➢ Complex regional pain syndrome is a clinical diagnosis and a diagnosis of exclusion; hence, a thorough clinical examination and a clear understanding of its clinical presentation and diagnosis based on the Budapest criteria are important.
➢ A multidisciplinary approach involving the orthopaedic team, pain services, allied health services (physiotherapists and occupational therapists), and psychological services should be considered when managing patients who have complex regional pain syndrome.
➢ Early diagnosis, early referral to a multidisciplinary team, and judicious mobilization are key to the treatment of complex regional pain syndrome.
➢ The administration of ascorbic acid (vitamin C) starting on the day of the fracture has been proposed for prophylaxis against complex regional pain syndrome in patients with wrist fractures.
Complex regional pain syndrome (CRPS) is a term that was introduced twenty years ago by the International Association for the Study of Pain (IASP)1. The intentions behind the nomenclature change were to replace the myriad terms that were used to describe a group of similar conditions (for example, reflex sympathetic dystrophy, Sudeck dystrophy, causalgia, and algodystrophy), to remove the emphasis that names such as reflex sympathetic dystrophy placed on outdated theories about the mechanisms underlying the condition2, and to propose a set of standardized diagnostic criteria.
Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, changes in skin blood flow, abnormal sudomotor activity, and motor and trophic changes in a limb2,3. Complex regional pain syndrome may develop with or without a specific inciting event such as fracture, peripheral nerve injury, or surgical treatment of a limb3,4. In the orthopaedic clinic, the presence of complex regional pain syndrome may be first evident when plasters and splints are removed, pain medications have been reduced, and patients are commencing mobilization programs. Early recognition and appropriate treatment is indicated as the majority of cases will resolve with simple interventions over time, thus reducing progression to the long-standing, distressing, and disabling form of complex regional pain syndrome that impairs quality of life and places a heavy burden on health care5. However, recognizing and diagnosing this condition can be a challenge as there has been a lack of agreement regarding standardized diagnostic criteria for complex regional pain syndrome6. This lack of agreement in part stems from an incomplete understanding of the pathophysiology of this complex condition. The treatment of complex regional pain syndrome is further complicated by the lack of large controlled studies investigating the efficacy of various pharmacological and nonpharmacological therapies for this condition7.
The purpose of the present review is to inform the orthopaedic community about the most current and clinically relevant information regarding the epidemiology, diagnosis, and pathophysiology of complex regional pain syndrome. We also will highlight current options for the treatment and prevention of this condition.
Diagnosing Complex Regional Pain Syndrome
The translation of the existing body of evidence regarding complex regional pain syndrome into clinical practice has been affected not only by nomenclature issues but also by the use of disparate sets of diagnostic criteria8-10. However, there has been an evolution toward a so-called gold standard diagnostic suite for complex regional pain syndrome11. This evolution firmly places physical examination at the forefront, making the diagnosis accessible to clinicians but also potentially weakening the diagnosis because of the inherent subjectivity of such testing12. However, within the most contemporary sets of diagnostic criteria1,3,9,13, greater objectivity has been demonstrated over time, thus reducing the potential for bias. Early diagnostic criteria were based on expert consensus alone and, while successfully focusing attention on the need to rethink this group of diagnoses, these criteria were later found to lead to overdiagnosis and potentially an overpopularization of the diagnosis1,13-15.
The diagnostic criteria known as the Budapest criteria (Table I) have now been accepted and codified for clinical and research purposes by the Committee for Classification of Chronic Pain of the IASP6. The Budapest criteria build on the foundation provided by the previous IASP criteria from 19941, additionally requiring findings of either sensory changes (evidence of hyperalgesia), vasomotor changes (evidence of temperature asymmetry), sudomotor changes and/or edema, motor changes (weakness/tremor), and/or trophic changes2. In 2010, an international multicenter study was conducted to compare the validity of both the 1994 IASP criteria and the Budapest criteria9. The study involved a structured evaluation, with use of both sets of diagnostic criteria, of complex regional pain syndrome-related signs and symptoms in 113 patients with complex regional pain syndrome and forty-seven patients with neuropathic pain that was unrelated to complex regional pain syndrome. On the basis of that study, the Budapest criteria were found to retain the exceptional sensitivity of the 1994 IASP criteria (0.99 compared with 1.00) while showing improved specificity (0.79 compared with 0.68)9.
