UpToDateOfficial reprint from UpToDate® www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Wolters Kluwer Health Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis Author:Salahadin Abdi, MD, PhDSection Editor:Jeremy M Shefner, MD, PhDDeputy Editor:April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2018. | This topic last updated: Jun 06, 2018. INTRODUCTION — Complex regional pain syndrome (CRPS) is a disorder of a body region, usually of the distal limbs, which is characterized by pain, swelling, limited range of motion, vasomotor instability, skin changes, and patchy bone demineralization. It frequently begins following a fracture, soft tissue injury, or surgery. The etiology, pathophysiology, clinical manifestations, and diagnosis of CRPS in adults are reviewed here. Other aspects of CRPS in adults and children are presented separately. (See "Complex regional pain syndrome in adults: Prevention and management" and "Complex regional pain syndrome in children" and "Evaluation of chronic pain in adults".) DEFINITION AND TERMINOLOGY — The consensus definition of CRPS is as follows [1]: "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." There are many older alternative names for CRPS in the literature, including reflex sympathetic dystrophy, algodystrophy, causalgia, Sudeck atrophy, transient osteoporosis, and acute atrophy of bone. Upper extremity involvement following stroke or myocardial infarction was sometimes referred to as the "shoulder-hand syndrome." In the modern era, these disorders are grouped under the single heading of CRPS [2]. Two subtypes of CRPS have been recognized [1,2]: ●Type I (the form also known as reflex sympathetic dystrophy) corresponds to patients with CRPS without evidence of peripheral nerve injury and represents approximately 90 percent of clinical presentations. ●Type II was formerly termed "causalgia" and refers to cases in which peripheral nerve injury is present. However, the pathophysiologic basis for and clinical utility of the distinction between these two subtypes of CRPS is uncertain [1,3-5]. Some investigators also recognize "warm" and "cold" subtypes of CRPS [6]: ●"Warm" CRPS is distinguished by increased skin temperature at the onset of symptoms, further suggesting this as an inflammatory type ●"Cold" CRPS is differentiated by decreased skin temperature at the onset of symptoms The term "sympathetically maintained pain" is considered to be a variable phenomenon associated with a variety of disorders, including CRPS types I and II. PATHOGENESIS — The pathogenesis of CRPS is unknown. Proposed mechanisms include classic inflammation, neurogenic inflammation, and maladaptive changes in pain perception at the level of the central nervous system [7]. A number of studies suggest that patients with CRPS have significant increases in proinflammatory cytokines (eg, IL-1beta, IL-2, IL-6, and TNF-alpha) in affected tissue as well as in plasma and cerebrospinal fluid [8-11]. Among the mechanisms proposed for the persistent pain and allodynia that are a hallmark of CRPS is the release of inflammatory mediators and pain-producing peptides by peripheral nerves [7,12,13]. Neuropeptides that produce pain and signs of inflammation when experimentally administered include substance P, neuropeptide Y, and calcitonin gene-related peptide. In a process known as neurogenic inflammation, nerve impulses that propagate in an antidromic fashion (that is, from proximal to distal in a sensory, particularly nociceptive, nerve axon) could lead to the release of neuropeptides. There may also be cross-talk between afferent and efferent nerves at a site of nerve injury. This model also offers a possible explanation for the phenomenon of allodynia, in which a normally painless stimulus to the affected limb, such as light touch, produces significant pain. Another possible explanation for pain and allodynia in CRPS involves central sensitization, whereby increased activity in nociceptive afferents due to peripheral noxious stimuli, tissue damage, or nerve injury leads to increased synaptic transmission at somatosensory neurons in the dorsal horn of the spinal cord [7]. The role of the sympathetic nervous system in CRPS is unclear; however, autonomic manifestations previously ascribed to sympathetic overactivity could be due to catecholamine hypersensitivity [14] and may involve the formation of a reflex arc after an inciting event [4]. The arc follows the routes of the sympathetic nervous system and is modulated by cortical centers to produce peripheral vascular disturbances. The pain sensation in response to injury may lead to increased sensitivity of injured axons to epinephrine and other substances released by local sympathetic nerves. The enhanced sensitivity can be blocked by the intravenous administration of sympatholytic agents. The possible role of the central nervous system in the etiology of CRPS is based on studies suggesting cortical reorganization in sensory and motor regions of the brain [15-18], which could result from persistent activity of primary nociceptive neurons [7]. Although data are limited, genetic factors also may be involved in the pathogenesis of CRPS. One case-control study reported a significantly increased frequency of HLA-DQ1 among patients affected by CRPS type I [19]. The results of another study suggested that the phenotype of CRPS that progressed to develop multifocal or generalized dystonia was associated with HLA-DR3 [20]. EPIDEMIOLOGY — Population-based studies estimate an incidence between 5 and 26 per 100,000 per year [21-23]. CRPS is more common in women, with a female-to-male ratio of 2:1 to 4:1 [21-25]. The incidence appears to be highest in postmenopausal women [22]. Inciting events — The most common inciting events leading to CRPS are fractures, crush injuries, sprains, and surgery. However, no precipitating factors are identified in up to 10 percent of patients [21-23]. In a large retrospective cohort of 1043 patients with CRPS at a single-center referral clinic, the most common inciting events were fractures (44 percent), blunt traumatic injuries including sprains (21 percent), surgery (12 percent), and carpal tunnel syndrome (7 percent) [23]. The distribution of inciting events varied by subtype, particularly for carpal tunnel syndrome, which was significantly more common in type II cases compared with type I (36 versus 3 percent). Several earlier reports suggested that psychosocial issues and personality traits acted as predisposing factors for CRPS [26-29]. However, this notion remains controversial because subsequent studies have not confirmed such an association [30-32]. CLINICAL MANIFESTATIONS — The main clinical symptoms of CRPS are pain, sensory changes, motor impairments, autonomic symptoms, and trophic changes in the affected limb [33]. The onset of CRPS generally occurs within four to six weeks of the inciting event (see 'Inciting events' above) [33,34]. The initial symptoms usually include pain, erythema, and swelling of the affected limb [12]. In most cases, the limb is warm initially, though some are cold at presentation or evolve from warm to cold. CRPS in adults more commonly occurs in the upper limbs [21,23]. Involvement of both upper and lower limbs in the same patient is unusual [35]. However, the symptoms of CRPS may spread over time to involve adjacent areas of the affected limb or, occasionally, other ipsilateral or contralateral limbs [36,37]. Pain — Pain is typically the most prominent and debilitating symptom of CRPS. The pain of CRPS is described as a burning, stinging, or tearing sensation that is felt deep inside the limb in most cases, though it may be superficial in some [28]. The pain is most often continuous and undulating but can be paroxysmal. Pain may be worse at night and exacerbated by limb