Article Item

Complex Regional Pain Syndrome: A Problem-Based Learning Discussion

Mar 13, 2023, 16:25 PM by Salomon Poliwoda MD, Ayaz Khan MD, Keith Newton MD, Jianguo Cheng MD, PhD


A 53-year-old female with a history of rheumatoid arthritis controlled with methotrexate came to our institution with progressively severe pain in her left hand and wrist. She denied a history of trauma. Her physician added steroids and NSAIDs to her medical treatment plan, but these did not alleviate her symptoms, reason for which she was referred to our clinic. On physical examination, she was seen to have hyperalgesia and allodynia over the volar/palmar and dorsal aspect of her left hand and wrist, along with edema, erythema, warmness, and hyperhidrosis. She was also noted to have reduced passive and active range of motion of her left wrist with associated brittleness in her nails. 


What are the differential diagnoses of complex regional pain syndrome (CRPS)?

- Peripheral nerve entrapment syndromes
- Peripheral vascular disease 
- Deep vein thrombosis 
- Thrombophlebitis 
- Fibromyalgia 
- Rheumatoid arthritis 
- Post herpetic neuralgia 
- Neuronal radiculopathy 
- Raynaud’s phenomenon 
- Soft tissue infections 
- Septic arthritis1 

What are the differential diagnoses of CRPS? What are the different types of CRPS?

CRPS is a debilitating chronic pain disorder that results in severe non-dermatomal pain patterns affecting an upper or lower limb with associated sensory, motor, sudomotor, and tropic changes. The term CRPS was first introduced in 1993 to better describe chronic pain states that had previously been referred to as causalgia, reflex sympathetic dystrophy, or shoulder-hand syndrome. Causalgia or causalgia like-syndrome was a term first introduced during the American Civil War. This term was used to describe chronic pain states that had been observed in military soldiers who had suffered from traumatic nerve-related injuries. The term, reflex sympathetic dystrophy was further introduced to describe the associated sympathetic nervous system changes that were noted in the disease course. The term CRPS was later introduced to better describe and categorize the basic pathophysiology of the disease course and guide available treatment options.2

To better understand CRPS, it can be useful to breakdown the term into individual words. The word complex is used to signify the dynamic nature of the disease course and its varied clinical presentation. Regional describes the distribution of symptoms that occur in a non-dermatomal regional pattern, typically affecting the distal portion of the affected upper or lower extremity limb. Pain describes the allodynia or out-of-proportion pain and hyperalgesia patients experience compared to the initial inciting event. Finally, syndrome describes the constellation of symptoms that a patient may experience from the sensory, motor, autonomic, tropic, or psychological changes that occur during the disease course.2

There are two types of CRPS: CRPS type 1 (formerly known as reflex sympathetic dystrophy) and CRPS type 2 (formerly known as causalgia)3. Both types are clinically indistinguishable, and symptoms occur in a non-dermatomal sensory pattern. However, type 2 is associated with nerve injury and type 1 is unassociated with nerve injury. Type 1 accounts for 90% of the cases of CRPS while type 2 accounts for 10% of the cases.3 Both cases are more common to present after an incident of trauma. In rare occasions, like in this case, trauma may be absent. 

What are the epidemiology and risk factors for CRPS? 

In the United States, the largest population-based study was published in 2016. From 2007 to 2011, out of a retrospective analysis of 33,406,123 patients, 22,533 were diagnosed with CRPS. This accounts for 0.07%.4

Risk factors associated with CRPS are female gender, Caucasian race, higher median household income, past extremity injuries (fractures, sprains, surgery, carpal tunnel syndrome), and certain comorbidities (history of headaches, depression, fibromyalgia and rheumatoid arthritis).4 This syndrome is more common to present itself in the upper extremities, compared to lower extremities.

What are the diagnostic criteria for CRPS? 