Subtypes of complex regional pain syndrome have received some consideration in the literature but are of unknown clinical utility, are inconsistently recorded, and are not required for the diagnosis of complex regional pain syndrome on the basis of the Budapest criteria2. These subtypes include CRPS-1 and CRPS-2 (indicating the absence or presence of evidence of a peripheral nerve injury, respectively) and CRPS-NOS (not otherwise specified) for cases in which the diagnostic criteria are not fully met but cannot be better explained by another diagnosis6.
To avoid overdiagnosis of complex regional pain syndrome, differential diagnosis remains crucial. The physician also should consider the potential for complex regional pain syndrome to coexist with other conditions, including those in the list of potential differential diagnoses (Table II). In the presence of ongoing inexplicable or inconsistent physical presentations, consideration should be given to psychiatric differential diagnoses. Psychiatrists or psychologists with expertise in somatic symptom disorders can assess for possible factitious and malingering diagnoses with the aid of structured diagnostic interviews, standardized psychometric tests, and a comprehensive history.
Currently, there is no investigation or blood biomarker that is diagnostic for complex regional pain syndrome. Laboratory techniques that have been found to be sensitive but not specific for complex regional pain syndrome include thermography (measurement of temperature differences between limbs), sudomotor tests, and isolated cold stress testing16-18. Imaging modalities may help in supporting or rejecting an alternative diagnosis and, to an extent, provide objective signs of disease progression or regression (Table III)19-27. However, comparison studies of imaging modalities have shown either poor sensitivity or poor specificity for detecting complex regional pain syndrome, thus limiting their diagnostic value (Table IV)19,21,22,27,28. For example, radiographic findings may reflect disuse osteoporosis, whereas the increased bone metabolism demonstrated on bone scanning may reflect fracture-healing in patients with acute complex regional pain syndrome or the effects of disuse or immobilization in patients with long-standing complex regional pain syndrome19,20,27,29. Magnetic resonance imaging (MRI) signs of abnormal signal pattern of muscle in patients with complex regional pain syndrome may resemble that of other inflammatory myopathies, whereas other soft-tissue and bone findings may represent the consequences of trauma or surgery19,22,24.
Epidemiological and Demographic Characteristics of Complex Regional Pain Syndrome
Our understanding of the epidemiological and demographic characteristics of complex regional pain syndrome has been hampered by the historical lack of standardized diagnostic criteria for complex regional pain syndrome and the scarcity of large prospective studies investigating the incidence of complex regional pain syndrome following injury. de Mos et al., in a population-based retrospective cohort study in The Netherlands in 2007, reported an overall incidence of complex regional pain syndrome of 26.2 per 100,000 person years30, whereas Sandroni et al., in Olmsted County, Minnesota, reported an incidence of 5.46 per 100,000 person years31. The age of the patients at the time of onset was similar in both studies (mean, fifty-three years30 and forty-seven years31). Females were more commonly affected than males (female:male ratio, 3.4:130 and 4:131); this finding was similar to those reported in previous studies (female:male ratio, 3:13 and 2.3:132), suggesting a potential hormonal role in complex regional pain syndrome30,33. Some studies have demonstrated that the upper extremities are almost two times more likely to be affected than the lower extremities3,30,31. The reasons for this upper limb bias are currently unclear.