movement, contact, temperature variation, or stress [23,33]. Sensory — Various types of sensory abnormalities are common in CRPS. Some patients have evidence of hyperalgesia, allodynia, or hypesthesia on examination [28]. Sensory disturbances are usually distal in the limb, sometimes in a stocking/glove pattern. Motor — Approximately two-thirds of patients with CRPS have functional motor impairments related to pain [23,28,33]. Impairment is typically manifest by a reduction of complex muscle strength in handgrip or during tiptoe-standing. Limb movement may be limited by edema, pain, or contractures. Some patients develop central motor manifestations such as tremor, myoclonus, dystonic postures, or impaired initiation of movement. Autonomic — Differences in skin temperature, skin color, sweat, or edema (comparing the affected with the unaffected side) are common symptoms of CRPS [33]. Of note, edema may be a result of inflammation and/or autonomic dysfunction. In one large cohort of patients, the most common autonomic signs were skin color change (74 percent, mostly livido or hyperemia), edema (70 percent), and increased sweating (40 percent) [23]. The mean temperature difference between affected and unaffected sides was 0.08 degrees Celsius; half of patients had an absolute difference in skin temperature of ≥1 degree Celsius. Trophic — Trophic changes affecting the connective tissue in CRPS may include increased hair growth, increased or decreased nail growth, contraction and fibrosis of joints and fascia, and skin atrophy [33]. Stages — Though some early reports described three sequential clinical stages of CRPS [38-43], this concept has been largely abandoned by most experts for lack of evidence to support the existence of discrete stages [3,44]. Nevertheless, staging is still considered useful by a declining proportion of clinicians. The purported stages are as follows: ●Stage 1 – Either after an event or without apparent cause, the patient develops pain in a limb. The essential features include burning, throbbing pain; diffuse, uncomfortable aching; sensitivity to touch or cold; and localized edema [45]. The distribution of the pain is not compatible with a single peripheral nerve, trunk, or root lesion. Vasomotor disturbances occur with variable intensity, producing altered color and temperature. The radiograph is usually normal but may show patchy demineralization. ●Stage 2 – The second stage is marked by progression of the soft tissue edema, thickening of the skin and articular soft tissues, muscle wasting, and the development of brawny skin. This may last for three to six months. ●Stage 3 – The third stage is most severe and is characterized by limitation of movement, the shoulder-hand syndrome (capsular retraction producing a frozen shoulder), contractures of the digits, waxy trophic skin changes, and brittle, ridged nails. Bone radiography reveals severe demineralization. EVALUATION AND DIAGNOSIS — The diagnosis of CRPS is based upon the clinical features as determined by the history and physical examination. The diagnosis is suspected in the following circumstances [33]: ●Symptoms (eg, pain, sensory changes, motor symptoms, autonomic dysfunction, or trophic changes) develop after limb trauma, usually within four to six weeks. ●Symptoms are no longer fully explained by the initial trauma. ●Symptoms affect the distal limb, go beyond the region involved in the trauma, or extend beyond the territory innervated by a single nerve or nerve root. The diagnosis can be made if patients with these symptoms fulfill the clinical diagnostic criteria for CRPS discussed in the next section below. (See 'Diagnostic criteria' below.) There is no "gold-standard" test or method for confirming the diagnosis. However, some investigators assert that certain investigations are useful for the diagnosis of CRPS, particularly three-phase bone scintigraphy showing increased radiotracer uptake in joints distant from the trauma site. Other tests with some possible utility include side-by-side radiographs (eg, both hands imaged on the same radiograph) showing spotty bone decalcification, and long-term or repetitive skin temperature measurements showing >1°C difference for the affected versus unaffected side [33]. Diagnostic criteria — The Budapest consensus criteria for the clinical diagnosis of CRPS are as follows [1,3]: ●Continuing pain, which is disproportionate to any inciting event ●For the clinical diagnosis of CRPS, the patient must report at least one symptom in three of the following four categories (the more stringent research criteria require at least one symptom in all 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) ●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 (the more stringent research criteria require at least one sign in three of the four 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) ●There is no other diagnosis that better explains the signs and symptoms The Budapest criteria do not explicitly incorporate certain key features of CRPS, including involvement of the limbs but not the head or trunk, the predominant occurrence of symptoms and signs in the distal part of the limb, and the presence of symptoms and signs that do not correspond to the territory of a nerve or nerve root [33]. However, these concepts are encapsulated in the definition of CRPS provided by the Budapest consensus group conference [1] as noted above. (See 'Definition and terminology' above.) The Budapest criteria appear to be equally sensitive and more specific compared with earlier CRPS consensus criteria [2,46] for differentiating patients with CRPS from patients with other types of neuropathic pain [47]. In a cohort of over 700 patients with a clinical diagnosis of either CRPS (n = 609) or other chronic pain disorders (n = 104) in which various diagnostic criteria were applied, the Budapest criteria had the best combination of sensitivity and specificity (82 and 68 percent, respectively) [23]. A proposed weighted CRPS prediction score was developed from the cohort, which, if validated, may be useful as a screening tool. Bone scintigraphy — Bone scintigraphy (ie, bone scan) is a sensitive technique for the detection of any of a large variety of bone, joint, and periarticular disorders, including fracture, infection, tumor, arthritis, and metabolic bone disease. Triple-phase bone scintigraphy is useful for detecting alterations in bone metabolism in patients with CRPS who have active bone resorption. Although CRPS is a clinical diagnosis that does not depend upon the results of imaging studies, bone scintigraphy performed within the first five months after onset of symptoms can support the diagnosis if there is increased (ipsilateral >1.32 compared with contralateral) radiotracer uptake by a quantitative region-of-interest evaluation during the mineralization (ie, third) phase in joints distant from the trauma site [33,48]. Of note, a negative bone scan does not rule out the diagnosis of CRPS [33]. Plain film radiography — Plain radiographs often demonstrate patchy osteoporosis, but the sensitivity of this finding for CRPS is very low [33]. Some experts suggest that imaging both hands on the same radiograph can be supportive of the diagnosis of CRPS if there is patchy bone osteoporosis involving the affected hand [33]. Autonomic testing — Autonomic tests that have been used to evaluate patients with suspected CRPS include the resting sweat output (RSO), the resting skin temperature (RST), and the quantitative sudomotor axon reflex test (QSART). Some experts advocate serial measurement of skin temperatures [33], based upon evidence from one small study that a 2°C difference for the affected versus unaffected side was supportive of the diagnosis of CRPS [49]. However, this method requires monitoring for five to eight