An Overview of Complex Regional Pain Syndrome and its Management

Complex regional pain syndrome (CRPS) is a chronic pain syndrome of unclear etiology. Prior to 1994, CRPS was divided into two conditions: reflex sympathetic dystrophy, which included a history of initiating injury (type 1); and causalgia, which included a history of known nerve injury (type 2).1 CRPS typically affects an extremity, such as the hand or foot, and frequently follows a traumatic event such as a fracture, sprain, surgery, immobilization (tight casts or frozen shoulder), and even stroke.2,3 However, patients may not know what precipitated CRPS—physicians may hear “it just happened,” for instance, after striking one’s hand but without significant injury.

CRPS is a complex medical problem and, for the patient, a significant source of suffering, disability, and poor quality of life for those afflicted—in fact, the pain and disability of CRPS are much worse than the initial injury. Furthermore, there are no clear and uniform current guidelines on the treatment and management of the disease. This article provides an overview of the pathophysiology and management of CRPS with recommendations on when specialized pain management and interventions may be most beneficial.


The pathophysiology of CRPS is unknown but is likely to be multifactorial, with neuropathic, autonomic, vascular, and inflammatory components, as well as both peripheral dysfunction and central sensitization.2-7 Dysfunction of peripheral nociceptive fibers (lightly myelinated A-delta fibers and unmyelinated C fibers) after repetitive noxious stimuli can result in lowered pain thresholds and enhanced activation of dorsal horn cells, leading to the hyperalgesia of CRPS.7,8 Central sensitization via afferent processing by second-order nociceptor-specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord lead to changes in dorsal horn morphology and are thought to be the cause for the allodynia and spread of pain past the initial site of injury seen in some CRPS patients.7,8

The autonomic nervous system dysfunction is thought to be a main source of the vasomotor, temperature, hydrosis, and trophic changes seen in CRPS.7-9 Current theories suggest that the sympathetic and nociceptive systems in CRPS are coupled in an aberrant manner such that the sympathetic efferents activate the sensory afferents, leading to persistent afferent activity.7-11 Neurogenic inflammation may also be involved and contribute to the vasodilation, protein extravasation, and edema seen in CRPS via release of neuropeptides such as calcitonin gene-related peptide, substance P, and proinflammatory cytokines like tumor necrosis factor.7,10,11 However, it is unclear what maintains the inflammatory process throughout the disease.

Higher central nervous system changes in the cortex may be involved; contralateral (to affected side) somato-
sensory cortex reorganization, bilateral motor cortex disinhibition, and thalamic disinhibition have all been demonstrated in patients with CRPS.7,11-13 The neural plasticity in cortical restructuring may be responsible not only for the motor symptoms seen in many CRPS patients, but contribute to the maintenance and progression of the disease.

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CRPS is a clinical diagnosis made with history, presentation, and exam; tests may be useful to support the diagnosis or rule out other differentials. The diagnostic criteria for CRPS as set by the International Association for the Study of Pain includes “the presence of an initial noxious event or cause for immobilization of the affected region, continuing pain disproportionate to the inciting event, and the presence of edema, changes in skin blood flow, or abnormal sudomotor activity in the affected region sometime during the course of the syndrome.”1

The condition often starts in an extremity, though can occur anywhere in the body, and is characterized by a combination of autonomic, sensory, and vasomotor symptoms. The hallmark of CRPS is pain out of proportion to the severity of the initial injury.1,2,4 Pain, temperature asymmetry, edema, impaired movement, change in skin color, hyperesthesia, hyperalgesia, hyperpathy, tremors, involuntary movements, muscle spasms, paresis, pseudoparalysis, skin, muscle and bone atrophy, hyperhidrosis, and changes in hair and nail growth have all been reported in patients with this syndrome (Figure 1).1-4,6 In regards to temperature changes, the initial symptom is usually a warmer sensation in the affected area and heat hyperalgesia; this may progress to cold hyperalgesia and lower skin temperature on the affected side.4,6