The three most common inciting events among 238 patients with complex regional pain syndrome as reported by de Mos et al.30 were fractures (105 patients; 44.1%), sprains (forty-two; 17.6%), and elective surgery (e.g., carpal tunnel release and Dupuytren fasciectomy) (twenty-nine; 12.2%). These findings are consistent with those in the study by Sandroni et al.31, in which thirty-four (46%) of seventy-four cases of complex regional pain syndrome resulted from fractures and nine (12%) resulted from sprains, as well as with those in the study by Veldman et al.3. As fractures were identified as the most common precipitating event for complex regional pain syndrome, a multicenter prospective cohort study with one-year follow-up investigated the demographic and medical parameters of the condition and demonstrated that 289 (48.5%) of 596 patients with a fracture involving the wrist, scaphoid, ankle, or fifth metatarsal were diagnosed with complex regional pain syndrome on the basis of the 1994 IASP criteria34. The study also demonstrated that intra-articular fractures, fracture-dislocations, rheumatoid arthritis or musculoskeletal comorbidities, and ankle fractures were linked to an increased risk of complex regional pain syndrome. In a separate prospective study investigating predictors of complex regional pain syndrome following total knee arthroplasty, patients who presented with greater preoperative pain were found to have a higher risk of developing complex regional pain syndrome35.
There is mounting evidence suggesting a genetic predisposition for complex regional pain syndrome, particularly in certain human leukocyte antigen (HLA) types. Studies have shown that patients with HLA DQ1, DQ8, DR15, DR13, A3, B7, and DR2 are at an increased risk for the development of complex regional pain syndrome following trauma, suggesting a genetic basis for at least a subgroup of this disorder36-39. The link between psychological factors (critical life events or inadequate coping strategies and certain personality traits, e.g., avoidant or anxious personality) and complex regional pain syndrome is controversial; currently, there is little evidence to suggest a causal link between psychological factors and complex regional pain syndrome40-43.
The pathophysiology of complex regional pain syndrome is multifactorial, complex, and incompletely understood. Possible mechanisms involve interplay between peripheral and central sensitization, altered sympathetic nervous function, inflammation, autoimmunity, genetic factors, and brain plasticity. A putative model of the pathophysiology of complex regional pain syndrome can be derived from currently available data44. Following tissue injury with minimal nerve trauma, an exaggerated release of pro-inflammatory cytokines and neuropeptides occurs, producing signs of inflammation and locally increased nociceptive responsiveness (peripheral sensitization)45,46. Subsequently, nociceptive fibers in the affected area begin to express adrenergic receptors, exaggerating sympathetic nervous system activity, and enabling circulating catecholamines to directly trigger nociceptive firing47. The presence in complex regional pain syndrome of auto-antibodies directed to adrenergic and muscarinic receptors may alter sympathetic nervous system outflow; however, the precise role of this mechanism is yet to be elucidated48. Following an alteration of sympathetic nervous system outflow to the region, an exaggerated vasoconstrictive response ensues, favoring an accumulation of pro-nociceptive substances (enhancing hyperalgesia) while triggering local hypoxia and trophic changes49. The resultant intense noxious stimuli trigger increased excitability of nociceptive neurons in the spinal cord (central sensitization), which exacerbates hyperalgesia and permits normally nonpainful stimuli such as light touch and cold to activate nociceptive pathways (allodynia)44. This altered afferent input thus contributes to neuroplasticity, in which there is substantial reorganization of somatotopic maps; specifically, there is both a reduction in the size as well as a shift of the representation of the complex regional pain syndrome-affected limb in the somatosensory cortex. The extent of this reorganization is associated with the intensity of pain and the level of impairment of other sensory functions such as tactile sensation50,51. Additional studies are required to confirm these putative mechanisms in patients with acute tissue injury.
