Diagnosis of complex regional pain syndrome (CRPS) is challenging and remains a hot topic of debate as despite decades of research, the etiology remains entirely unclear.
Recent randomized controlled trials have questioned the role of vitamin C as a prophylactic treatment of CRPS in patients with distal radius fractures (DRFs).
The risk of CRPS following DRFs is independent of the fixation technique. However, tight casts and over distraction of the wrist joint using a spanning external fixator should be avoided.
Early detection and identification of a peripheral nerve compression that can be approached surgically is crucial to avoiding possible negative consequences such as drug dependency and long-term disability.
Physiotherapy with behavioral therapy components may be effective in ameliorating symptoms of CRPS and help the patient build coping mechanisms to regain functionality.
A 67-year-old women with a history of fibromyalgia fell on her right wrist and suffered a DRF. The fracture was reduced to an acceptable position and treatment consisted of short arm casting. She presents to clinic 2 weeks after the fracture with disproportionate pain and finger stiffness. Swelling appears within normal limits and she is not showing signs of acute carpal tunnel syndrome or compartment syndrome. What are the best methods to prevent, diagnose, and eventually treat CRPS type 1 in this patient?
Importance of the Problem
Complex regional pain syndrome (CRPS) type I is defined as chronic pain without an identifiable nerve injury and is one of the principal causes of long-term disability following distal radius fractures. Pain is accompanied by trophic changes, impaired function, and finger stiffness as well as autonomic dysfunction ( Fig. 1 ). Patients with fibromyalgia, women, and smokers have a higher likelihood of developing this condition. Incidence of DRFs complicated by CRPS varies and is reported to affect 1%–37% of patients ; however, the etiology of this complication is not well understood. It has been correlated to tight casts and over distraction of the wrist joint with spanning external fixators ( Fig. 2 ), but these scenarios only account for a small fraction of the known clinical scenarios. Surgical decompression, particularly of the median nerve, has been shown to be effective in modulating the sequelae of CRPS associated with a DRF.
Diagnosis of CRPS is challenging as it is based on clinical criteria ( Box 1 ) with mainly subjective components. Several diagnosis algorithms have been published over the years and currently, the most validated and internationally accepted is the Budapest Criteria ( Box 1 ). Radiographs may show disuse osteoporosis and peri-articular demineralization. Bone scan may show increased uptake, especially in phase 3 of the scan, but has low sensitivity. In general, imaging studies should be interpreted in light of the clinical findings and are usually not essential to diagnose CRPS. Early diagnosis is possible even 2 weeks after the injury and is associated with recovery in 80%–90% of cases. Late diagnosis of CRPS and inappropriate treatment can lead to chronic CRPS with residual pain and long-term disability up to 10 years after the injury with significant sociomedical and welfare consequences. Conversely, some prominent hand surgeons claim that CRPS does not exist and the symptoms can be explained by another pathology that was overlooked such as subclinical nerve compression, undetected nonunion, or fracture malreduction. Certainly, imaging and other advanced studies should be performed to rule out any pathology that may cause disproportional pain that may have been overlooked.
Continuing pain, which is disproportionate to any inciting event
At least one symptom in three of the four following categories:
Vasomotor: temperature/color change or asymmetry
Sudomotor/edema: edema/sweating change or asymmetry
Motor/trophic: decreased range of motion, motor dysfunction, or trophic changes
At least one sign in two or more of the following categories:
Sensory: hyperalgesia (to pinprick) and/or allodynia (to light touch)
Vasomotor: temperature/color asymmetry
Sudomotor: edema/sweating change or asymmetry
Motor/Trophic: decreased range of motion, motor dysfunction and/or trophic changes
There is no other diagnosis that better explains the signs and symptoms
The purpose of treatment of CRPS in DRFs is to restore the affected upper extremity within the acceptable mobility and durability requirements. There are many treatment modalities to treat CRPS, most with poor supporting evidence. Treatments such as bisphosphonates, N -acetylcysteine, glucocorticoids, calcitonin, pregabalin, gabapentin, antidepressant, antiepileptic drugs, clonidine, epidural infusion systems, and neurostimulation have all been reported yet limited studies exist. However, there has been extensive research regarding the role of vitamin C in the treatment of CRPS in patients with DRFs as well as literature regarding the role of physical therapy and cognitive behavioral therapy. These latter treatment modalities will be the focus of this chapter.