The diagnosis of CPRS can be challenging given the non-specific symptoms and variable disease course. There are no serum markers or imaging studies available to diagnose CRPS, but adjunct imaging studies can be considered and may be useful to aid clinicians in confirming the diagnosis. The diagnosis of CRPS is largely based on clinical history, exam, and exclusion of other similar disease processes. The Budapest Criteria, developed in 2003, is currently considered the primary criteria tool used to diagnose CRPS with a sensitivity of 99% and specificity of 68% (Table 1).5 This criterion requires the presence of the following four points:

1) Pain is disproportionate to any inciting event.

2) The patient must report at least one symptom in three out of the four categories. 

3) On evaluation, there must be at least one sign in two out of the four categories.

4) There are no other diagnoses that better explain the signs and symptoms.5

Table 1. Symptoms and signs associated with CRPS

Categories SymptomsSigns
SensoryHyperesthesia, allodyniaEvidence of hyperalgesia and/or allodynia
VasomotorTemperature asymmetry, skin color changes, skin color asymmetryEvidence of temperature asymmetry and/or skin color changes/asymmetry
Sudomotor/EdemaEdema, sweating, sweating asymmetryEvidence of edema and/or sweating changes/asymmetry
Motor/TrophicDecreased range of motion; weakness; tremor; dystonia; trophic changes affecting the skin, nails, or hairsEvidence of decreased range of motion and/or weakness; tremor; dystonia; and/or trophic changes affecting the skin, nails, or hairs

Additional adjunct diagnostic imaging studies that may be considered include diagnostic ultrasound, X-ray or MRI imaging, and a triple-phase bone study (TPBS). Diagnostic ultrasound, X-ray, and MRI imaging may be normal early in the disease course but can be used to exclude other musculoskeletal, neurological, or vascular conditions that may mimic CRPS. In the first six months, TPBS may demonstrate asymmetric increased uptake of radionucleotide flow and increased periarticular activity in the delayed phase portion of the study. It has been suggested that TPBS has a sensitivity of roughly 80% and a specificity of 70% in diagnosing CRPS. Later in the disease course, X-ray or MRI imaging may show evidence of regional osteopenia in the affected limb. 2

What is the natural history of CRPS?

Typically, CRPS follows three stages during its development. Stage 1 usually lasts 1-3 months and is composed of allodynia, fluctuations in skin temperature, joint pains, muscle spasms, increased sweating, edema, and changes in skin color and texture.6 Stage 2 can last 3-6 months and involves progression of the mentioned signs and symptoms along with increased levels of pain and appearance of muscle weakness.6 If refractory to treatment or left untreated, CRPS can progress to stage 3, which is characterized by muscle atrophy and contractures of the effected extremity. These changes may become permanent. Stages 1 and 2 are considered part of the warm phase, and stage 3 is considered the cold phase.6

What is the pathogenesis of this disease?

The pathogenesis of CRPS is not completely clear. It has been proposed that the syndrome is pathologically multifactorial with several contributing factors such as classic inflammation, neurogenic inflammation, impairment of the autonomic nervous system, and changes in the central nervous system.

The warm phase of this syndrome implies presence of classic inflammation. Trauma results in an exaggerated and prolonged release of cytokines such as tumor necrosis factor-a, interleukin (IL)-1, and IL-6.7 These transmitters maintain a cascade that perpetuates localized edema, erythema, and pain.

Neurogenic inflammation is also a factor that plays a role in this syndrome. Stimulation of the peripheral endings of the nociceptive C-fibers results in conduction centrally via the dorsal ganglia but also peripherally back to the affected extremity via efferent branches. This leads to a release of several neuropeptides such as substance P, calcitonin gene-related peptide (CGRP), neurokinin A, neurokinin B, neuropeptide Y, and gastrin-releasing peptide.8 CGRP promotes vasodilation. Substance P and neurokinin A promote vascular permeability. These processes contribute to perpetuating the localized classic inflammation. CGRP also promotes sweat gland function as well as hair growth.8

