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Complex Regional Pain Syndrome
Introduction
Complex regional pain syndrome (CRPS) is a neuropathic pain disorder characterized by persistent pain that is disproportionate to the severity of the tissue injury and continues beyond the usual expected period of tissue healing.[1] The pain is accompanied by sensory, motor, and autonomic abnormalities. Such abnormalities include allodynia, hyperalgesia, sudomotor and vasomotor abnormalities, and trophic changes. The pain is regional and does not follow a specific dermatome or myotome pattern. This disabling condition often develops after a trauma, fracture, or surgery.[2][3] Some spontaneous cases have also been reported.[4]
In the 16th century, Ambroise Paré first reported cases with symptoms similar to CRPS, which developed after phlebotomy.[5] In 1864, Silas Mitchell observed this syndrome after gunshot wounds. He used the term causalgia to describe this syndrome in 1872. James A. Evans coined the term reflex sympathetic dystrophy in 1946 to describe a similar condition, in which he suspected that sympathetically mediated pain was involved.[6] Finally, in 1994, the International Association for the Study of Pain (IASP) named this condition complex regional pain syndrome and proposed diagnostic criteria. Due to low specificity, a widely accepted revised set of criteria was proposed in 2010 and is commonly referred to as the Budapest Criteria.[7]
CRPS is classified into 2 subtypes—type 1, previously referred to as reflex sympathetic dystrophy, and type 2, formerly called causalgia. Type 1 arises without nerve trauma, whereas type 2 follows a known nerve injury. These conditions present with indistinguishable clinical features, typically affecting a regional area rather than following a dermatomal or peripheral nerve distribution. Symptoms typically involve the distal extremities but may extend proximally or to the contralateral limb. CRPS can also be categorized as warm or cold and may be sympathetically maintained or independent—classifications that influence prognosis and treatment strategies.[8]
In addition to impairing function, sleep, and activities of daily living, CRPS imposes a substantial psychological and psychosocial burden.[9][10][11] The condition's variable clinical spectrum and poorly defined pathophysiology complicate management.
Etiology
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Etiology
CRPS typically develops after tissue trauma of varying severity, but it has also been reported to occur without an identifiable injury or following prolonged immobilization. Fractures represent the most common inciting event, although surgery, sprains, contusions, and crush injuries are also frequent triggers. Some cases arise after seemingly minor procedures, such as intravenous line placement. Heightened psychological distress at the time of injury may contribute to the severity of symptoms and influence overall prognosis.
Fracture
CRPS commonly develops following extremity fractures. A large, multicenter, prospective study reported that 48.5% of patients met the IASP criteria for CRPS after sustaining a single fracture of the ankle, wrist, scaphoid, or fifth metatarsal, with persistent symptoms at 1-year follow-up. Identified risk factors included rheumatoid arthritis, intraarticular ankle fractures, and dislocations, although no significant difference emerged between upper and lower limb fractures.[12] Another cohort study noted symptom onset within 8 weeks of a noxious event. Although some individuals showed clinical improvement at 3 months, symptoms persisted in others at 1 year.[13]
Studies on distal radius fractures have linked older age, psychosocial stressors, and psychiatric comorbidities to an increased risk of developing CRPS.[14][15] However, other prospective data failed to establish a clear link between psychological factors and disease development.[16]
Surgery
Extremity surgeries, such as those for fractures, are frequently associated with the development of CRPS. In a retrospective study involving 390 individuals undergoing foot or ankle procedures, 4.36% developed CRPS.[17] Surgical fixation of fractures carries additional risk; among patients treated with closed reduction for distal radius fractures, 32.2% developed CRPS.[18] Carpal tunnel release has been linked to a 2% to 5% incidence of CRPS, whereas Dupuytren contracture surgeries show a broader range of 4.5% to 40%.