hours with recording of skin temperature at one-minute intervals using temperature sensors applied to the index fingers. Thus, it is not practical as a routine clinical test [50]. Other tests and interventions — There is no clear role for magnetic resonance imaging (MRI) or computed tomography (CT) scanning in the evaluation of suspected CRPS, nor is there any role for the response to sympatholysis to confirm the diagnosis of CRPS. MRI may be useful for excluding some conditions in the differential diagnosis (see 'Differential diagnosis' below) but is not useful for confirming the diagnosis of CRPS [33]. Limited data suggest that CT scanning can show focal areas of osteoporosis in a Swiss cheese-like appearance [51]. However, weighing the cost, radiation dose, and limited experience with use of CT scanning in evaluation of patients with CRPS, we suggest not using CT as a diagnostic test. Historically, abrupt transient relief from pain and dysesthesia with a systemic chemical sympatholysis (ie, intravenous regional anesthesia, also termed a "Bier block," and/or a regional sympathetic nerve block such as stellate ganglion or lumbar sympathetic nerve blocks) was considered necessary to make the diagnosis of CRPS. However, as the role of the sympathetic nervous system in the pathogenesis of CRPS remains unclear and contradictory, it is now widely accepted that a positive response to sympathetic block is not diagnostic of CRPS. Rather, such a response is an important indicator of sympathetically maintained pain. DIFFERENTIAL DIAGNOSIS — Conditions that can have some of the clinical features of CRPS include the following [52]: ●Infection of skin, muscle, joint, or bone, which is characterized by redness (erythema), swelling (edema), warmth, and pain. Laboratory tests that are indicators of an infection, such as increases in the erythrocyte sedimentation rate (ESR) or in the C-reactive protein (CRP) and elevations in the peripheral blood white blood cell count, are unremarkable in CRPS. (See "Synovial fluid analysis" and "Infectious tenosynovitis" and "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Cellulitis and skin abscess: Clinical manifestations and diagnosis".) ●Compartment syndrome, caused by increased pressure within a compartment bounded by unyielding fascial membranes. Acute compartment syndrome is a surgical emergency that usually develops soon after significant trauma, particularly involving long bone fractures of the lower leg or forearm. Acute compartment syndrome may also occur following minor trauma or from nontraumatic causes such as ischemia-reperfusion injury, coagulopathy, certain animal envenomations and bites, extravasation of intravenous fluids, injection of recreational drugs, and prolonged limb compression. Early symptoms include progressive pain out of proportion to the injury; signs include tense swollen compartments and pain with passive stretching of muscles within the affected compartment. (See "Acute compartment syndrome of the extremities".) ●Peripheral vascular disease, which leads to hypoperfusion of the feet and legs, resulting in cold feet with discoloration, leg cramps, or pain that is worse with activity and better with rest (ie, vascular claudication). (See "Clinical features and diagnosis of lower extremity peripheral artery disease".) ●Deep vein thrombosis, which can lead to swelling, redness, and pain of the extremity involved. However, this problem generally can be distinguished from CRPS by history and physical examination together with Doppler ultrasound vascular testing. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".) ●Peripheral neuropathy (eg, diabetic neuropathy), which occasionally can present with hypersensitivity and dystrophic changes of the extremities. (See "Overview of polyneuropathy" and "Clinical manifestations and diagnosis of diabetic polyneuropathy".) ●Vascular thoracic outlet syndrome, which may present with swelling (often a sensation of swelling without visible change), paresthesia, and erythema. (See "Overview of thoracic outlet syndromes".) ●Rheumatoid arthritis, a chronic inflammatory autoimmune disease that affects the synovium of the joints, can have signs and symptoms similar to those in CRPS. However, the symptoms of rheumatoid arthritis are present in various joints (eg, wrists, knees, shoulders, hands, and feet), as opposed to just a region of the body. Furthermore, laboratory blood work is helpful in diagnosing rheumatoid arthritis. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".) ●Raynaud phenomenon, an exaggerated vasoconstrictive response to cold temperature and emotional stress. The phenomenon is manifested clinically by sharply demarcated color changes of the skin of the digits. The diagnosis of Raynaud phenomenon is made if the fingers are unusually sensitive to cold and change color (to white, blue, or both) when exposed to cold temperatures. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses is thought to underlie the disorder. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon".) ●Erythromelalgia, an acquired or (rarely) inherited clinical syndrome characterized by the intermittent occurrence of red, hot, painful extremities. The syndrome usually affects the legs (predominantly the feet) but may also involve arms (predominantly hands) and rarely involves the face. (See "Erythromelalgia".) ●Conversion disorder, an involuntary condition in which neurologic symptoms are present in the absence of a neurologic disease but are not feigned. (See "Conversion disorder in adults: Terminology, diagnosis, and differential diagnosis".) ●Factitious disorder, an intentional production of physical or psychologic symptoms or findings to assume the "sick role." (See "Factitious disorder imposed on self (Munchausen syndrome)".) INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Complex regional pain syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS ●Complex regional pain syndrome (CRPS) is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is not restricted to 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. (See 'Definition and terminology' above.) ●The etiology and pathophysiology of CRPS are unknown. Proposed mechanisms include classic inflammation, neurogenic inflammation, and maladaptive changes in pain perception at the level of the central nervous system. (See 'Pathogenesis' above.) ●CRPS is more common in women than in men. The most frequent inciting events for CRPS are fractures and soft tissue injuries. CRPS seldom occurs in the absence of an identifiable trigger. (See 'Epidemiology' above.) ●The main clinical symptoms of CRPS are pain, sensory changes, motor impairments, autonomic symptoms, and trophic changes in the affected limb. Of these, pain is typically the most prominent and debilitating symptom. (See 'Clinical manifestations' above.) ●The diagnosis of CRPS is based upon the clinical features as determined by the history and physical examination. Diagnostic criteria are based upon four symptom/sign categories (sensory, vasomotor, sudomotor/edema, and motor trophic) and require that the patient report one symptom in three of the four categories and display one sign at the time of evaluation in two of the four categories. Importantly, the criteria require that no other diagnosis better explains the symptoms and signs. (See 'Evaluation and diagnosis' above and 'Diagnostic criteria' above.) ●The differential diagnosis of CRPS includes a large number of conditions that can have some of the clinical features of CRPS, including (see 'Differential diagnosis' above): •Infection of skin, muscle, joint, or bone •Compartment syndrome •Peripheral vascular disease •Deep vein thrombosis •Peripheral neuropathy •Vascular thoracic outlet syndrome •Rheumatoid arthritis •Raynaud phenomenon •Erythromelalgia •Conversion and factitious disorders ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Robert Sheon, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. Topic 5628 Version 22.0 Print Options Print | Back Text References Contributor Disclosures Close The use of UpToDate is subject to the Subscription and License Agreement. 