The presence of certain signs and symptoms indicates an autonomic system impairment in the development of CRPS. These include changes in skin color, temperature, hyperhidrosis, or hypohidrosis. Not only are localized autonomic changes present, but systemic effects have also been observed, such as increased heart rate, increased blood pressure, and impaired orthostatic response. Pain intensity in CRPS is correlated with an increased sympathetic activation.9

Brain plasticity has been suggested as a contributing factor of this disease. Birklein et al found that in 97% of 145 cases of CRPS had manifestations of motor dysfunction such as tremors, hyperreflexia, dystonia, and myotonic jerks.10 The brain areas that seem to participate in these manifestations include the primary motor cortex, posterior parietal cortices, and supplementary motor cortices.10 The somatosensory cortex has also been investigated and thought to contribute to the manifestation of hyperalgesia and allodynia.10 It is hypothesized that continuous peripheral nociceptor stimulation induces plastic changes in the motor and sensory cortices which, in turn, contribute to these additional manifestations seen in CRPS. 

What are the available non-pharmacological and pharmacological treatment options for patients with CRPS? 

CRPS is known to be a difficult chronic pain syndrome to treat. Treatment usually requires an interdisciplinary team approach focused on symptom management with a combination of therapies, medications, and interventional procedures. Treatment should not only address biological changes associated with the condition but also psychological and social stresses associated with the condition.

Physical Rehabilitation

Early in the disease course or in patients with mild CRPS, physical rehabilitation is considered the mainstay of treatment for CRPS. Depending on the severity of symptoms and disease course, therapy should focus on improving and maintaining flexibility, range of motion, and strength in the affected limb(s). Immobilization of the affected limb should be avoided, and adjunct medications and treatment should be provided to obtain reasonable pain control to optimize participation in therapy. Therapy can also be used as a setting to introduce other complementary treatment modalities such as desensitization, myofascial release, massage therapy, mirror therapy (MT), and edema management.11

In patients with severe symptoms who are unable to tolerate any traditional active therapy, graded motor imagery (GMI) therapy should be considered. GMI is a form of therapy that uses the recognition of hand laterality, MT, and explicit motor imagery (imaginary movements) to gradually activate cortical motor networks without triggering protective pain responses. This type of therapy is effective in patients with CRPS as the condition has been shown to disrupt cortical mapping in the affected limb. This disruption in cortical mapping tends to be directly proportional to the severity of symptoms.12 Currently, the level of evidence for GMI and MT remains limited with a few large case series and one single randomized controlled trial showing modest improvement in neuropathic pain and two-point discrimination. Pending additional research, the evidence currently remains insufficient to recommend GMI and or MT therapy over other conventional therapies in the management of CRPS.

Psychological and Behavioral Rehabilitation

CRPS is a chronic pain condition that can lead to emotional distress, avoidance behaviors, and social isolation. The condition often has a significant impact on a person’s quality of life, and symptoms may be influenced by other psychological factors such as stress, anxiety, or depression. There is strong evidence for the use of cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT) in the treatment of chronic pain conditions such as CRPS. Treatments such as CBT and ACT work to help individuals develop psychological flexibility and recognize the relationships between thoughts, feelings, behaviors, and pain. These therapies can help reintroduce control into an individual’s life with CRPS and help overcome pain-related fears. 11

Pharmacological Therapy

Some pharmacological treatments that have been shown to alleviate patients’ symptoms with CRPS are steroids, bisphosphonates, anticonvulsants, and ketamine. Since classic inflammation seems to be an important contributing factor in the acute/warm phase of CRPS, it is logical to consider that corticosteroids may play a beneficial role in treating CRPS. In a randomized placebo-controlled trial of 23 patients with CRPS type 1, 10 mg of oral prednisone three times daily for 12 weeks proved to be more effective than placebo in reducing symptoms.6 In another study composed of a case series of 31 patients with CRPS, 40-60 mg of oral prednisone daily reduced symptoms of pain, swelling, mobility, and motor function.6 These benefits were preferentially seen in the acute phase of CRPS as opposed to the chronic phase.