How can CRPS type-1 be effectively prevented, diagnosed, and/or treated in patients with DRF?
The diagnosis of CRPS remains challenged and debated because of its lacking objectifiable character and etiologic understanding. Several treatment modalities have been offered over the years to treat CRPS following DRF, most with poor supporting evidence. There is an ongoing debate, accompanied by high quality evidence, about the role of Vitamin C in the prevention of CRPS. Other areas of controversy relate to the role of physical therapy with behavioral components in the treatment of CRPS and if there is an association between the distal radius fixation method to the occurrence of CRPS. Additionally, in recent years, a paradigm shift among surgeons has developed to find the culprit of the pain and offer surgical treatment. This paradigm shift is currently supported mainly by expert opinion and case series.
Finding the Evidence
The search was conducted in MEDLINE via PubMed and the Cochrane library. The search terms were broad and included the intervention (“vitamin C,” “physiotherapy,” “physical therapy,” “psychotherapy,” “cognitive behavioral therapy,” “nerve block,” “cast,” “external fixation,” “open reduction internal fixation”), population (“wrist fracture,” “distal radius fracture”), and disease of interest [“complex regional pain syndrome (or CRPS),” “reflex sympathetic dystrophy (or RSD),” “Sudeck’s atrophy”]. Additionally, we searched for review articles of CRPS in DRF using the general terms “distal radius fracture” and “CRPS.” No time limits were set. The reference list of the review articles and metanalyses retrieved were additionally reviewed to identify other papers not included in our other broader search.
Quality of Evidence
We attempted to limit our examination to level I or II prospective randomized trials and metanalyses. However, to better define the role of surgery in the treatment of CRPS, we included several case series.
Level I—4 randomized controlled trials, 5 systematic review and metanalysis.
Level II—3 randomized controlled trials with methodological limitations.
Level III—5 case series.
Prevention of CRPS in Patients With DRFs With Prophylactic Vitamin C Treatment
Vitamin C, a free radical scavenger, was proposed as a treatment to address the prevailing theory that CRPS was caused by free oxygen radicals released at the time of injury. Zollinger et al. performed two level I randomized controlled trials touting the beneficial effects of vitamin C in the prevention of CRPS and in fact, their studies contributed to the 2009 AAOS recommendation supporting its routine use in DRFs.
In their first study in 1999, 115 patients with DRFs treated with cast immobilization were randomized to receive either 500 mg of vitamin C daily or placebo for 50 days starting on the first day of fracture. CRPS was defined by clinical symptoms ( Table 1 ). The authors reported a statistically significant advantage for vitamin C at 1-year follow-up with 22% of patients treated with the placebo being diagnosed with CRPS as compared to 7% in the vitamin C treatment group. Other statistically significant factors associated with CRPS in the study were fracture comminution (odds ratio 0.09, P = 0.0037) and compliance with the plaster immobilization (odds ratio 0.1, P = 0.0002).