Genetics
The role of genetic predisposition in CRPS remains under investigation. Specific polymorphisms, such as those involving human leukocyte antigen and tumor necrosis factor-alpha (TNF-α), may contribute to earlier onset and greater severity. Some retrospective reports have suggested a possible familial inheritance pattern.[19]
Epidemiology
The incidence of CRPS varies geographically. A 2003 study by Sandroni et al in Olmsted County, Minnesota, reported an incidence of 5.46 per 100,000 person-years for type 1 CRPS and 0.82 per 100,000 person-years for type 2 CRPS.[20] In contrast, a 2006 study by Mos et al in the Netherlands found a significantly higher incidence of 26.2 cases per 100,000 person-years. Both studies reported a higher prevalence in females. The Minnesota study indicated a 4 times increased risk in females compared to males, whereas the Netherlands study estimated a 3 times difference.
Age and extremity involvement also differed between studies. The Netherlands research reported peak incidence between ages 61 and 70, whereas the American study found a median age of onset at 46 years. Both studies noted that the upper extremities were more frequently affected. Diagnosis in both studies relied on the IASP criteria for CRPS. Fracture was the most common precipitating event in 44% to 46% of cases. The most frequent clinical features included vasomotor symptoms, such as swelling, temperature fluctuations, and skin discoloration.[21]
Among diagnostic tools, 3-phase bone scans were most useful (85%), followed by autonomic testing (80%). Identified risk factors for CRPS include asthma, use of angiotensin-converting enzyme inhibitors, menopause, osteoporosis, migraine, and cigarette smoking.[22][23]
Pathophysiology
Multiple pathophysiologic mechanisms have been described in the literature to explain CRPS. Scientific evidence does not point to a single principal mechanism. The condition is therefore considered multifactorial, involving inflammatory, immunologic, central, and peripheral sensitization, and autonomic dysregulation.
Inflammatory Changes
Both the clinical presentation and elevated inflammatory laboratory markers suggest that inflammation is a key mechanism underlying the development of CRPS. The basic signs of inflammation, such as increased temperature, swelling, redness, pain, and functional impairment, are commonly associated with CRPS.[24] Elevated levels of pro-inflammatory cytokines, such as TNF-α and interleukins 1β, 2, and 6, have been found in both the serum and cerebrospinal fluid of patients with CRPS.[25][26][27][28] Elevated levels of neuropeptides such as calcitonin gene–related peptide, bradykinin, and substance P released from peripheral nerve endings, likely due to tissue injury in CRPS, trigger neurogenic inflammation. Elevated levels of inflammatory markers and neuropeptides lead to vasodilation and tissue extravasation.[29][30][31][32]
Immunological Changes
Autoimmune factors appear to play a role in the pathogenesis of CRPS. Autoantibodies targeting β2-adrenergic, α1a-adrenergic, and muscarinic 2 receptors have been identified in patients with CRPS.[33][34] Goebel et al noticed a significant improvement in pain following intravenous immunoglobulin treatment in patients with CRPS, which further supports potential autoimmune pathophysiology.[35]
Peripheral Sensitization
Sensitization of the peripheral nervous system is triggered by the release of pro-inflammatory markers after the initial injury. Markers such as TNF-α, released during this process, reduce the stimulation threshold, leading to local sensitization and hyperalgesia in patients with CRPS. Catecholamine sensitivity of peripheral nerve fibers has also been noted in patients with CRPS.
Central Sensitization and Neuroplasticity
Increased excitability of secondary dorsal horn neurons occurs in CRPS. Hyperalgesia and allodynia develop as a result of sensitization. The release of substance P, bradykinin, and glutamate plays an important role in this process. Persistent noxious primary afferent traffic into the dorsal horn leads to wind-up phenomena and central sensitization. The activation of spinal N-methyl-D-aspartate (NMDA) receptors appears to play a crucial role in the pathogenesis of CRPS, as demonstrated by the response to ketamine infusions, an NMDA antagonist, in patients with CRPS.[36][37] The improvement of CRPS symptoms with intrathecal baclofen suggests that gamma-aminobutyric acid is involved in the process of sensitization.
There is evidence of cortical reorganization in CRPS, with a reduction in the somatosensory cortex area corresponding to the affected extremity.[38] The degree of neuroplasticity seems to correlate with the intensity of pain and severity of hyperalgesia, both of which indicate central sensitization.[39][40]
Autonomic Changes
Sympathetic-afferent coupling occurs in CRPS due to the upregulation of sympathetic receptors on nociceptive nerve fibers. Thus, sympathetic hyperactivity leads to increased pain and sympathetic sensitivity of nociceptive nerves. Local swelling, color, and temperature variations associated with this disorder suggest an involvement of the autonomic nervous system.[41] Widespread autonomic dysregulation in CRPS can affect heart rate and lead to orthostatic dysfunction.[42] In warm CRPS, vasodilation occurs due to reduced catecholamine release, whereas the opposite phenomenon occurs in cold CRPS.