댓글 SoYuz 2018.09.11 16:54 UpToDateOfficial reprint from UpToDate® www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Wolters Kluwer Health Complex regional pain syndrome in adults: Prevention and management Author:Salahadin Abdi, MD, PhDSection Editor:Jeremy M Shefner, MD, PhDDeputy Editor:April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2018. | This topic last updated: Sep 04, 2018. INTRODUCTION — Complex regional pain syndrome (CRPS) is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is not restricted to 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. The prevention and management of CRPS will be reviewed here. Other aspects of CRPS in adults and children are presented separately. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis" and "Complex regional pain syndrome in children" and "Overview of the treatment of chronic non-cancer pain".) PREVENTION — There has been interest in preventive strategies for CRPS in high-risk groups, such as older patients with distal radius fractures. Vitamin C in particular has been suggested as a low-risk intervention that might accelerate fracture healing and limit excessive soft tissue injury via antioxidant mechanisms. Data in patients have been inconsistent, however. Support for vitamin C is based on results of two randomized trials from the same group [1,2]. In the larger of the two trials, 416 older women with distal wrist fractures were randomly assigned to one of three daily doses of vitamin C (200, 500, or 1500 mg) or placebo for 50 days [2]. Over a one-year follow-up period, CRPS was less prevalent in those who received vitamin C (any dose versus placebo, 2.4 versus 10.1 percent). A subsequent trial of vitamin C (500 mg daily) versus placebo in 336 adults with acute distal radius fractures found no difference between groups in the rate of CRPS (8 percent in both groups), disability scores, and other functional outcomes at six weeks and one year post-fracture [3]. A meta-analysis of the three trials (n = 890) found a nonsignificant trend towards benefit of vitamin C (risk ratio 0.45, 95% CI 0.18-1.13) [4]. Overall quality of the evidence was assessed as low based on the low number of events and inconsistency among trials. While vitamin C is a low-risk intervention, we do not find the evidence to be compelling enough to warrant routine use in all patients with distal fractures or other high-risk injuries. We counsel all adults with fractures to maintain adequate whole-food intake of protein, vitamin C, calcium, and vitamin D for six to eight weeks following fracture to promote healing. Vitamin C is reasonable to supplement for six to eight weeks after distal radius fractures in patients with poor baseline nutritional status or those who cannot comply with whole-food intake. A typical dose is 500 mg daily. (See "General principles of definitive fracture management", section on 'Overview and basic measures'.) A 2009 clinical guideline from the American Academy of Orthopaedic Surgeons includes a moderate-strength recommendation for vitamin C in patients with distal radius fractures for the prevention of disproportionate pain but has not been revised since publication of the third randomized trial [5]. At least one CRPS guideline also includes a recommendation for vitamin C for preventive purposes [6]. Early mobilization after limb injury may also reduce the risk of CRPS, though there are no high-quality data to confirm benefit. Patients with fractures require accurate assessment of fracture healing to strike an appropriate balance between proper fracture healing, which requires a sufficient period of immobilization, and avoidance of prolonged immobilization, which increases the risk of complications. (See "General principles of acute fracture management" and "General principles of definitive fracture management", section on 'Fracture healing'.) MANAGEMENT — A multidisciplinary approach is suggested for the management of CRPS [7,8]. Clinical experience suggests that treatment is more effective when begun in early in the course of the disease, ideally as soon as the diagnosis is established and before radiographic changes appear. However, it is uncertain whether immediate referral to a specialist in pain management results in superior outcomes compared with early physical or occupational therapy (OT) for protective and assisted mobilization of the affected limb within pain limits, supplemented by conservative pharmacologic interventions, and followed by referral to a pain management specialist if the patient does not improve. On the other hand, early referral to an interventional pain specialist for appropriate nerve block may reduce pain and enable patients with CRPS to tolerate aggressive physical therapy (PT). Some interventions that are appropriate for all patients with CRPS include the following: ●Patient education (see 'Patient education' below) ●PT and OT, which are initiated as quickly as is practical following diagnosis of CRPS (see 'Physical and occupational therapy' below) Patients with CRPS who have pre-existing or suspected psychologic or psychiatric issues and those who have insufficient improvement with physical, pharmacologic, and interventional therapies may benefit from psychosocial and behavioral management. (See 'Psychosocial and behavioral management' below.) Pharmacologic and interventional procedures for pain control are utilized in an escalating fashion, beginning with those that are relatively safe and for which there is some evidence of effectiveness, and progressing to more risky interventions if a desired response is not achieved after a few weeks of therapeutic trial. The goals of pain management are to allow active participation in a rehabilitation regimen and to restore movement and strength of the affected limb. For patients with early CRPS, we suggest starting with one or more of the following agents: ●A nonsteroidal anti-inflammatory drug (NSAID). A typical initial regimen is ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily. Dose adjustments must be made for older adult patients. (See 'Nonsteroidal anti-inflammatory drugs' below.) ●An anticonvulsant, such as gabapentin or pregabalin. (See 'Anticonvulsants' below.) ●A tricyclic or other antidepressant drug that is effective for neuropathic pain. We typically start with amitriptyline or nortriptyline (10 to 25 mg at bedtime or earlier in the evening if morning drowsiness occurs) and increase the dose, as tolerated. Other tricyclic antidepressants and dual uptake inhibitors that are indicated for treatment of neuropathic pain are alternatives to amitriptyline. (See 'Antidepressants' below.) ●Bisphosphonate treatment; intravenous (eg, clodronate 300 mg or pamidronate 1 mg/kg) or oral (eg, alendronate 70 mg weekly) bisphosphonates may be used. (See 'Bisphosphonates' below.) ●Topical lidocaine cream (2 to 5 percent) or topical capsaicin cream (0.025 to 0.075 percent), which may be discontinued if it is too irritating or if there is no benefit after three to five days of use. The author prefers topical lidocaine instead of capsaicin for most patients. (See 'Topical lidocaine and capsaicin' below.) Referral to a pain management specialist with experience in management of CRPS is appropriate for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to the measures outlined above, as well as for patients with severe or chronic CRPS. Trigger point/tender point injections, regional sympathetic nerve block, spinal cord stimulation, or