beta], IL-2, IL-6, and tumor necrosis factor-[alpha] (TNF-[alpha]). Neurogenic inflammation ensues after the release of neuropeptide mediators, substance P, calcitonin gene-related peptide, and bradykinin.24 Elevated mRNA expression levels of proinflammatory cytokines and reduced levels of anti-inflammatory cytokines have been reported in patients with CRPS, as compared with healthy controls.25

Although systemic elevations in inflammatory mediators may contribute to the pathogenesis of CRPS, increased migration of mast cells to the site of injury and local release of inflammatory and neurotrophic mediators released by mast cells are thought to play a significant role.26 The increased density of mast cells in affected regions may sensitize neurons in the peripheral and central nervous system, resulting in the classic signs of allodynia and hyperalgesia.

In addition, mast cells are near the unmyelinated and thinly myelinated sensory nerve fibers affected in CRPS.26 Peripheral fibers, or terminal twigs, of C- and A-[delta] nociceptive afferents appear damaged. The afferent fibers carry signals not only to the spinal cord but also to surrounding blood vessels, causing them to dilate or constrict. With ongoing vessel constriction, the surrounding tissue can be damaged from ischemia and release adenosine triphosphate, which may induce abnormal signaling between sympathetic and sensory nerve cells. There is some evidence that genetics may play a role in the risk of CRPS, and rare family clusters of CRPS have been reported, with earlier onset, increased dystonia, and involvement of more than 1 limb.

Treatment Strategies

Early multimodal interdisciplinary treatment of CRPS is supported by current clinical practice guidelines.27 Patient education is provided by all members of the interdisciplinary team, including nurses, physicians, clinical psychologists, physical and occupational therapists, and other rehabilitation specialists. Aligned with the biopsychosocial model of pain, the education of CRPS should include information about the syndrome and psychological, spiritual, and social protective factors that can help the patient and the family to cope with the condition. It is important to emphasize that the sensory, vasomotor, and autonomic disturbances of CRPS are symptoms that require management-as opposed to a disease that requires protection of the affected limb.5

Physical and occupational therapists, and other rehabilitation specialists, play an im-portant role in maintaining functional movement of the affected limb, guiding desensitization therapies, and strengthening exercises. Desensitization therapy involves applying self-administered tactile stimulation and discrimination techni-ques using different props such as warm/cold, rough/soft, and blunt/sharp.28 The stimulation should always be applied to both limbs, starting with the nonpainful limb first and gradually involving the painful area. Elevation of the affected limb, massage, contrast baths, transcutaneous electrical nerve stimu-lation, isometric strengthening, aquatherapy, and stress-loading may all be tailored to enable the patient to maintain or regain function.

Mirror therapy and graded motor imagery may be used to aid in the reorganization of cortical networks.

For mirror therapy, the affected limb is concealed behind the mirror, whereas the nonaffected limb is positioned so that its reflection is superimposed where the affected limb should be.5 Movement of the unaffected limb appears as though it is the affected limb functioning normally, and it is important that it is performed with both limbs moving in a synchronous manner, so the individual can feel the movement at the same time as observing the reflection of the normal limb moving.

Graded motor imagery involves performing mental exercises, such as identifying left and right extremities while looking into the mirror and visualizing the movement of the affected area without actually moving it. There is typically a 3-stage motor imagery component. Stage 1 involves asking the patient to rapidly identify in each of a series of photographic flash cards (of the affected limb and the unaffected limb) whether the correct answer is the left or right extremity.

In stage 2, the patient visualizes moving the limb into the position demonstrated on the photograph while resting the affected limb.

Stage 3 involves mirror therapy. The effectiveness of graded motor imagery was examined in a small randomized controlled trial (RCT) and demonstrated a significant decrease in pain from pre- to posttreatment, and functional gains that were maintained at 6-month follow-up.28

Recently, the effectiveness of physical therapy under hypnotherapy was evaluated in a small retrospective study that included 20 patients with CRPS type I of the wrist and hand.29 The sample included 13 women and 7 men with an average age of 56 years, and the main end points were pain, stiffness, and strength. The results of the treatment were reported as satisfactory by all participants after a mean of 5 sessions, the mean visual analog scale score decreased by 4 points, and analgesic use was reduced to the use of paracetamol. Secondary outcomes were also improved with return to work possible in 80% of cases.

Pharmacologic Agents

Although there are many therapeutic classes of medications that can be used to treat CRPS, there is a dearth of evidence on the effectiveness of these agents for pain and function specific to this condition. Along with physical and occupational therapy, medications used to treat neuropathic pain, a primary component of CRPS, are commonly used. These include gabapentin, tricyclic antidepressants, and/or carbamazepine.30 Corticosteroids may be used early on to treat the inflammatory features of CRPS. However, due to the side effects, long-term therapy is not advised.31 Several recent guidelines have been published.32-34

Guidelines for CRPS type I advocate several pharmacologic classes to reduce pain and support physical rehabilitation, but they do not provide guidance about which agent should be prioritized when designing a therapeutic regimen. A recent meta-analysis examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS type I and provided a rank order of various substances stratified by length of illness duration.35 In total, 16 studies were included in the analysis.

The findings were as follows:

* Bisphosphonates seem to be the treatment of choice in early stages of CRPS type I.

* The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. Although most medications demonstrated some efficacy on short-term follow-up, only bisphosphonates and N-methyl-D-aspartate (NMDA) analogs were associated with significant improvements.

* Vasodilators demonstrated better long-term pain reduction than placebo.

This network meta-analysis indicates that a rational pharmacologic treatment strategy of pain management should consider bisphosphonates in early CRPS I and a short-term course of calcitonin in later stages.