Some investigators have reported a spontaneous resolution of most of the signs and symptoms of complex regional pain syndrome within one year after onset31,52,53. Bickerstaff and Kanis, in a prospective study of 274 patients with a Colles fractures, reported that 28% of patients exhibited early symptoms of complex regional pain syndrome (pain, swelling, vasomotor symptoms, swelling, and stiffness); however, at one year of follow-up, only 2% of the patients still had all of these features52. This finding was similar to that in the population-based retrospective study by Sandroni et al., in which 74% of seventy-four cases of complex regional pain syndrome resolved spontaneously in an average of twelve months31. Similarly, in the study by Galer et al., retrospective surveys that were completed by thirty-one patients with complex regional pain syndrome over a three-year period indicated that symptoms of complex regional pain syndrome most often tended to remain stable or to improve rather than deteriorate54.
Surgery on a limb that is already affected by complex regional pain syndrome requires special consideration as there is a risk that the symptoms will worsen or recur. The optimal time to perform surgery is unknown; however, it is recommended that complex regional pain syndrome be intensively treated and given time to resolve before any operative intervention is performed55,56. When surgery is considered necessary, a perioperative pain-management plan should be devised in consultation with the anesthesiologist.
The clinical features of complex regional pain syndrome are diverse and may vary over time57. Complex regional pain syndrome typically manifests within three months after an injury, although it may be recognized as early as two weeks after an injury34,58-60. The clinical presentation of complex regional pain syndrome can be categorized into four categories, as described below (Table I) (Fig. 1, Fig. 2, and Fig. 3)2,61.
Pain and Sensory Disturbance
Pain often appears to be out of proportion to the degree of the initiating injury3,54. It may be described as neuropathic in nature (burning, throbbing, or stinging) and may follow a glove or stocking distribution3. A prospective study of 145 patients with complex regional pain syndrome demonstrated that 63% of patients complained of a tearing, deep pain in the affected limb, whereas 31% described superficial pain on the skin, with both types being aggravated by lowering the affected limb and by temperature changes62. The severity of pain can result in avoidance of movement of the limb, potentially contributing to a body perception disturbance in which the affected limb feels “foreign,” “strange,” and “difficult to locate.”63-66 Hyperalgesia (increased sensitivity to noxious stimuli, e.g., severe pain resulting from a pin prick), allodynia (pain elicited from non-noxious stimuli, e.g., light touch), hyperthermesthesia or hypothermesthesia (increased or decreased sensation to thermal stimuli), and limited proprioception are commonly associated with complex regional pain syndrome.
Sudomotor Changes and Edema
Distal extremity edema has been reported in association with 69% of cases of complex regional pain syndrome and usually occurs soon after onset3. Factors known to exacerbate the edema include orthostasis (lowering the affected limb) and physical activity57. Sudomotor disturbances occur in almost half of patients with complex regional pain syndrome, with hyperhidrosis being more common than hypohidrosis3,67 Hyperhidrosis commonly occurs in the palmar and plantar surface of the skin68.
Classically, in cases of early complex regional pain syndrome, the affected limb is warm, red, purple, or pink, whereas in cases of long-standing complex regional pain syndrome, the skin appears cold, pale, or blue67; however, either cluster of manifestations may occur at any time. Exercising the limb may lead to a rapid increase in temperature, with the skin becoming progressively hyperemic and painful3.
Motor and Trophic Changes
Motor disturbances may include weakness, incoordination, stiffness, tremors, dystonia, spasms, and contractures3,69,70. Many patients with early complex regional pain syndrome present with increased hair growth and nail changes. In patients with long-standing complex regional pain syndrome, the skin may undergo atrophy and appear shiny or pigmented71,72.
Evidence-Based Therapy for Complex Regional Pain Syndrome
The treatment of complex regional pain syndrome is particularly challenging, considering its diverse manifestations, multifaceted pathophysiology, and relatively unknown natural history. To address the therapeutic challenges associated with complex regional pain syndrome, early and aggressive intervention is recommended73-75. This recommendation has been supported by two meta-analyses that demonstrated an improvement in functional outcomes for patients with chronic pain undergoing multidisciplinary pain palliation76,77. Such interventions should be targeted toward the three core elements of treatment of complex regional pain syndrome, i.e., rehabilitation, pharmacological and procedural pain palliation, and psychological therapy. The goal of any intervention should be to achieve functional restoration with an emphasis on graded increases in physical activity and sensory desensitization, ideally progressing steadily from gentle treatment to complete rehabilitation in all aspects of the life of the patient6,78,79.