History and Physical
Patients with CRPS may present with a range of sensory, motor, or autonomic symptoms. Sensory symptoms include allodynia (pain triggered by typically nonpainful stimuli) and hyperalgesia (exaggerated pain response to normally painful stimuli). Autonomic symptoms may manifest as changes in skin color and temperature (vasomotor dysfunction) and altered sweating (sudomotor dysfunction). Motor symptoms of CRPS include weakness, reduced range of motion, tremor, and, in some cases, dystonia in the affected extremity.[43]
CRPS is often associated with worsening depression, anxiety, impaired function, and reduced quality of life. A systematic review by Lohnberg et al explored psychosocial factors linked to CRPS and found no clear evidence in the literature supporting specific personality traits or psychopathologies as predictors of CRPS. However, patients with significant psychological comorbidities or poor coping mechanisms may exhibit pain-related behaviors and catastrophic thinking.
In addition, CRPS has been associated with a variety of systemic medical complications, including:
- Neuropsychological deficits, such as executive functioning, memory, and word retrieval
- Constitutional symptoms, such as lethargy, weakness, and disruptions in sleep
- Cardiopulmonary issues, such as neurocardiogenic syncope, atypical chest pain, and chest wall muscle dystonia causing shortness of breath
- Endocrinopathies, such as impaired hypothalamic-pituitary-adrenal axis with low serum cortisol and hypothyroidism
- Urologic dysfunction, such as increased urinary frequency, urgency, and incontinence
- Gastrointestinal dysmotility, such as nausea, vomiting, diarrhea, constipation, and indigestion [44][45][46][47][48]
Evaluation
No definitive pathophysiologic mechanism has been identified for CRPS. Therefore, there is no gold-standard diagnostic test. The diagnosis is primarily clinical and is based on the widely accepted Budapest criteria, outlined below. Compared to the previous IASP criteria, the Budapest criteria offer similar sensitivity (0.99) but higher specificity (0.68).
To make a clinical diagnosis, all 4 of the following criteria must be met:
- The patient should report ongoing pain that is disproportionate to the inciting event.
- The patient should report at least 1 symptom in 3 of the following 4 categories:
- Sensory: Evidence of hyperalgesia or allodynia
- Vasomotor: Evidence of temperature asymmetry, skin color changes, or skin color asymmetry
- Sudomotor or edema: Evidence of edema, sweating changes, or sweating asymmetry
- Motor or trophic: Evidence of decreased range of motion; motor dysfunction, such as weakness, tremor, and dystonia; or trophic changes affecting hair, skin, and nails
- The patient must display at least 1 sign in 2 or more of the following categories:
- Sensory: Evidence of hyperalgesia (to pinprick) or allodynia (to light touch or deep somatic pressure)
- Vasomotor: Evidence of temperature asymmetry, skin color changes, or skin color asymmetry
- Sudomotor/edema: Edema, sweating changes, or sweating asymmetry
- Motor/trophic: Evidence of decreased range of motion; motor dysfunction, such as weakness, tremor, and dystonia; or trophic changes affecting hair, skin, and nails
- There is no other diagnosis that better explains the signs and symptoms.
Various objective tests, including thermography, triple-phase bone scans, and the quantitative sudomotor axon reflex test, are used to aid in diagnosis. Although these tests can provide additional data, they are not required to diagnose CRPS. The diagnosis is primarily clinical and made by exclusion. Differential diagnoses include small-fiber sensorimotor neuropathy, large-fiber sensorimotor neuropathy, cellulitis, erythromelalgia, vasculitis, vascular insufficiency, lymphedema, deep vein thrombosis, and Raynaud phenomenon. These diagnostic tests are mainly used to help rule out potential differential diagnoses.
