Complex Regional Pain Syndrome

Introduction and Pathogenesis

• CRPS is a neuropathic pain disorder, usually affecting the distal limbs, characterized by pain, swelling, limited range of motion, vasomotor instability, skin changes, and patchy bone demineralization.^1,2 It often begins following a fracture, soft tissue injury, or surgery.
• A consensus definition of CRPS is as follows: “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.”²
• There are two subtypes of CRPS.¹
  • Type I CRPS (previously known as reflex sympathetic dystrophy) occurs in patients without evidence of peripheral nerve injury and represents approximately 90% of cases.
  • Type II CRPS (previously known as causalgia) occurs when peripheral nerve injury is present.
• Clinically, they are indistinguishable and follow a regional rather than dermatomal or peripheral nerve distribution.³
• CRPS is further subdivided into “warm” or “cold,” and “sympathetically maintained or sympathetically independent,” which affect prognosis and treatment options.³
• The exact pathogenesis of CRPS remains unknown.^1,3 Proposed mechanisms include:
  • Inflammatory changes with the release of inflammatory mediators (tumor necrosis factor-alpha, interleukin 1b, 2, and 6) and pain-producing peptides (bradykinin, substance P, calcitonin gene-related peptide) by peripheral nerves
  • Immunologic changes with autoantibodies against beta-2 adrenergic receptors, alpha 1a adrenergic receptors, and muscarinic-2 receptors
  • Peripheral sensitization of the nervous system is triggered by the release of proinflammatory mediators.
  • Central sensitization and maladaptive changes in pain perception at the central nervous system level. Increased excitability of the secondary dorsal horn neurons often occurs.
  • Autonomic changes result from catecholamine hypersensitivity.

Epidemiology and Inciting Factors

• The estimated incidence of CRPS in the United States is 5-26 per 100,000 per year.
• CRPS is much more prevalent in women, with estimates of 2-4 times the rate in men. The incidence is highest in postmenopausal females.¹
• The most common inciting factors for CRPS are fractures, crush injuries, sprains, surgeries, or carpal tunnel syndrome.^1-3
• Other risk factors include fibromyalgia, rheumatoid arthritis, and psychological factors (depression and/or posttraumatic stress disorder).^1,2
• The impact of genetics is unclear.³

Clinical Presentation

The main clinical findings of CRPS are listed below:

Pain

• Pain is the most common and debilitating symptom of CRPS. It is often described as a burning, stinging, or tearing sensation that is felt deep within the extremity in most cases.¹
• The pain is often continuous and undulating but can be paroxysmal.
• It may be worse at night and exacerbated by limb movement, contact, heat/cold, or stress.¹
• The pain is not restricted to a specific nerve territory or dermatome, is disproportionate to the degree of tissue injury, and persists beyond the normal expected time for tissue healing.

Sensory Abnormalities

• Hyperalgesia: increased sensitivity to pain; usual painful stimuli cause exaggerated pain.
• Allodynia: pain is experienced in response to stimuli that are typically not painful (light touch, temperature changes, etc.).
• Hypesthesia: decreased capacity for physical sensation
• These sensory disturbances are usually distal in the extremity, often in a glove/stocking pattern.

Motor Symptoms

• Decreased grip strength or tip-toe standing is present in approximately two-thirds of patients with CRPS.
• Limb movement may be limited by pain, edema, or contractures.
• Central manifestations such as tremors, myoclonus, or dystonic postures may occur.

Autonomic Changes

• The most common are skin color changes (mostly livedo or hyperemia), edema, and increased sweating.
• A temperature difference between the affected and unaffected sides may be seen.
• Other skin changes include increased hair growth, increased or decreased nail growth, and skin atrophy.
• Joint contractures may be seen.

Diagnosis

• The diagnosis of CRPS is primarily based on a thorough history and physical examination.
• The Budapest consensus criteria for the clinical diagnosis of CRPS are as follows.²
  • 1. Continuing pain, which is disproportionate to any inciting event
  • 2. For the clinical diagnosis of CRPS, the patient must report at least one symptom in three of the following four categories:
    • Sensory: Reports of hyperesthesia and/or allodynia
    • Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
    • Sudomotor/edema: Reports of edema and/or sweating changes and/or sweating asymmetry
    • Motor/trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
  • 3. For the clinical diagnosis of CRPS, the patient must display at least one sign at the time of evaluation in two of the four following categories:
    • Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
    • Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry
    • Sudomotor/edema: Evidence of edema and/or sweating changes and/or sweating asymmetry
    • Motor/trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
  • 4. There is no other diagnosis that better explains the signs and symptoms.
• There is no gold-standard test for confirming the diagnosis. Nonetheless, certain testing measures have been proven useful.
  • Triple-bone scans illustrating increased radiotracer uptake in joints distant from the trauma site.¹
  • Side-by-side plain radiographs illustrating patchy osteoporosis.¹
  • Skin temperature measurements show a temperature difference of more than 1°C between the affected and unaffected sides.¹
  • Increased resting sweat output¹
  • Testing obtaining abrupt transient relief from pain and dysesthesia with a systemic chemical sympatholysis (i.e., a “Bier block”).¹ However, the role of the sympathetic nervous system in the pathogenesis of CRPS remains unclear. Thus, a positive test is no longer considered a diagnostic indicator of CRPS.¹ Rather, this response is an important indicator of sympathetically maintained pain.
• Although these tests mentioned above may support the diagnosis of CRPS, they are rarely implemented; the diagnosis of CRPS is largely clinical and one of exclusion.³

Treatment

• A multidisciplinary approach is suggested for the management of CRPS. The goals of therapy include restoring function, reducing pain and disability, and enhancing quality of life while minimizing medication side effects.⁵
• Treatment is most successful when implemented early in the disease course.⁵ Table 1 illustrates the different treatment options for CRPS.