Physiotherapy and occupational therapy have long been recommended as first-line therapy for complex regional pain syndrome, and there is now an expanding evidence base supporting their role in the treatment of this condition8,80-83. A randomized controlled trial involving 135 patients with one year of follow-up showed that physiotherapy and occupational therapy helped to reduce pain and improve function in patients who had had complex regional pain syndrome for less than one year84,85. Furthermore, a randomized controlled trial of twenty-eight adolescents with complex regional pain syndrome who were managed with combined physiotherapy and cognitive behavioral therapy sessions for six weeks showed improvement in terms of pain and function86. Those studies suggest that early diagnosis and referral for both physiotherapy and occupational therapy is important for quicker resolution of symptoms and return of function. Stanton-Hicks et al. recommended that early mobilization and return to normal use of the affected limb rather than prolonged immobilization is important for the rehabilitative process82.
Novel rehabilitative techniques that have been shown to be effective include mirror visual feedback and graded motor imagery (Fig. 4). The rationale of these techniques is to retrain brain pathways by coordinating visual, sensory, and motor functions that have become abnormally reorganized as a result of complex regional pain syndrome. In mirror visual feedback, the patient is asked to position the affected limb behind a mirror so that it lies hidden from view and the reflected image of the unaffected limb is perceived as the affected one. Observing movement of the normal limb will create the illusion that the patient is exercising the affected limb without increasing pain in the limb87,88. Mirror visual feedback has been shown to be effective in cases of early and intermediate complex regional pain syndrome but not chronic complex regional pain syndrome87. It has been postulated that mirror visual feedback restores motor output and sensory feedback, thereby activating the pre-motor cortex, which has intimate connections with the visual processing area89-91. Graded motor imagery is a more recent development that utilizes two strategies prior to engaging in mirror therapy; the aim of graded motor imagery is to initially avoid activating the primary motor cortex as early movement execution may trigger pain resulting from the close association between pain and motor output92. In the first stage, a limb laterality recognition task is practiced in which the patient is required to determine whether pictures of hands or feet are left or right-sided. In the second stage, the patient progresses to imagining moving the affected limb into the positions depicted in the pictures. Once this can be done without pain, the patient then progresses to observing movements of the unaffected limb in a mirror (i.e., mirror visual feedback). In a small, single-blinded randomized controlled trial involving thirteen patients who had had chronic complex regional pain syndrome for more than six months, Moseley showed that a six-week graded motor imagery program was effective for reducing pain93.
A recent Cochrane review demonstrated greater improvement in function and reduction of pain in patients who underwent graded motor imagery and mirror visual feedback as compared with conventional physiotherapy94. Furthermore, a systematic review revealed that mirror therapy was effective for the management of patients who had complex regional pain syndrome or stroke affecting an upper limb95. However, the authors of both reviews concluded that current evidence on the effectiveness of both techniques is still limited and that additional studies involving a wider community of patients with complex regional pain syndrome are required to verify the findings.
Medical and Procedural Therapies
The pain associated with complex regional pain syndrome can be addressed through oral, intravenous, or topical pharmacotherapy and interventional pharmacological and neuroablative approaches, including neuraxial and peripheral nerve blocks, sympathectomies, and neuromodulation techniques94. Although there have been few well-designed trials demonstrating the efficacy of these modalities in the treatment of complex regional pain syndrome, pharmacological therapies have been observed clinically to work synergistically with rehabilitative and psychological interventions6. Medication should be individualized; monotherapy is simplest, but a multimodal pharmacological approach may be required to achieve optimal analgesia6.