Bisphosphonates have shown benefit in the treatment of CRPS, though their exact therapeutic mechanism remains unclear. These drugs are believed to regulate inflammatory mediators and inhibit proliferation and migration of bone marrow cells.13 A randomized, double-blinded trial of IV alendronate (7.5 mg daily for three days) showed significant improvement in pain, tenderness, swelling, and motor function compared to placebo.13 Several other studies showed these benefits as well.

Gabapentin and pregabalin are known to reduce pain symptoms in neuropathic pain syndromes. Therefore, Van de Vusse et al conducted a placebo-controlled crossover trial using gabapentin to treat CRPS type 1.14 Gabapentin did not show to relieve pain significantly, but sensory deficits improved in these patients.14

Ketamine is another drug that has shown some benefit in treating CRPS. It has been shown to decrease pain by inhibiting NMDA receptors. 15 In a review of 14 studies, 13 of the studies showed a decrease in pain scores and relief of symptoms in patients receiving infusions of ketamine.15

Are there procedures / interventions that can alleviate the signs and symptoms of CRPS? 

Procedures that have been used for treatment of CRPS are sympathetic blocks, transcranial magnetic stimulation (TMS), spinal cord stimulations (SCS), implantable peripheral nerve stimulation (PNS), dorsal root ganglion stimulators (DRG), and, in extreme cases when nothing else works, amputation.

Given that an important pathogenic factor of CRPS is autonomic dysregulation, it is known that sympathetic blocks can be of benefit for this disease. When present in lower extremities, the target for procedure is a lumbar sympathetic block. When present in upper extremities, the target is a stellate ganglion sympathetic block. If there is a positive response to this procedure, the pain relief may last weeks to months. According to a retrospective study of 255 patients with CRPS who received a sympathetic block, 61% had more than 50% reduction in pain.16

Given that a component of this pathologic process involves the central nervous system as described above, studies have demonstrated TMS to be of benefit for patients with CRPS. TMS is a non-invasive procedure that applies magnetic stimulation to areas of the brain cortex. Gaertner et al provided TMS to 21 patients with CRPS and 60% of the patients responded favorably from just one session at week 1 post intervention. More than 50% of these patients responded favorably at week 2 post intervention if they had five sessions. 17

Because pain from CRPS travels to the brain via the spinal cord, it is understandable that SCS and DRG stimulation can be beneficial for this disease. Level one evidence supports the use of DRG stimulation and SCS in the treatment of CRPS. According to a retrospective study by Gopal et al, 80 patients with CRPS were subjected to SCS. At 1 year follow-up, 40% of the patients were no longer requiring oral analgesics, 37.5% had their pain manageable with just first line analgesics, and 17.5% had manageable pain with just occasional use of tramadol or codeine.18 Furthermore, a prospective. multicenter, comparative trial compared safety and efficacy of DRG neurostimulation compared to traditional SCS at 3 and 12 month follow-up periods in patients with CRPS. The study involved 152 patients diagnosed with CRPS of the lower extremities with a predefined primary endpoint of 50% or greater decrease in visual analog pain scale. Subjects using DRG stimulation had a statistically higher treatment success (81%) compared with traditional SCS (57%) at the three-month follow-up period. At 12 months, the DRG group continued to have greater statistical pain relief (74% vs 53%) compared with SCS with no major differences in the serious adverse events between the two groups.19

PNS is another modality that has shown to improve symptoms in patients with CRPS. A retrospective chart review was performed on 160 patients who had CRPS and received PNS from 1990-2017. The mean pain scores at baseline were 7.4 +/- 1.6, and, after 12 months of PNS, the mean decreased to 5.5 +/- 2.4.20 This showed a decrease difference of almost 2 points (95% CI: 1.29-2.46, p<0.001).20 At baseline, 62% of patients were on chronic opioid therapy; 12 months after PNS treatment, this percentage dropped to 41%.20

What are some future treatment modalities that are being investigated?

Different modality treatments under investigation are the use of naltrexone, botulinum toxin A, plasma exchange therapy, cannabis-based treatments, mycophenolate, and others.3




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