|Author||Study Design and Number of Participants||Intervention||Definition of CRPS||Occurrence of CRPS at 1 Year Follow Up, n (%)||Other Outcome Measures||Authors Recommendation for Use of Vitamin C in Prevention of CRPS|
|Zollinger (1999)||Prospective RCT, n = 123||500 mg of Vit C vs placebo on fracture occurrence for 50 days with 1 year follow up||4/6 Symptoms: unexplained diffuse pain; difference in skin temperature relative to the other arm; difference in skin color; diffuse edema; limited range of motion; increase of these symptoms after activity.||Placebo: 14 (22%) |
500 mg Vit C: 4 (7%), P < 0.05
|Yes—Vitamin C is effective in CRPS prevention|
|Zollinger (2007)||Prospective RCT, n = 416||200, 500, or 1500 mg of Vit C vs placebo on fracture occurrence for 50 days with 1 year follow up||4/5 Symptoms: unexplained diffuse pain; difference in skin temperature; difference in skin color; diffuse edema; limited range of motion; increase of these symptoms after activity.||Placebo: 10 (10.1%) |
200 mg Vit C: 4 (4.2%), NS
500 mg Vit C: 2 (1.8%), P = 0.007
1500 mg Vit C: 2 (1.7%), P = 0.005
|Yes—Vitamin C is effective in CRPS prevention|
|Ekrol (2014)||Prospective RCT, n = 336||500 mg of Vit C vs placebo on fracture occurrence for 50 days with 1 year follow up||Atkins criteria, 3/5 symptoms: neuropathic pain, vasomotor instability and abnormalities of sweating, swelling, loss of joint mobility, and joint and soft-tissue contractures.||Placebo: 14 (8.3%) |
500 mg Vit C: 14 (8.2%), P = 1
|Placebo : |
Grip deficit: 13.9%
Pain at use (VAS): 1.1
500 mg Vit C :
Grip deficit: 16.9%
Pain at use (VAS): 1.8
|No—Vitamin C has no effect in CRPS prevention|
|Ӧzkan (2019)||Prospective RCT, n = 134||500 mg of Vit C vs placebo within 2 weeks of fracture occurrence for 50 days with 6 months follow up||Objective measurements only: |
Distance of fingers to palmar crease (DTPC); function (PROMIS); pain (NRS)
|N/A||At 6 weeks no association of Vit C to DTPC (RC -0.23, P = 0.7) at 6 months no association to PROMIS (RC, − 0.21, P = 0.9) or NRS (RC, 0.31, P = 0.5)||No—Vitamin C does not facilitate recovery from distal radius fracture|
Subsequently, Zollinger et al. sought to examine the dose-response of vitamin C on patients with DRFs. Three hundred and seventeen patients were equally randomized to receive 200, 500, or 1500 mg of vitamin C per day while 99 patients received pacebo. The prevalence of CRPS in the placebo group was 10.1% as compared to 2.4% in the vitamin C groups ( P = 0.0002). In the sub-analysis of vitamin C dosage, the prevalence of CRPS was 4.2% in the 200 mg group (NS), 2% in the 500 mg group ( P = 0.007) and 2% in the 1500 mg group ( P = 0.005). Patients receiving 200 mg of vitamin C did not differ significantly from the placebo group. Other factors associated with higher rates of CRPS were female gender and older age. In conclusion, the authors reported that a vitamin C dose of 500 mg for 50 days after the fracture was sufficient for the prevention of CRPS.
However, two further randomized prospective trials performed by other groups could not reproduce these beneficial effects ( Table 1 ). In 2014, Ekrol et al. published their randomized controlled trial examining the effects of vitamin C by allocating 167 patients to the placebo group and 169 patients to the vitamin C group. Study design was similar to the protocol described by Zollinger et al. original paper with 500 mg of vitamin C or placebo for 50 days after the day of fracture with follow-up of 1 year. The primary outcome of interest was DASH (Disability of the Arm, Shoulder and Hand) score and secondary outcomes were complications, wrist and finger motion, grip strength, pain, and CRPS score. CRPS was defined using Atkins Criteria ( Table 1 ) requiring three positive symptoms of five: (1) neuropathic pain; (2) vasomotor instability and abnormalities of sweating; (3) swelling; (4) loss of joint mobility; and (5) joint and soft-tissue contractures.
The authors found no effect of vitamin C on the DASH score throughout the study period and the prevalence of CRPS was significantly higher at 6 weeks for patients treated with vitamin C. Additionally, at 26 weeks, the vitamin C group had significantly more complications and greater pain with wrist use. The authors concluded that there was no difference in functional outcome or any other objective measurement between patients treated with vitamin C or placebo. Interestingly, the authors reported a strong correlation between the functional outcome after distal radius fracture to the patient baseline level of anxiety (measured with the Hospital Anxiety and Depression Score).