The natural history of CRPS has been described in three stages. The first stage is characterized by pain, burning, temperature hyperalgesia, local edema, and restricted mobility. The second stage is generally a worsening of the edema, skin thickening, atrophy, and wasting of the muscles in the affected region. The third stage is when symptoms have worsened to limited range of motion, irreversible skin and nail changes, hair growth changes, and demineralization seen on x-ray.2-6Because these characteristics can intermingle at any given time, and since there is not a reliable progression along these stages, the staging of CRPS has fallen out of favor.

Tests can be supportive in the diagnosis or ruling out of other differentials. One test to consider is nerve conduction studies or electromyograms (EMGs), which test only the large (fast-conducting) myelinated fibers in mixed peripheral nerves, and can reveal peripheral neuropathy.4 They do not test the pain transmitting small A-δ and C fibers implicated in painful, small fiber neuropathies. Nerve conduction studies and EMGs are normal in CRPS type 1, but may be abnormal in CRPS type 2—reflecting the nerve damage that is associated with type 2. Punch skin biopsies are rarely performed but can reveal a cutaneous sensory neuropathy common in small fiber and inheritable neuropathies but there are no findings that are specifically diagnostic for CRPS.4-6 Quantitative sensory testing (QST) may be helpful in assessing small fiber function; however, in the assessment of CRPS it is still primarily a research tool rather than a diagnostic clinical test. Plain radiographs (x-rays) may show demineralization and osteopathic changes in chronic and more severe cases. A bone scan with technetium, or bone density scan, may reveal earlier osteoporotic changes than plain film. Thermography, QST, and sweat tests may be positive for specific symptoms of CRPS (abnormal sensation, hyperhidrosis, or temperature gradients) but are not diagnostic.4-6,14,15

There is current controversy over whether sympathetic blocks may be helpful diagnostically.16 A positive response is unpredictable but indicates sympathetically maintained pain, while an ineffective block suggests that the pain is sympathetically independent but does not rule out the diagnosis of CRPS.

Differential Diagnosis

As CRPS is a clinical diagnosis of exclusion, it is important to rule out neurologic, rheumatologic, infectious, metabolic, and vascular diagnoses that can present with similar symptoms. Examples include peripheral neuropathies, focal neuropathies, unilateral arterial or venous occlusions, thoracic outlet syndrome, infection, thrombophlebitis, lymphedema, gout, multiple sclerosis, stroke, neoplasm, autoimmune disorders, porphyria, and toxin exposure.2-4,6

Patient Population
The mean age of patients who present with CRPS ranges from 36 to 42 years, with 60% to 80% of patients being female.3,4,6,17,18 Psychiatric comorbidities such as anxiety and depression are common in CRPS sufferers, though it is unclear whether these patients had premorbid anxiety and depression greater than the general population.3,4,17,18 The majority of CRPS occurs after a fracture, but can also occur after soft tissue trauma and without identifiable triggering trauma.2,3,17,18The efficacy of preventative techniques is uncertain. Nevertheless, for surgery, adequate perioperative analgesia, limitation of operating time, limited tourniquet use, and regional anesthesia techniques are recommended for secondary prevention of CRPS.


Once the diagnosis is made, the primary goal is to treat early and facilitate functional restoration.19-21 The three principles of treating CRPS are motivation, desensitization, and mobilization—all of which are facilitated by pain relief (pharmacologic and/or interventional procedures).19-21 These principles are carried out through a combination of physical therapy, pain management, and psychological treatment and should be carried out simultaneously and in a timely manner.