epidural clonidine may be the preferred intervention, depending upon the expertise of the specialist and the values and preferences of the patient. (See 'Interventional procedures' below.) An alternative approach, suitable for patients with progressive CRPS who are unwilling to consider interventional procedures, is the sequential addition of different pharmacologic agents, including calcitonin and oral glucocorticoids, to the initial treatment regimen. (See 'Pharmacologic approaches' below.) Patient education — Patient participation in physical and OT may be facilitated by an explanation that the pain associated with CRPS, which is presumably related to neuropathic and central mechanisms, does not indicate tissue damage in the hyperalgesic region but arises from an unknown cause. Prior to a referral to a specialist in rehabilitation or to a physical or occupational therapist, the clinician should stress the importance of working to regain use of the affected limb while recognizing the difficulty of doing so in the face of ongoing pain. A support group available for patients and families in the United States is the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA). Psychosocial and behavioral management — We suggest consulting a clinical psychologist if any of the following are present: ●CRPS of more than two months duration at presentation ●Insufficient response to treatment ●Suspected comorbid psychologic or psychiatric disorder The goals of psychosocial and behavioral management include the following [9,10]: ●Identify any psychologic factors contributing to pain and disability ●Treat anxiety and depression ●Identify, explore, and proactively address any internal factors (eg, counter-productive behavior patterns) or external influences (eg, perverse incentives, family dynamics, etc) that may perpetuate disability or dependency ●Consider needs of family and caregivers and provide psychologic intervention and counseling where appropriate ●Provide a practical problem-solving, goal-orientated approach (involving both the patient and their family) to reduce barriers and promote healthy functioning Although psychologic assessment and therapy have not been well studied in patients with CRPS, their usefulness in other chronic painful disorders suggests that this approach may be beneficial to those with CRPS. Patients with severe or chronic CRPS may benefit from cognitive behavioral therapy [9]. (See "Overview of the treatment of chronic non-cancer pain", section on 'Cognitive-behavioral therapy'.) Case reports and personal experience suggest that a skilled hypnotherapist can be helpful for patients with heightened arousal, manifested by features of fear, anxiety, excessive sweating, and weakness, and in whom exercise is otherwise impossible [11,12]. Hypnosis allowed PT to progress in some patients with otherwise intractable disease. Physical and occupational therapy — PT and OT are considered first-line treatments for CRPS [7,13,14], though most of the relevant studies are limited by methodologic problems, including but not limited to lack of control groups and small patient numbers [15,16]. A number of general therapeutic methods of PT and OT have been employed to treat CRPS, including but not limited to the following list [10]: ●General exercises and strengthening ●Functional activities ●Gait retraining ●Transcutaneous electrical nerve stimulation (TENS) ●Postural control ●Pacing, prioritizing, and planning activities ●Goal setting ●Relaxation techniques ●Coping skills ●Hydrotherapy ●Sleep hygiene ●Edema control strategies ●Vocational support ●Facilitating self-management of condition ●Splinting There is no definitive evidence in favor of any of these methods [17]. Other rehabilitation techniques have been developed in centers with particular CRPS expertise [10]: ●Graded motor imagery [18-20] ●Pain-exposure PT [21] and graded exposure in vivo [22] to reduce pain avoidance behaviors ●Self-administered tactile and thermal desensitization with the aim of normalizing touch perception [23] ●Mirror visual feedback and immersive virtual reality [24-28] ●Functional movement techniques to improve motor control and awareness of affected limb position [29] ●Principles of stress loading [30] ●Conflict allodynia re-education to reduce fear of physical contact with others in community settings [31] Perhaps the strongest evidence is for graded motor imagery, which led to significant reductions in pain and swelling in patients with CRPS in three small single-center randomized controlled trials [18-20]. However, a prospective observational study from two centers with a special interest in CRPS found no improvement in pain despite the use of graded motor imaging [32], suggesting it does not translate well into clinical practice [33]. Aside from cost and inconvenience, there is little downside to PT and OT for patients with CRPS. We suggest referral to an appropriate therapist immediately after the diagnosis is established. PT, which can be performed twice daily at home for patients in all stages of disease, should ideally begin before limitation of movement occurs in order to maintain range of motion and prevent contractures. Resting splints for the affected limb are sometimes used with a goal of preventing progressive joint contractures. However, the effectiveness of splinting is uncertain. Pharmacologic approaches — Multiple treatment modalities are available to provide pain relief in patients with CRPS. The key to success is to use whatever works to reduce pain so that patients can tolerate PT. Pharmacologic agents that we use to treat CRPS include some agents in the following drug classes: ●NSAIDs (see 'Nonsteroidal anti-inflammatory drugs' below) ●Anticonvulsants (see 'Anticonvulsants' below) ●Antidepressants (see 'Antidepressants' below) ●Bisphosphonates (see 'Bisphosphonates' below) ●Topical lidocaine or capsaicin (see 'Topical lidocaine and capsaicin' below) ●Nasal calcitonin (see 'Calcitonin' below) ●Oral glucocorticoids (see 'Glucocorticoids' below) ●Other medication classes (see 'Others' below) Nonsteroidal anti-inflammatory drugs — NSAIDs are often used in the initial treatment of CRPS, and some experts find them effective for some patients [7], but they are not well studied for this condition [6,34]. A typical initial regimen is ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily. Depending on the stage and severity of CRPS, NSAIDs are generally combined with any of the other agents listed below. For patients who cannot tolerate nonselective NSAIDs, the selective COX-2 inhibitors are alternative options. Anticonvulsants — Anticonvulsants may be beneficial in neuropathic pain [6]. However, there are few data regarding efficacy in CRPS [17]. In one placebo-controlled randomized trial of 58 patients with CRPS, gabapentin (maximum 1800 mg daily) produced no significant improvement in pain [35]. Pregabalin can be used as an alternative to gabapentin. The key to using these medications is to start slowly and to titrate the dose as needed and tolerated; both drugs may cause dose-dependent dizziness and sedation that can be reduced by starting with lower doses and titrating cautiously. Pregabalin has been reported to cause euphoria, and is classified as a Schedule V controlled substance in the United States. (See "Overview of the treatment of chronic non-cancer pain", section on 'Anticonvulsants'.) Although unproven in CRPS, the author's clinical experience suggests that gabapentin and pregabalin may be useful for pain management. However, other experts believe that gabapentin has only a marginal and clinically unimportant benefit for CRPS [36]. Antidepressants — Though not specifically studied in CRPS, antidepressant medications are often effective in reducing neuropathic pain [6]. The author's clinical