US Pharm. 2007;32(4):HS29-HS39.

Complex regional pain syndrome (CRPS) is one of the most perplexing and debilitating disorders facing health care professionals involved with pain management. The exact incidence is unknown, and the lack of precise diagnostic criteria has hampered efforts to improve research involving therapeutic interventions.

The disorder was originally reported in the medical literature after the Civil War and was described as a syndrome of pain, autonomic disturbances, involuntary movements, and changes in the skin or hair in an extremity with a nerve injury. This constellation of symptoms was originally named causalgia. Early descriptions of the pathophysiology of the disorder in the 1940s emphasized the involvement of an overactive sympathetic nervous system–leading to the diagnosis of reflex sympathetic dystrophy. Other names used for this disorder include algodystrophy, shoulder–hand syndrome, posttraumatic dystrophy, and Sudeck's atrophy.1

The identification of the syndrome remains problematic. Current consensus guidelines have established diagnostic criteria (Table 1). Pain and hyperesthesia, an increased sensitivity or awareness of pain, are present in almost all patients with CRPS. Pain is usually described by these patients as neuropathic in nature and having the characteristics of burning, pricking, or shooting. Most patients describe the location of the pain as deep within the affected limb. 2,3 Up to one half of patients will experience deficits in temperature and tactile perception on examination.2

Autonomic symptoms may include swelling or edema, skin color changes, abnormal sweating, or alterations in skin temperature. More than half of patients experience edema in the affected limb, and the skin temperature difference between limbs is often greater than 1°C. Early in the course of the syndrome, patients are likely to report edema and a warm extremity. As the disease progresses, edema usually regresses and the patient will often report a cooler extremity. Skin may appear to be paler, or even discolored to a blue or purple undertone.2

Motor symptoms vary widely among patients. In one study, more than 75% of the patients reported weakness in the affected limb, and 50% reported tremor.3 Patients are also found to have decreased range of motion and may eventually experience contractures after disuse of the affected limb.2 In severe cases, patients may even lose perception of limb positioning to the point of ignoring the impacted limb. This particular symptom is known as limb neglect.4 Patients often notice decreased hair and nail growth as well as thinning of the skin with time.2

Incidence and Risk Factors

Very little is known about the incidence of the disorder. In fact, up to 10% of patients will not be able to identify an event or injury that precipitated their symptoms.5 Although the disorder has been reported in children, the usual age of onset is between 36 and 46 years. The majority of cases occur in women. The most common inciting events include surgery, fracture, casting or immobilization, sprain, crush injury, and stroke with motor involvement.2

The majority of patients with CRPS are not able to continue with regular employment, and many of them require significant assistance with normal household responsibilities such as cooking, cleaning, and laundry.6


In most cases, an inciting event such as trauma or immobilization leads to the release of proinflammatory neurotransmitters such as substance P and prostaglandins. This normal response to pain transmits the stimuli to the spinal cord to initiate a pain response. As with many injuries, these mediators start the initial warmth and swelling or edema at the site.3 Up until this point, the pain response is characterized as a normal physiologic one.

The mystery of this disorder centers on the perpetuation of this response into a vicious cycle of pain and disuse of the affected limb. Two theories are proposed in the medical literature for CRPS. The first is that the mechanism causing the release of the inflammatory mediators does not terminate appropriately. The second theory proposes that the clearance of the inflammation mediators is altered and that they exist in the periphery for prolonged periods. In either case, an excess of these substances sensitizes the nervous system, both peripherally and centrally, to the perception of pain. This perpetual painful stimulation is thought to increase sympathetic tone in the area in response to increased levels of epinephrine and other constricting catecholamines. Eventually, this increase in sympathetic drive leads to vasoconstriction, cooling of the extremity, and possibly atrophy.3 Patients naturally avoid painful stimuli through decreased use and guarding of the limb. Disuse further decreases the clearance of catecholamines and impairs venous drainage of edema in the area.7 In one study, depression and emotional impairment related to pain associated with increased levels of catecholamines.8 X-rays of limbs impacted by CRPS often show osteoporotic changes in the bone even as quickly as four to eight weeks after symptoms appear.9

Psychiatric Comorbidity
A long-running controversy surrounding CRPS and its treatment involves its association with psychiatric illness. Patients with CRPS commonly experience depression, anxiety, and phobias with a prevalence that ranges from 18% to 64%. The incidence of individual psychiatric disorders within this patient population, however, does not differ significantly from the chronic pain patient population.10 The severity of depression in CRPS has been linked to the severity of associated pain, which may indicate a physiologic or neurochemical link between the two conditions.8 In an evaluation of a CRPS population, Lynch and colleagues found no evidence that previous psychiatric illness predisposed to the development of CRPS.11

Nonpharmacologic Therapy
Therapy including physiotherapy, psychological counseling, behavioral therapy, and potentially neurostimulation are key to success in the management of CRPS (Table 2 ). Lack of multidisciplinary care often results in poor outcomes; however, finding clinicians with knowledge and experience specific to this disorder can be difficult. Obtaining insurance company reimbursement for these interventions can also be problematic.8

Physiotherapy is usually directed at gradual restoration of normal sensory function. This process is accomplished through occupational and physical therapy. Examples of successful therapy include progressing from gentle movement of the affected limb to weight bearing and then on to normal activities. Another example for sensory therapy may involve initial therapy with textures such as silk and increasing to rougher textures, and incorporating temperature changes into therapy.12 In one study retrospectively examining 145 cases, those who received physical therapy reported significantly less pain and a better functional status.13 Successful therapy is most likely to occur with effective pain management through pharmacologic intervention; see discussion below. Trigger point injections of anesthetics or pain medications may facilitate therapy with range of motion exercises. The goal of this rehabilitation should be normalization of activity or an ergonomically adapted environment to improve functionality.2