In a patient with early CRPS, physical therapy (PT) and occupational therapy (OT) are critical components of treatment. A positive therapeutic alliance between the patient and therapist is an important tool in improving the motivational and psychological state of the patient, while a poor alliance can actually adversely impact the patient’s motivation and progress.2 Therapies include transcutaneous electrical nerve stimulation, stress loading, tactile desensitization, massage, graded motor imagery, and mirror therapy.20,21

Graded motor imagery involves using techniques of visualization to theoretically restore cortical representation of the affected area in CRPS. It consists of phased limb laterality recognition, imagined movement, and mirror movement phases over a 6-week period. Although the mechanisms behind this therapy are unknown, normalization of cortical reorganization and sustained attention to the affected area are proposed theories.22-24

Desensitization techniques are repetitive and graded stimulations of the affected area with very soft materials, which are built up to more textured, harsher fabrics, with the goal of reducing hyperalgesia and allodynia. Desensitization to cold and heat hyperalgesia is done using contrast baths, which gradually increase the temperature gradient that the patient can tolerate.20,21,24

Stress loading is defined as compression of the affected joints by scrubbing and loading techniques, both of which are designed to increase use of the affected area and prevent muscle atrophy. Though it may initially cause more pain for the patient, a decrease in symptoms will prevail after several days. Stress loading should be encouraged as much as possible and tailored to each patient’s individual capabilities.20,21,24

The time frame required for PT and OT is variable and may be as intensive as 3 to 5 times per week initially. Interventions such as sympathetic nerve blocks and conjunctive pharmacologic management may be beneficial to allow patients to actively participate in PT and OT.

Psychological Therapy

Most patients may not need or want psychological treatment during the early stages of CRPS due to confusion and possible stigmatizing feelings surrounding the diagnosis.3,4 However, patients experiencing significant CRPS symptoms for more than 8 weeks are encouraged to have a psychological assessment focusing on identifying stressors and any existing comorbid Axis I disorders.3,4Psychological treatment for CRPS should also address the three principles as mentioned previously: motivation, functional rehabilitation, and desensitization. Techniques developing pain coping skills, training on relaxation skills or biofeedback, cognitive behavioral therapy, and improving quality of life are all taught and developed during sessions. In addition, therapies aimed at treatment of any comorbid depression and anxiety should be pursued.

Pharmacologic Treatment

Pharmacologic management should begin with a neuropathic agent such as tricyclic antidepressants (TCAs) (ie, amitriptyline or nortriptyline) or antiepileptics such as gabapentin or pregabalin (Lyrica) (Table). The analgesic effects of TCAs are well studied in neuropathic pain and likely related to enhancement of noradrenergic and serotonergic descending inhibitory pathways. The analgesic effect is independent of their antidepressant effects.25,26 The side effects of TCAs are their main limitation and must be considered for each patient. Antiepileptics are widely prescribed for a variety of neuropathic pain states, and are thought to produce analgesic effects via modulating voltage-dependent calcium ion channels at the postsynaptic dorsal horns.25

N-methyl-D-aspartate (NMDA) receptor antagonists such as magnesium, dextromethorphan, methadone, and ketamine are an increasingly popular class of medication as various lines of evidence suggest that glutamate and the NMDA receptor may play a role in central sensitization. Topical, oral, and intravenous ketamine has been given in anesthetic and sub-anesthetic doses, with promising but mixed effects.26-29 Further study is still necessary to confirm the efficacy of these NMDA receptor antagonists.

On the basis that inflammation plays a role in the development of CRPS and is associated with the production of oxygen free radicals, free radical scavengers (dimethyl sulfoxide 50% and N-acetylcysteine) have been tried with some success.30

Bisphosphonates have been shown to improve analgesia in early CRPS and are not specifically aimed at reducing bone resorption, as other peripheral and central mechanisms may be responsible for their analgesic effects. Oral and intravenous forms have been used; side effects such as gastrointestinal upset, esophageal erosion, and jaw necrosis should be discussed with the patient.31-33

Alpha-adrenergic antagonists (eg, phentolamine, phenoxybenzamine, clonidine, and reserpine) have been used for CRPS on the basis of sympathetic blockade providing pain relief. However, clinical response is mixed and more studies are needed to assess their efficacy.25

Topical local anesthetics are popular agents used in CRPS due to minimal side effects and ease of use. There are currently no controlled studies on their use in CRPS though they are indicated for neuropathic pain states such as postherpetic neuralgia.25

There are also times that low-dose opioid therapy is very helpful, but opioids are given cautiously due to concerns of inducing hyperalgesia. If the patient is not rapidly responding to the initial treatments, CRPS is a diagnosis that warrants early referral to a pain specialist.