Authors who conducted a recent systematic review of IV therapies for CRPS found supporting evidence for the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine in selected patients with CRPS.36

The following conclusions were drawn:

* IV bisphosphonates

* Inhibits bone resorption; potential to reduce pain associated with bone loss in patients with CRPS type 1

* IV immunoglobulin (IVIG)

* Eliminates proinflammatory cytokines (such as IL-2, TNF, and IL-6)

* Stimulates macrophages to increase the catabolism of immunoglobulins; potential to eliminate noxious autoantibodies present in the serum

* Anti-inflammatory action via binding C3b and C4b and reduction in the number of activated complement fragments

* Downregulates production of autoantibodies in B cells or inhibition of cytotoxic T cells; based on the level of evidence reviewed, the authors recommended IVIG be considered in CRPS with refractory pain (2B+/2C+)

* IV NMDA receptor antagonists

* Activation of NMDA receptor signaling has been proposed in induction and maintenance of CRPS

* Ketamine and magnesium might be effective in refractory CRPS by blocking central sensitization of pain transmission neurons through inhibiting NMDA receptors; this observation may suggest an increased risk of ketamine-induced liver injury if infusion is prolonged and/or repeated within a short period

* IV regional block (IVRB) with anti-inflammatory medications

* Acts against the local neural inflammatory process, which may be involved in the pathophysiology of CRPS

* IVRB with ketorolac (preferably with lidocaine) may be considered for short-term pain reduction in CRPS (2B+/2C+)

* Effectiveness of IVRB with methylprednisolone or parecoxib not supported by RCTs (2B-/2C+)

* IV free radical scavengers

* RCT and retrospective studies failed to demonstrate effectiveness of IV mannitol in CRPS (2B-)

* IVRB with sympatholytics

* Evidence of heightened expression of [alpha]1-adrenoreceptors in the dermal nerves and epidermal cells of patients with CRPS

* Sympathetic activation leads to vasoconstriction, cold skin, and tissue hypoxemia

* Only case studies have demonstrated phenoxybenzamine and labetalol to be effective

* IVRB with ketanserin reported superior to placebo in pain reduction in an RCT, but evidence is weak because of the small number of patients

* IV anti-TNF-[alpha] antibodies

* TNF-[alpha] signaling reported to contribute to the development of nociceptive sensitization in a tibia fracture animal model of CRPS type I

In summation, the review found that most studies of IV therapies for CRPS are not of high quality, and that further studies based on standard RCT quality are required. Currently, it is not clear whether bisphosphonates or other drugs are preferable in acute or chronic CRPS. High-quality studies are needed to further examine the safety, efficacy, and cost-effectiveness of these therapies for patients with CRPS.

In patients who demonstrate sympathetically mediated symptoms, sympathetic blockade may be particularly beneficial. Local anesthetics are injected along the stellate ganglion for the upper limbs or the lumbar sympathetic chain for lower limbs. Anticipated response to the block includes increase in temperature in the affected limb, reduced pain, and increased range of motion.5

A retrospective pilot case series evaluated the use of ultrasound-guided SGBs combined with pharmacologic and occupational therapy in patients with CRPS of the hand.37 A total number of 156 blocks were evaluated in 16 patients with CRPS of the hand. The overall mean pain reduction was 63.2% regarding spontaneous and 45.3% regarding evoked pain. Mild complications, such as hoarseness or dysphagia, occurred in 13.5% of the blocks (21 SGBs). Serious complications, such as plexus paresis or accidental puncture of vessels or other structures, did not occur. In this pilot case series, the combination of ultrasound-guided SGB and pharmacology and occupational therapy, all of which occurred simultaneously, demonstrated encouraging treatment results. However, more research is needed among a larger number of participants to confirm these results.

Another recent pilot study compared the efficacy of continuous stellate ganglion (CSG) block with that of continuous infraclavicular brachial plexus (CIBP) block in management of CRPS type I of upper extremity.38 The investigators randomly assigned 33 patients with CRPS type I of upper extremity to either CSG or CIBP group. Participants were treated for 1 week with continuous infusion of 0.125% bupivacaine at 2 mL/h (CSG group) or with continuous infusion of 0.125% bupivacaine at 5 mL/h (CIBP group).

The outcomes were evaluated in terms of the following and compared with their baselines using the Neuropathic Pain Scale Score (NPSS), edema scores (grades 0-2), and range of motion (ROM) of all upper extremity joints.

There was a statistically significant improvement in the NPSS among the CIBP group compared with the CSG group during the first 12 hours after initiation of the block, after which the NPSS was comparable between groups. One month after the infusion, both groups demonstrated significant improvements in edema and ROM of all upper extremity joints compared with baseline. The pilot findings demonstrate that CSG and CIBP are feasible with preliminary efficacy for more immediate pain reduction demonstrated with CIBP. Further study with a large RCT is recommended, particularly focused on long-term pain relief and functional improvement in patients with upper extremity CRPS.

Conclusion

CRPS is a chronic pain condition characterized by sensory, vasomotor, sudomotor/edema, and trophic changes and can result in significant disability and impaired quality of life. Clinicians need to stay vigilant in recognizing the signs and symptoms of CRPS, particularly in patients with traumatic extremity injuries and individuals undergoing surgery. Diagnosis is based on exclusion of other pathologic conditions, including infection, thrombosis, and rheumatologic conditions. Treatment should ensue with clinical suspicion of CRPS and involves a multimodal interdisciplinary plan to manage pain and restore function. Active treatment with physical and occupational therapy and pharmacologic agents offers the best strategy at this time for patients affected by CRPS and their families.

References