Treatment / Management
Although spontaneous improvement may occur in some patients with CRPS, early aggressive management is crucial, given the syndrome's debilitating nature. Delayed intervention is associated with poorer outcomes, whereas early-stage CRPS tends to be more responsive to therapy and carries a more favorable prognosis.[49] The primary goals of treatment are to alleviate pain, restore function, and prevent disability. Effective management requires an interprofessional approach, including physical and occupational therapy, pharmacotherapy, behavioral therapy, and procedural options.
Physical and Occupational Therapy
In addition to manual therapy and exercises, other treatment modalities for CRPS include transcutaneous electrical nerve stimulation, ultrasound, laser therapy, pain education, mirror therapy, and graded motor imagery. Although various mechanisms contribute to the effectiveness of physical therapy, no conclusive theory has been established. Manual therapy and exercise improve range of motion and function while reducing disability by releasing endorphins and activating both central and peripheral analgesic mechanisms.[50] Pain education helps improve patients' understanding of pain mechanisms, enabling behavioral adjustments that support recovery. Mirror therapy and graded motor imagery target maladaptive cortical neuroplastic changes linked to chronic pain conditions such as CRPS.[51]
A 2016 Cochrane review suggested that mirror therapy and graded motor imagery may improve both pain and function in patients with CRPS, although the quality of evidence was limited. Two clinical trials demonstrated improvements in pain and function at 6 months for graded motor imagery and mirror therapy. Very low-quality evidence suggested that multimodal physiotherapy may reduce impairment in patients with CRPS.
An updated Cochrane review in 2022, which included 16 new trials, confirmed that multimodal physiotherapy, aerobic exercise, graded motor imagery, mirror therapy, virtual reality, transcutaneous electrical nerve stimulation, and exposure in vivo may reduce pain or disability in some patients with type 1 CRPS compared to controls. However, the evidence remains uncertain, with most beneficial effects being short-term.[52](A1)
Pharmacotherapy
Multiple pharmacotherapeutic agents are used in managing CRPS. Common options include anti-inflammatory medications, anticonvulsants, antidepressants, transdermal lidocaine, opioids, NMDA antagonists, and bisphosphonates. A multimodal pharmacologic regimen combining several classes may yield superior outcomes.
Anti-Inflammatory Medications
Oral corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the management of CRPS due to the presumed role of inflammation in disease pathogenesis. A 2013 Cochrane review, based on 3 trials comparing oral corticosteroids to placebo, found no significant reduction in pain from oral steroids. This conclusion was supported by very low-quality evidence. However, oral corticosteroids appeared to improve composite pain scores.[53](A1)
In a separate study, oral prednisone was found to be more effective than piroxicam, an NSAID, in improving composite CRPS scores in poststroke patients.[54] A recent study confirmed that a 2-month course of low-dose oral prednisone was safe and effective for poststroke CRPS.[55] In 2022, CRPS treatment guidelines recommended initiating a short course of steroids (30 mg daily for 2-12 weeks, followed by tapering) early in treatment. However, 1 or more trials in the systematic review were considered to be of poor quality.[56](A1)
Bisphosphonates
Bisphosphonates are commonly used in bone-related conditions as they inhibit osteoclastic activity. Several mechanisms of action have been proposed in CRPS, with the most widely accepted involving the inhibition of bone marrow cell proliferation and migration and modulation of inflammation.[57] A 2017 meta-analysis concluded that bisphosphonates appear to reduce pain in patients with type 1 CRPS.[58] A 2013 Cochrane review found low-quality evidence suggesting a similar response in CRPS, particularly in individuals with concurrent osteopenia or osteoporosis.(A1)
Anticonvulsants and Antidepressants
Gabapentin is the most widely studied anticonvulsant for CRPS, working by inhibiting the α2δ subunit of voltage-gated calcium channels. Despite its common use, very low-quality evidence suggests that gabapentin may be ineffective in treating type 1 CRPS. A 2016 study comparing amitriptyline and gabapentin for type 1 CRPS and pediatric neuropathic pain found that both medications significantly reduced pain intensity and disability, with no significant difference in efficacy between these agents.[59](A1)
Opioids
The role of opioids in treating CRPS remains uncertain due to limited research. Given the potential for their addiction and adverse effects, opioids should be used cautiously and typically as part of a comprehensive pain management strategy for short-term relief, with a focus on minimizing long-term dependence.