experience suggests that tricyclic antidepressants reduce pain and are a valuable addition to PT for patients with CRPS. (See "Overview of the treatment of chronic non-cancer pain", section on 'Antidepressants'.) Bisphosphonates — Bisphosphonates may be effective for reducing pain in patients with early CRPS who have abnormal uptake on bone scan, even though their positive effects in this condition are probably not related to their antiresorptive properties [17,37]. Supporting evidence comes from several small placebo-controlled randomized trials, including trials of intravenous and oral alendronate, intravenous neridronate, intravenous pamidronate, and intravenous clodronate [34,38-42]. Four of these trials enrolled only patients who had evidence of osteopenic or osteoporotic changes in the affected limb [38-40,42]. Illustrative trials include the following: ●The largest trial enrolled 82 subjects with CRPS of the hand or foot who had a disease duration of four months or less and abnormal uptake in early and late phases of three-phase bone scintigraphy [40]. The trial participants were randomly assigned to intravenous neridronate (100 mg given four times over 10 days) or placebo. At the end of the double-blind phase, 40 days after the first infusion, there was a significantly greater decrease in the visual analog pain scale for neridronate treatment group compared with the placebo group (-47 mm versus -22.6 mm). Neridronate also led to improvement on several secondary outcomes including indices of quality of life. The most common adverse events were acute-phase reactions (polyarthralgia and fever) with bisphosphonate administration; no serious adverse events were reported. ●Another trial randomly assigned 32 patients with early CRPS either to 300 mg of intravenous clodronate given daily for 10 days or to placebo [42]. After 40 days, pain decreased by a mean of 36 mm and 6 mm (on a 100 mm visual analog pain scale) in the clodronate and placebo groups, respectively, a difference that was statistically significant. The only side effect of active therapy was asymptomatic hypocalcemia in three patients. Serious adverse effects of bisphosphonates include esophageal ulceration with oral use and osteonecrosis of the jaw. Patients who have difficulty swallowing, those with disordered esophageal motility, and those who cannot sit or stand for 30 minutes should not receive oral bisphosphonate therapy. Most reported cases of osteonecrosis have been in patients with malignant disease receiving potent intravenous bisphosphonates. However, osteonecrosis has been reported in some patients receiving oral bisphosphonates for benign disorders. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Osteonecrosis (avascular necrosis of bone)", section on 'Other risk factors'.) Topical lidocaine and capsaicin — Topical application of lidocaine or capsaicin cream is used for treating neuropathic pain, but only limited data suggest efficacy in CRPS [6,43]. By analogy with treatment of painful diabetic neuropathy, lidocaine or capsaicin cream may be applied topically three to four times daily over painful areas. Local burning and skin irritation can occur with capsaicin, but this may become less of a problem with continued use. Topical lidocaine and capsaicin are probably best suited for patients with early CRPS and mild to moderate pain despite the use of anticonvulsants, antidepressants, and/or NSAIDs. A treatment trial of three to five days may suffice to assess effectiveness and tolerability of these agents. Calcitonin — The rationale for use of calcitonin involves the ability of this hormone to retard bone resorption and a putative analgesic effect. The mechanism responsible for analgesia is uncertain. (See "Calcitonin in the prevention and treatment of osteoporosis".) There is conflicting evidence regarding the benefit of calcitonin for CRPS [17,34,37]. Calcitonin has been evaluated in three small placebo-controlled randomized trials for the treatment of CRPS, including two of nasal calcitonin [44,45] and one of subcutaneous calcitonin [46]. However, only one of these three trials detected benefit [45]. The optimal dose and duration of calcitonin treatment is uncertain. A dose of 300 international units daily was used in the one positive randomized trial [45]. If pain and/or function are improved with use, it can be continued, tapered, and discontinued as tolerated. Considering the evidence for efficacy and the low risk associated with its use, we suggest calcitonin for patients with CRPS in combination with PT for patients who have mild or moderate symptoms despite the use of the agents listed above. Glucocorticoids — Oral glucocorticoids (eg, divided doses of prednisone, 30 to 80 mg/day) may be effective for CRPS, but there is only low-quality evidence from small randomized trials with substantial methodologic limitations [17,34]. The findings of one small trial suggest that oral glucocorticoids are more effective than NSAIDs [47]. The trial randomly assigned 60 patients with CRPS following stroke to prednisolone (40 mg daily) or piroxicam (20 mg daily). At one month, a significantly greater proportion of patients in the prednisolone group than those receiving piroxicam met criteria for improvement (83 versus 17 percent, respectively). Patients with chronic CRPS usually do not respond to glucocorticoids. Although the limited data discussed above suggest that glucocorticoids are more effective than NSAIDS for CRPS [47], we suggest using NSAIDs first and reserving use of glucocorticoids for those who do not respond to all the other aforementioned drugs. Others — Other pharmacologic treatments for CRPS with limited evidence include alpha adrenergic drugs, ketamine, and intravenous immune globulin (IVIG). ●Alpha-adrenergic antagonists and agonists – Sympathetically maintained pain may respond to the addition of an alpha-1 adrenoceptor antagonist, which is supported by the clinical experience of the author and other experts [48]. The author has noted apparent benefit in some patients with the use of either prazosin (1 to 6 mg/day as tolerated) or phenoxybenzamine (10 to 30 mg/day as tolerated). Hypotension can be a limiting side effect of alpha-adrenergic blockers. The author has also treated patients using a clonidine patch (0.1 mg), which is changed every seven days, usually in combination with anticonvulsants and/or antidepressants; this approach has generally not resulted in significant side effects. ●Ketamine infusion – Systematic reviews have found that there is only low- to moderate-quality evidence supporting the use of ketamine for CRPS [17,34,49,50]. In one of the higher-quality randomized trials, ketamine infusion was compared with placebo in 60 patients with type I CRPS [51]. Patients assigned to five-day ketamine infusions had a statistically significant decline in pain scores from weeks 1 through 11 of follow-up compared with the placebo group, but the reduction was no longer statistically significant by week 12. Frequent side effects of ketamine in this trial included psychomimetic symptoms (eg, hallucinations, delirium), nausea, and vomiting. ●Intravenous immune globulin – IVIG does not appear to be beneficial for CRPS, despite promising preliminary studies. A single-center randomized trial involving 13 patients with CRPS found that low-dose IVIG reduced pain at 6 to 19 days following infusion by a modest degree compared with normal saline [52]. However, in a later multicenter randomized trial of 111 patients with chronic CRPS of one to five years duration, low-dose IVIG given for six weeks was not effective for pain reduction compared with placebo [53]. ●Opioids – The use of opioids for neuropathic pain continues to be controversial, and there is a paucity of high-quality data supporting their efficacy for CRPS [6,54]. The use of opioids may be justified in select cases when other approaches have failed. Based on the author's clinical experience, there are patients who can benefit from a small dose of opioids in combination with other drugs for neuropathic pain described above. That said, escalating the dose can result in the risk outweighing the benefit. Interventional procedures — Interventional procedures for the treatment of pain related to CRPS include trigger/tender point injections, regional sympathetic nerve block, spinal cord stimulation, epidural clonidine, and chemical or mechanical sympathectomy, among others. The published evidence for these methods, though generally limited and of low quality, does not support their efficacy. However, in the author's clinical experience, a number of patients derive meaningful benefit from these interventional procedures. Patients receiving noninvasive therapy who are not improving are candidates for increasingly invasive interventions, allowing two weeks for improvement before moving on to the next type of treatment. In some tertiary centers, spinal cord stimulation, arguably the most invasive therapy, would be considered by 12 to 16 weeks from the time therapy for CRPS is initiated [55]. The author prefers to begin with sympathetic nerve blocks, and reserves the use of spinal cord stimulation for willing patients who do not respond to sympathetic nerve blocks. Trigger point/tender point injections — Trigger/tender points may be found about the shoulder girdle when CRPS is limited to the upper limb. These trigger/tender points are located in the trapezius and suprascapular muscles in most patients. If unilateral involvement occurs, the other side can be used for comparison. The author's clinical experience is that trigger/tender point injections are sometimes effective and are safer than other treatment modalities. Injection of each trigger/tender point with local anesthetics with or without glucocorticoids is used for patients with early CRPS, before proceeding to more invasive and risky procedures. Regional sympathetic nerve block — Temporary sympathetic nerve block may be accomplished by infiltration of a local anesthetic into the region of the sympathetic ganglia or by intravenous regional infusion of a sympathetic blocker, typically in combination with a local anesthetic. Sympathetic nerve block is an option at centers with expertise in this technique for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to the traditional measures outlined above. However, the limited evidence base for such treatment suggests there is no benefit. Despite what the literature shows, it is the author's experience, and that of many interventional pain physicians, that this procedure could be beneficial for many patients and indeed life changing for some. ●A systematic review updated in 2016 identified 12 studies with a total of 461 participants that evaluated the effect of sympathetic blockade with local anesthetics in children or adults with CRPS [56]. All the included studies were considered to have a high or unclear risk of bias. The following observations were noted: •Two small trials compared regional sympathetic nerve block with sham or placebo and found no significant difference for short-term pain reduction. •Two studies investigated regional sympathetic nerve block as an addition to rehabilitation treatment; only one of these reported pain outcomes and found no additional benefit from regional sympathetic nerve block. •Eight small randomized studies compared sympathetic blockade with a different active intervention. In most of these reports, there was no difference in between sympathetic block and other active treatments for pain outcomes. ●A 2010 guideline noted that intravenous sympathetic blockade with guanethidine for CRPS, as evaluated in eight small studies, had no added value for pain reduction compared with placebo [6]. Stellate ganglion blocks may be performed at one-week intervals and may be repeated several times. This treatment is abandoned if an immediate response (eg, improved temperature and decreased pain) does not occur following the first or second nerve block. Oral medications and intensive mobilizing PT should continue in patients who receive stellate ganglion blocks or intravenous regional (Bier) blocks. Each block should result in a longer duration of pain relief. Spinal cord stimulation — Spinal cord stimulation (also termed "dorsal column stimulation") may be helpful if traditional therapeutic modalities fail [36], particularly in patients with disease limited to one extremity. In a randomized study of 36 patients and 18 controls, spinal cord stimulation plus PT reduced pain and improved health-related quality of life more than PT alone for up to two years but did not improve functional outcome measures [57,58]. No significant difference in pain was present during the period from three to five years following implantation [59]. Methodologic limitations of this trial include lack of sham intervention for control group and unblinded outcome assessment [60]. Complications of spinal cord stimulation are common and are mostly associated with improper positioning of the electrode. This technique should only be attempted at expert centers [36]. Epidural clonidine — Clonidine administered by epidural injection or infusion may reduce the pain of CRPS, but side effects such as hypotension and sedation can occur depending upon the dose [61,62]. Potential complications of epidural injection have limited study of this treatment to patients with severe refractory CRPS. In one trial, 26 patients with severe chronic CRPS that was unresponsive to sympathetic blocks were randomly assigned to epidural clonidine (300 or 700 microgram bolus injection) or to placebo and were assessed for up to six hours [62]. Epidural clonidine provided significantly greater pain relief than placebo injections. Pain relief was similar with both doses of epidural clonidine, though numeric pain scores were not provided in the report [17]. We suggest that epidural clonidine be used only for patients refractory to other, less invasive approaches. The author has experience in using clonidine in combination with local anesthetics for stellate ganglion and lumbar sympathetic nerve blocks successfully, but its value needs to be systematically studied. Sympathectomy — Sympathectomy for CRPS has not been compared with placebo or sham surgery in randomized controlled trials [63]. Low-quality observational evidence suggests the possibility of benefit from chemical or surgical sympathectomy. However, sympathectomy is associated with high rates of adverse effects including increased pain, new neuropathic pain, and bothersome sweating [64]. In the author's experience, aggressive PT, pain management, and encouragement of the patient to work beyond the pain typically obviates the need for procedural treatments. Sympathectomy should be used only in patients who have shown a previous response to nerve blockade (eg, who have sympathetically dependent pain) and who are fully informed about the potential complications of the procedure. Other modalities — Intrathecal baclofen may relieve dystonia in patients with CRPS [65], though data are limited [6]. Focal dystonia may also respond to botulinum toxin injections [7,14]. Hyperbaric oxygen therapy may be useful when skin breakdown and ulcer occurs in CRPS patients. However, it may take many sessions to achieve benefit, and only one randomized trial supports the use of this approach [66]. Recurrent CRPS — In patients with exacerbations or recurrence of CRPS due to exposure to cold, new surgery, or emotional trauma, small doses of tricyclic antidepressants (eg, amitriptyline or nortriptyline) and anticonvulsants (eg, gabapentin or pregabalin) have been helpful