A wide variety of drugs has been used to treat pain resulting from complex regional pain syndrome. Antineuropathic agents are commonly used, as are conventional analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. In addition, novel agents such as immunomodulators, bisphosphonates, and calcitonin might be useful. Anecdotally, these agents have a role as adjuncts to physiotherapy and psychological therapies; however, evidence on their use for the treatment of complex regional pain syndrome lacks randomized controlled data.
Anti-inflammatory drugs such as oral corticosteroids have been investigated in several trials; however, the authors of a recent Cochrane review concluded that there was a lack of high-quality evidence that oral corticosteroids were effective for the treatment of complex regional pain syndrome when compared with placebo94. A randomized controlled trial (n = 60) comparing the NSAID piroxicam with oral corticosteroids for the treatment of complex regional pain syndrome showed a reduction in symptoms in the corticosteroid group; however, a systematic review described differences in baseline function between study groups, thus rendering the results questionable96.
Currently, there is a lack of evidence to support the use of oral opioids as an option for pain management in patients with complex regional pain syndrome. A randomized controlled trial investigating the effects of sustained-release morphine in thirty-eight patients who had been pretreated with spinal cord stimulation for neuropathic pain (including complex regional pain syndrome) showed that opioids did not achieve significant pain relief97. However, a Cochrane review that included five randomized controlled trials involving a total of 374 participants who received tramadol or placebo showed that tramadol was effective for the treatment of neuropathic pain, which may be an element of complex regional pain syndrome98.
Controversy exists over the inclusion of complex regional pain syndrome as a type of neuropathic pain. Clinically, however, the condition shares some symptomatology with neuropathic pain, and, anecdotally, improvement has been seen when antineuropathic agents are used. There is limited evidence that the anticonvulsant gabapentin is effective for the treatment of complex regional pain syndrome94,99. A randomized, double-blind, placebo-controlled crossover study (n = 58) showed that gabapentin did not reduce pain in patients with complex regional pain syndrome but was associated with a wide variety of side effects (dizziness, somnolence, and lethargy) compared with placebo100. In a small case series, pregabalin and tramadol successfully mitigated the symptoms of complex regional pain syndrome when used as part of a multidisciplinary treatment101. Additional work is required to demonstrate an evidence base for the use of gabapentin and other anticonvulsants such as carbamazepine, pregabalin, and phenytoin for the treatment of complex regional pain syndrome.
The NMDA (N-methyl-D-aspartate) receptor antagonist ketamine has been used intravenously for the treatment of neuropathic pain, including complex regional pain syndrome. Two randomized, controlled, double-blind trials (n = 19 and n = 60) investigating the efficacy of outpatient intravenous administration of ketamine for the treatment of complex regional pain syndrome revealed a significant reduction in pain in the ketamine group compared with the placebo group (p < 0.05 and p < 0.001)102,103. However, a meta-analysis indicated heterogeneity and failed to indicate a positive pooled effect of intravenous ketamine on pain relief in patients with complex regional pain syndrome104.
The authors of a systematic review of four randomized controlled trials investigating the use of bisphosphonates for the treatment of complex regional pain syndrome concluded that while there is potential for bisphosphonates to reduce pain in patients with complex regional pain syndrome, there is insufficient evidence to recommend their use in practice105. Although the mechanism of action of bisphosphonates in complex regional pain syndrome is unknown, it has been hypothesized that bisphosphonates act by counteracting osteoclast-induced bone resorption that may be associated with complex regional pain syndrome105. Similarly, the use of calcitonin has been evaluated in two meta-analyses and one systematic review, all of which demonstrated conflicting evidence with respect to its efficacy for the treatment of complex regional pain syndrome106-108.