N-methyl-D-aspartate Antagonists
NMDA receptor antagonists, such as ketamine, are hypothesized to reverse central sensitization and maladaptive cortical neuroplastic changes in CRPS. Low-quality evidence suggests that intravenous ketamine infusion may reduce pain for up to 4 to 11 weeks in some patients. However, the adverse effects and psychomimetic properties of ketamine have limited its widespread use. In contrast, data on magnesium as an NMDA antagonist in CRPS is sparse. A 2024 systematic review and meta-analysis referenced 2 studies, 1 from 2009 and another from 2013. In the first study, involving 10 patients, intravenous magnesium infusion of 70 mg/kg provided pain relief in patients with type 1 CRPS. However, the second study involving 56 patients found no benefit at the same dosage.[60](A1)
Immunotherapy
The immune system plays a significant role in the development and persistence of CRPS, particularly through the formation of autoantibodies. A narrative review outlined several immunotherapy options, including interleukin 1 receptor antagonists, glucocorticoid administration, intravenous immunoglobulin infusion, and TNF-α inhibitors.[61] The effectiveness of these treatments varies based on the specific agent and timing of administration. However, these treatments are associated with potential side effects and should be considered with caution.(B3)
Behavioral Therapy
Elevated catecholamine levels associated with depression can exacerbate CRPS by inducing central sensitization through adrenergic mechanisms. Reversing this effect is 1 of the proposed mechanisms of psychotherapy in CRPS. Although only 1 small trial and several case reports have evaluated the efficacy of behavioral interventions in CRPS, behavioral therapy has been recommended as a part of a comprehensive treatment approach despite the lack of strong evidence supporting its effectiveness in this context.[62]
Procedural Options
In treating CRPS, various procedures aim to address the underlying pathophysiology and alleviate symptoms. These interventions are considered when conservative treatments prove insufficient, offering patients alternative avenues for pain relief and improved function.
Sympathetic Blocks
Sympathetic hyperactivity is considered a key pathophysiological factor in CRPS, prompting the use of sympathetic nerve blocks as a treatment option. Lumbar sympathetic nerve blocks are commonly employed for lower extremity symptoms, whereas stellate ganglion blocks are typically used for upper extremity symptoms. Despite their widespread use, a 2013 Cochrane review concluded that sympathetic blocks with local anesthetics did not significantly reduce CRPS-related pain, with the evidence quality deemed to be low. A subsequent 2016 Cochrane review found insufficient evidence to draw definitive conclusions on the efficacy of these treatments for CRPS due to the lack of robust supporting data.
Spinal Cord Stimulation
Spinal cord stimulation involves delivering electrical impulses to the dorsal column of the spinal cord through electrodes placed in the epidural space. These electrodes are typically connected to an implanted pulse generator, although some devices use an external generator. The mechanisms of action for spinal cord stimulation are varied, including the inhibition of nociceptive neural conduction in the spinal cord, adrenergic inhibition, vasodilation, and the reversal of maladaptive neuroplastic changes in the cortex. A 2017 systematic review concluded that evidence strongly supports using spinal cord stimulation to improve pain scores, quality of life, and overall pain relief in patients with CRPS.[63](A1)
Dorsal Root Ganglion Stimulation
Dorsal root ganglion stimulation provides a more targeted neuromodulation approach compared to traditional spinal cord stimulation, as it specifically targets the dorsal root ganglion rather than the spinal cord. Approved by the United States Food and Drug Administration in 2016 for treating lower extremity pain in CRPS, dorsal root ganglion stimulation has shown promising results. A recent pooled analysis found dorsal root ganglion stimulation to be both safe and effective, with a 4.9-point mean reduction in pain intensity for patients with type 1 CRPS.[64] Furthermore, the 2017 ACCURATE study (a comparative, controlled, multicenter, randomized trial of dorsal root ganglion stimulation versus spinal cord stimulation in complex regional pain syndrome), which compared dorsal root ganglion stimulation to spinal cord stimulation in 152 patients with CRPS, found that dorsal root ganglion stimulation was more effective in reducing pain and improving quality of life.[65](B2)
Differential Diagnosis
Given the broad and often ambiguous presentation of CRPS, a wide range of differential diagnoses must be considered to avoid misdiagnosis. These conditions may exhibit similar symptoms to CRPS, particularly in terms of sensory, motor, and autonomic disturbances.