in our experience. (See 'Pharmacologic approaches' above.) Secondary prevention — There is limited evidence to guide strategies for the prevention and treatment of recurrences or relapses of CRPS. Elective surgery should be performed when features of previous episodes of CRPS have improved and when the patient is stable; surgery should be avoided during exacerbations. Additional perioperative and surgical strategies include maintenance of optimal perfusion of the affected limb, avoidance of tourniquet hemostasis, and perioperative intravenous infusion of mannitol. In one series of 47 patients with CRPS undergoing surgery involving a previously affected extremity, use of these measures was associated with a recurrence rate of CRPS of 13 percent. The recurrence was mild and temporary in five of the six patients in whom it occurred [67]. Other measures that have been proposed to prevent or minimize risk of recurrence include intensive rehabilitation, sympathetic block before surgery, regional anesthesia/analgesia techniques, pretreatment with perioperative calcitonin prophylaxis, and neuromodulation postsurgery [68-72]. However, the data supporting use of these approaches are limited. Most reports are of small case series, and some are limited to children. Thus, these approaches have not been tested in randomized trials, and it is uncertain whether the results in children can be generalized to CRPS in adults. CRPS in children is reviewed separately. (See "Complex regional pain syndrome in children".) PROGNOSIS — The prognosis of CRPS is uncertain, with highly variable rates of poor and favorable outcomes in different studies. Nevertheless, a substantial proportion of patients have some degree of prolonged disability. The range of findings is illustrated by the following: ●In a population-based report of 102 Dutch patients with CRPS followed for an average of 5.8 years since disease onset, the following outcomes were observed [73]: •Ongoing CRPS fulfilling diagnostic criteria was present in 64 percent •Patients considered themselves as either recovered, stable, or worse due to progressive disease in 30, 54, and 16 percent of cases, respectively •Patients resumed their previous work completely, resumed work with adjustments, or were unable to work in 41, 28, and 31 percent of cases, respectively ●A retrospective population-based study of 74 cases of CRPS found that resolution of symptoms, sometimes spontaneously, occurred in 74 percent of patients [74]. Symptom duration ranged from 1 to 60 months (median 7 months). Litigation and work-related compensation issues are involved in a substantial proportion of cases of CRPS cared for in tertiary pain management clinics, present in 17 and 54 percent, respectively, in one study in the United States [75]. Recurrence of CRPS is not uncommon; estimates of recurrence range from approximately 10 to 30 percent, with the higher rates occurring in younger patients, including children [76,77]. Recurrences can occur spontaneously or with cold exposure, but they also appear to be triggered by trauma or new surgery of the affected limb or of an unaffected remote site and by emotional trauma [68,69,77,78]. (See "Complex regional pain syndrome in children".) In a study of 1183 consecutive patients with CRPS, recurrences were seen in 10 percent of patients [77]. The recurrence of CRPS occurred twice as often in a different limb than in the initial episode (76 patients) compared with recurrence in the originally affected limb that had become largely asymptomatic (34 patients). In 10 patients, CRPS started in symmetric limbs. Recurrences were usually spontaneous (53 percent) and were often associated with few signs and symptoms. Most of the remainder was associated with trauma or surgery (32 and 12 percent, respectively). The estimated incidence of a recurrence was 1.8 percent per patient per year. SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain".) INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●Basics topics (see "Patient education: Complex regional pain syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS ●Complex regional pain syndrome (CRPS) is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is not restricted to 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. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis", section on 'Definition and terminology'.) ●Fractures are a common inciting injury for CRPS, and there is low-quality evidence that vitamin C may reduce the risk of CRPS in high-risk groups, such as older patients with distal radius fractures. We counsel all adults with fractures to maintain adequate whole-food intake of protein, vitamin C, calcium, and vitamin D for six to eight weeks following fracture to promote healing. In patients with distal radius fractures who have poor baseline nutritional status or who cannot comply with whole-food intake, we suggest vitamin C supplementation (Grade 2C). A typical dose of vitamin C is 500 mg orally daily for six to eight weeks after fracture. (See 'Prevention' above.) ●A multidisciplinary approach is suggested for the management of CRPS. Interventions appropriate for all patients with CRPS include patient education, physical therapy (PT), and occupational therapy (OT). (See 'Management' above and 'Patient education' above and 'Physical and occupational therapy' above.) ●Patients with CRPS who have pre-existing or suspected psychologic or psychiatric issues and those who have insufficient improvement with physical and pharmacologic therapies may benefit from psychosocial and behavioral management. (See 'Psychosocial and behavioral management' above.) ●Pharmacologic and invasive procedures for pain control are utilized in an escalating fashion, beginning with those that are relatively safe and for which there is some evidence of effectiveness, and progressing to more risky interventions if a desired response is not achieved after a few weeks of therapeutic trial. The goals of pain management are to allow active participation in a rehabilitation regimen and to restore movement and strength of the affected limb. (See 'Management' above and 'Pharmacologic approaches' above.) ●For patients with early CRPS who require treatment for pain, we suggest starting with one (or more) of the following agents (Grade 2C): •Ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily (see 'Nonsteroidal anti-inflammatory drugs' above) •Amitriptyline or nortriptyline (10 to 25 mg at bedtime as initial dose for both) (see 'Antidepressants' above) •Gabapentin (starting dose of 100 mg at bed time for older adults and 300 mg at bed time for the rest, titrating the dose up as tolerated and needed) (see 'Anticonvulsants' above) •A bisphosphonate (eg, oral alendronate 70 mg weekly) for patients with early CRPS who have pain and abnormal uptake on bone scan (see 'Bisphosphonates' above) •Topical lidocaine cream (2 to 5 percent) or topical capsaicin cream 0.075 percent (see 'Topical lidocaine and capsaicin' above) ●Referral to a pain management specialist with experience in management of CRPS is appropriate for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to the measures outlined above. Depending upon the expertise of the specialist, trigger/tender point injections, regional sympathetic nerve block, spinal cord stimulation, or epidural clonidine may be the preferred intervention. (See 'Interventional procedures' above.) ●The prognosis of CRPS is uncertain, but a substantial proportion of patients have some degree of prolonged disability. (See 'Prognosis' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 5630 Version 32.0 Print Options Print | Back Text References Contributor Disclosures Close This site uses cookies. By continuing to browse this site you are agreeing to our use of cookies. Continue or find out more.