Interventional Treatments

Sympathetic Block
Sympathetic block and sympathectomy is injection of local anesthetic at the stellate ganglion for the upper limb or at the lumbar sympathetic ganglion for the lower limb. Sympathetic blocks were once considered the diagnostic and therapeutic standard for CRPS, but its efficacy is not supported with well-controlled studies.34-37However, sympathetic blocks may allow short-term clinical improvement in some patients. Currently, the role of sympathetic blocks are as part of a balanced pain treatment strategy aimed at getting patients under cover of good analgesia and improved function in order to participate maximally in PT and OT. If a diagnostic sympathetic block is successful, a series of blocks may be administered.

Intravenous Regional Anesthetic Blockade
Intravenous administration of anesthetics delivers medication directly into the affected extremity of CRPS such as in a Bier block and various agents are used along with a local anesthetic, such as guanethidine, bretylium, clonidine, phentolamine, magnesium, ketamine, toradol, or reserpine. Combination therapy may be more effective than single-agent therapy, but the evidence is insufficient at present.34,35

Somatic Nerve Blocks and Epidural Infusions
Nerve blocks with local anesthetics as a single dose or continuous infusion are commonly used with anecdotal success.34 The block may be a brachial plexus block or continuous epidural infusion. The main limitation to continuous infusions is the high infection rate of indwelling lines.

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Implantable Stimulators

The implantation of peripheral nerve stimulators (PNS) and spinal cord stimulators (SCS) in patients with refractory CRPS has become more common. PNS may be indicated when symptoms are confined to one peripheral nerve distribution.

SCS may be considered in patients with symptoms that involve one or more nerve distributions. If trial stimulation with temporary electrodes results in a 50% or greater pain reduction and increased function over several days, then permanent placement is indicated.38-43 Analyses have shown generally positive effects, but robust evidence is lacking and complication rates of infection, electrode displacement, and equipment failure are high (34%-64%).38-43

In a systematic review of SCS, 13 electronic databases [including MEDLINE (1950-2007), EMBASE (1980-2007), and the Cochrane Library (1991-2007)] were searched. The review suggested that SCS was effective in reducing the chronic neuropathic pain of failed back surgery syndrome and CRPS type 1.40 SCS is usually reserved for those who have failed to obtain relief with PT, OT, psychological and pharmacological therapies, and less invasive interventional therapies—usually 3 to 6 months after appropriate therapy.

Other Treatments
Botulinum toxin inhibits non-cholinergic neurotransmitter release from sensory nerve terminals (in addition to its effects on blocking acetylcholine exocytosis). It has improved neuropathic pain symptoms in a small subset of CRPS patients when used in conjunction with sympathetic blockade.44,45

Acupuncture is being widely used in various neurologic as well as psychiatric conditions and several case reports describe an analgesic effect of acupuncture in CRPS. However, more research is needed in the area of acupuncture and complementary medicine in the management of CRPS.

Hyperbaric therapy was shown in a double blind, placebo-controlled, randomized control trial to increase mobility and decrease pain and edema compared to placebo in CRPS patients.46


CRPS is a challenging condition, both to diagnose and treat. It takes a high index of suspicion, a working knowledge of available treatment options, and a willingness to use a multi-modal team approach to effectively care for patients suffering from this condition. By combining medication management with interventional and non-interventional therapies, patients can often dramatically reduce their symptoms and lead full and functional lives.

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