- Arterial insufficiency
- Guillain-Barré syndrome
- Conversion disorder (formerly referred to as hysteria)
- Monomelic amyotrophy
- Multiple sclerosis
- Peripheral arterial disease
- Deep vein thrombosis (also known as phlebothrombosis)
- Porphyria
- Poliomyelitis
- Tabes dorsalis
Accurate diagnosis depends on a thorough clinical evaluation and exclusion of these mimicking disorders through appropriate investigations. Timely differentiation is essential, as the treatment and prognosis can vary significantly depending on the underlying condition.
Pertinent Studies and Ongoing Trials
Zalewski et al examined the limited body of original clinical research on the immunological, biochemical, and molecular dimensions of CRPS between 2018 and 2024. The group highlighted the pervasive methodological heterogeneity across studies, which complicates efforts to draw meaningful conclusions about the characterization and treatment of the condition.
In response, the authors recommended a shift in research priorities, advocating for smaller, methodologically rigorous studies, including detailed case reports and n-of-1 trials, given the rarity and heterogeneity of CRPS and limited data on treatment efficacy. Experimental designs should ideally include at least 30 participants and adhere strictly to the Budapest criteria for diagnosis, clearly stating whether the clinical or research version was used.
Due to ethical concerns about placebo use in managing severe pain, the authors recommended prioritizing comparative effectiveness designs over placebo-controlled trials. They recommended a minimum follow-up period of 24 months to assess long-term outcomes. Furthermore, outcome measures should be reproducible and comprehensive, encompassing not just pain but also anxiety, disability, quality of life, sleep quality, fear of movement (kinesiophobia), and cognitive function.[66]
Staging
In 1990, Bonica proposed a 3-stage model for CRPS. However, a study by Bruehl et al involving 113 patients found no significant differences in symptom duration across the proposed stages, suggesting that clearly defined, generalized disease stages may not exist in CRPS.[67]
Prognosis
The prognosis of CRPS is highly variable, ranging from spontaneous remission to chronic, refractory cases. However, evidence suggests that early intervention may significantly improve outcomes and reduce the risk of long-term disability.
Complications
Complications of long-standing CRPS may include dystonia, cognitive executive dysfunction, adrenal insufficiency, gastroparesis, and irritable bowel syndrome. These manifestations highlight the syndrome's potential to affect multiple organ systems beyond the musculoskeletal and nervous systems, underscoring the need for comprehensive, interprofessional care.
Deterrence and Patient Education
Oral vitamin C supplementation has been proposed as a preventive strategy against CRPS following fractures, primarily due to its antioxidant effects. A 2015 meta-analysis of 3 trials found that the current evidence did not definitively support its role in preventing CRPS after distal radial fractures, with the overall quality of evidence deemed low.[68] In contrast, a 2017 systematic review and meta-analysis reported that a daily dose of 500 mg of vitamin C for 50 days reduced the incidence of CRPS 1 year after wrist fractures. Despite these findings, further high-quality research is needed to clarify the preventive efficacy of vitamin C in this context.[69]
Enhancing Healthcare Team Outcomes
An interprofessional team approach is essential for optimizing recovery and minimizing long-term disability in patients with CRPS. Given the multifaceted nature of the condition—encompassing sensory, motor, autonomic, and psychological components—care must be coordinated across disciplines to address all aspects of the patient's needs. Early and continuous communication among healthcare professionals ensures a unified treatment plan, which is particularly important in a condition that often requires individualized, evolving care strategies.
Key members of the interprofessional team include social workers, pharmacists, nurses, physical and occupational therapists, and pain management specialists. Social workers can assist with psychosocial support and navigating healthcare access, whereas pharmacists play a crucial role in medication management and monitoring for adverse effects or interactions. Nurses provide ongoing assessment and education, and therapists focus on restoring function and preventing disuse. Early referral to pain management specialists allows for the timely initiation of pharmacologic and procedural interventions, which can improve symptom control and long-term outcomes.
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