Despite the common use of various interventional techniques, few data from randomized controlled trials exist to support the practice. Certainly, a trial of interventional therapies is considered for most patients who prove refractory to other forms of therapy. Intravenous sympathetic blocks with guanethidine, lignocaine, clonidine, droperidol, and reserpine have been investigated, but there is scant evidence that such blockade is beneficial for patients with complex regional pain syndrome, and substantial adverse effects have been reported94. There was a trend toward benefit in association with temporary sympathectomy with local anesthetic, but significance was not attained109. Permanent sympathectomy through the injection of phenol, surgical excision, or electrocoagulation may be considered for refractory cases; however, there is a lack of placebo-controlled evidence supporting their use for the treatment of complex regional pain syndrome94,110. One small trial showed that spinal cord stimulation through the implantation of an electrode in the spinal canal combined with physiotherapy in a select group of patients with severe complex regional pain syndrome reduced pain and improved health-related quality of life94,111.
The body of evidence supporting the efficacy of psychological therapies for the treatment of complex regional pain syndrome has been affected by issues of quality in trial design and reporting, thereby restricting the generalizability of the results112. However, two randomized controlled trials (n = 18 and n = 28) showed that a combination of physiotherapy and psychotherapy was associated with improvement in terms of pain and function in the complex regional pain syndrome group86,113. A number of small case series have suggested that pain in patients with complex regional pain syndrome can be reduced through the use of a variety of psychological techniques, such as biofeedback, relaxation, and hypnosis78,79,112. The strong evidence regarding the use of these techniques for patients with other types of chronic pain supports the utilization of psychological therapies for patients with long-standing complex regional pain syndrome6,114. Effective treatment of movement-related anxiety may lead to an overall reduction in anxiety and pain and an improvement in functional outcomes81.
Prevention of Complex Regional Pain Syndrome
In a double-blind, randomized trial (n = 129), ascorbic acid (vitamin C) was associated with a lower risk of complex regional pain syndrome in patients with wrist fractures who were managed nonoperatively33. Participants were managed with 500 mg of ascorbic acid per day starting on the day the fracture occurred and continuing for fifty days and were followed for one year. Complex regional pain syndrome was diagnosed in association with 22% of the fractures in the placebo group, compared with 7% of those in the ascorbic acid group. A subsequent multicenter, double-blind, dose-response study involving 416 patients with wrist fractures showed that the administration of 500 mg of ascorbic acid daily for fifty days was associated with a lower incidence of complex regional pain syndrome115. Similarly, a “before-and-after” quasi-experimental study (n = 195) demonstrated a 10% incidence of complex regional pain syndrome in the surgical treatment (control) group, compared with 2.1% in the ascorbic acid group116. Furthermore, a “before-and-after” quasi-experimental study investigating the efficacy of ascorbic acid for the prevention of complex regional pain syndrome in 392 patients undergoing elective ankle and foot surgery demonstrated a 9.6% incidence of complex regional pain syndrome in the placebo group, compared with 1.7% in the ascorbic acid group117. Ascorbic acid is simple, safe, and inexpensive and is recommended for prophylaxis against complex regional pain syndrome. Medications, including thyrocalcitonin, carnitine, corticosteroids, mannitol, and ketanserin, have not been found to be effective for prophylaxis against complex regional pain syndrome pending larger randomized controlled trials118.
Complex regional pain syndrome is a challenging, complex disorder that is not yet fully understood. Currently, there are few high-quality clinical trials to guide treatment. We recommend the use of ascorbic acid for prophylaxis against complex regional pain syndrome in patients with wrist fractures. We also see the potential for future studies investigating the use of ascorbic acid for the prevention of complex regional pain syndrome in patients with other skeletal injuries. In addition, we believe that early vigorous treatment with timely involvement of an expert multidisciplinary team emphasizing the principle of functional restoration is vital to the treatment of complex regional pain syndrome. Additional studies investigating the pathophysiology and treatment of complex regional pain syndrome are required to better understand and treat this complex and potentially debilitating disorder.
Source of Funding: No external funds were received in support of this study.
Investigation performed at the Department of Orthopaedic Surgery, Austin Health, Heidelberg, Victoria, Australia
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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