Behavioral therapy is less familiar to many clinicians, but it is a key part of therapy for these patients. One example is trained relaxation of muscle groups. This training begins with unaffected muscle groups and gradually proceeds to the affected limbs. In controlled evaluations, this practice has demonstrated the benefit of reducing the spread of symptoms. Another behavioral technique emphasizes the importance of patient involvement in the treatment process. This procedure, known as "reframing of symptoms as a call to action," prevents passivity on the part of the patient. Being actively engaged and involved in treatment is associated with more positive outcomes.8 Current consensus guidelines for CRPS recommend that patient's with symptom duration greater than two months should have a psychological evaluation.2 The combination of psychological and behavioral therapy may help to break the interaction between physical pain and stress behaviors, prevent disuse of the extremity, and encourage positive coping skills as a response to pain.8 The medical literature, including a meta-analysis, supports this approach for chronic pain patients but has not been evaluated in CRPS.14

Neurostimulation is a more invasive technique reserved for more severe cases. Both peripheral and spinal cord stimulation have been studied for these patients. These interventions are generally monitored by an interventional pain specialist and considered after failure of less invasive modalities.2

Pharmacologic Therapy
As with nonpharmacologic interventions, pharmacologic therapy for CRPS often requires implementing multiple types of therapy simultaneously. This therapy may include interventional procedures such as nerve blocks and regional injections of anesthetics, steroid therapy, therapy for osteoporosis, traditional neuropathic pain medications, and opiates. At the time of writing, no pharmacologic therapies were approved by the FDA for treatment of CRPS specifically. Experimental therapies for treating the disorder, however, are under evaluation.

Nerve blocks are utilized for CRPS patients for temporary pain relief and to facilitate compliance with physical and occupational therapy. These nerve blocks are typically administered in the medical office setting or as an outpatient surgery procedure by a trained interventional pain specialist. Although no controlled medical evidence exists to support their use in specific situations, they are one of the most commonly employed interventions for these patients. Trials evaluating the use of blocks often do so in isolation from other therapies. For example, in 2004 a study conducted by Taskaynatan et al. found no benefit to blocks containing lidocaine and steroids when compared to placebo. However, this study examined blocks as an isolated treatment and not in conjunction with other modalities, such as physical therapy.15 Different types of blocks are administered depending on the patient's symptoms and the area affected by CRPS. Sympathetic blocks, intravenous regional blocks, and somatic nerve blocks are all utilized for symptom management.2 These injections often include an anesthetic as well as steroids and, in some cases, agents to block sympathetic outflow.

Systemic therapy with steroids early in the course of CRPS has shown benefit in randomized trials. In one study evaluating 30 mg of prednisolone for 12 weeks in comparison to placebo, patients treated with the steroids experienced less pain over the study duration.16 A study comparing prednisolone 40 mg to an active control group, piroxicam 20 mg, in CRPS related to stroke demonstrated positive outcomes for both pain and quality of life (QOL) for the steroid-treated patients. The group receiving piroxicam did not show any significant change in either pain or QOL over the study period.17 Based on the available information, steroids should be considered early in management of CRPS to improve long-term outcomes.

As discussed earlier, CRPS is associated with osteoporosis in the affected limb. The bisphosphonate pamidronate has been evaluated in placebo-controlled trials in this population. Although long-term studies have not been conducted, short-term evaluations indicate improvements in pain scores and overall disease severity. Small but statistically significant improvements have been documented for this intervention to improve physical functionality in patients.18 Therapy with calcitonin has also been evaluated in short-term, nonblinded trials. Calcitonin combined with physical therapy was no better than physical therapy alone in a two-month evaluation of pain scales, trophic changes, and range of motion.19

The most common pharmacologic therapies utilized for these patients are medications for neuropathic pain. As with other interventions for CRPS, very little randomized or controlled data exist to support their use. Many large neuropathic pain trials excluded patients with CRPS. Most evidence to support their use is anecdotal.20 In a placebo-controlled trial evaluating gabapentin, pain scores improved initially but returned to baseline. Sensory deficits, measured by monofilament exams, improved in the gabapentin-treated groups. Patients in these groups were significantly more likely to report dizziness and somnolence associated with therapy.21 

Trials involving patients with CRPS are difficult to conduct. Enrollment is complicated by controversy regarding the diagnostic criteria as well as the heterogeneous nature of the symptoms. Evaluation of these trials is difficult because most do not value an integrated or multidisciplinary care team. For a therapy to be considered effective, it is generally accepted that pain scores should improve at least 50%,22 a degree of improvement rarely documented in interventions evaluating one type of therapy.

Two interventions have shown promise. The first was demonstrated in stroke patients, in whom occupational and physical therapy initiated in the first two to three days after stroke reduced the risk of developing CRPS. Administration of 500 mg of vitamin C for 50 days after wrist fracture and immobilization reduced the incidence of CRPS from 22% to 7% in a placebo-controlled evaluation.23

Complex regional pain syndrome is a debilitating disorder involving a sustained pain response after nerve injury. Successful therapy for the disorder should include pharmacologic as well as nonpharmacologic interventions aimed at returning the patient to a functional status.


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