The most recent study demonstrating discrepancy with initial positive reports was published in 2019 by Ӧzkan et al. The authors measured finger stiffness as a surrogate for CRPS as well as Patient-Reported Outcomes Measurement Information System (PROMIS) and pain scores with the numeric rating scale (NRS-pain) rather than dichotomizing the outcome of CRPS-based on subjective criteria. One hundred and thirty-four patients were equally randomized to receive 500 mg of vitamin C or placebo within 2 weeks of the fracture. At 6 weeks follow-up, patients were assessed for finger stiffness using the finger pulp to palmar crease distance and assessed for pain and function with NRS and PROMIS questionnaires, respectively. At 6 months follow-up, patients were assessed with the NRS and PROMIS questionnaires. They found that the administration of vitamin C was not associated with improved finger stiffness, range of motion, pain or function at 6 weeks or 6 months. Based on their findings and the paper by Ekrol et al., the authors concluded that vitamin C had no clinically important effect on pain intensity and upper extremity limitations.
A metanalysis of these conflicting studies, excluding the most recent paper by Ӧzkan et al. which only considered a surrogate of CRPS, finger stiffness, and not CRPS scores, was published in 2017. The authors found that the relative risk of CRPS after a DRF was not significantly diminished in the group given vitamin C with any dosage. However, when the analysis was confined to a dose of 500 mg of vitamin C, the relative risk for CRPS was 0.54 (0.33–0.91; P = 0.02). As a result, the authors concluded that vitamin C supplementation at a dose of 500 mg for 50 days may halve the risk of CRPS within the first year after fracture but recommended that further research is necessary to establish the effectiveness of the treatment. Another metaanalysis of the same three studies concluded that the evidences are conflicting and did not demonstrate a significant effect of vitamin C. The authors recommended that the decision to treat with vitamin C should be guided by patient preference and clinical expertise.
Is There a Correlation of CRPS to the DRF Fixation Technique?
Several fixation methods have been implicated as contributors to the development of CRPS in patients with DRFs. A poorly applied plaster cast may facilitate compartment syndrome, pressure ulcers, joint contracture, nerve damage, and chronic pain. Similarly, wrist spanning external fixation has been suggested to cause nerve damage because of proximal pin malposition while chronic pain and joint stiffness may result in cases of wrist joint overdistraction secondary to wrist spanning external fixators.
Wang et al. performed a network metaanalysis to compare 7 different treatment methods of fixation for DRFs and their effect on the development of CRPS. He included 17 RCTs in his metaanalysis with 1658 DRF patients treated with wrist spanning external fixation, nonspanning external fixation, K-wire fixation, plaster fixation, dorsal plating, volar plating, or dorsal and volar plating. They found no marked difference in CRPS risk between all treatment options. This network metaanalysis also ranked the association of the seven treatment methods to CRPS as follows: plaster fixation, nonspanning external fixation, spanning external fixation, dorsal plating, volar plating, dorsal and volar plating and K-wire fixation. Consequently, they reported that plaster fixation and nonspanning external fixation were most effective in reducing the risk of CRPS in DRF patients.
What Is the Role of Surgery for Treatment of CRPS
Many hand surgeons are reluctant to operate on patients that develop disproportionate pain following injury or surgery as they doubt surgery can improve the pain and even more worrisome is the concern of worsening the pain. However, in recent years, a paradigm shift in the surgical approach for CRPS is being led by prominent hand surgeons who believe that most cases classified as CRPS are actually caused by an underlying pathology that was overlooked. Under this premise, proper surgical treatment is advocated as a method to improve the disproportionate pain experienced by patients with CRPS, rather than rendering a suffering patient to prolonged and, at times, futile treatment in the pain clinic.
Such overlooked diagnoses that may induce severe pain were categorized by Del Piñal as unstable fractures, malreduced fractures, occult painful tumors (such as glomus tumors), and dysvascular states. However, the most overlooked diagnosis that may be surgically treated is subclinical nerve compression and injury. These irritative nerve injuries will present differently than classical carpal tunnel or cubital tunnel syndrome and in 66% of cases, negative findings will be present on nerve conduction studies. However, large case series demonstrated significant pain reduction in 99% of patients who received nerve decompression surgeries, mainly carpal tunnel release, yet were previously diagnosed with CRPS. Dellon et al. reported on 100 patients diagnosed with CRPS for whom 80% had an underlying nerve injury or compression that responded to surgery. Dellon recommended that the initial step to determine treatment success was the presence of pain reduction following a nerve block of the suspected compressed or injured nerve. Treatment is dependent on nerve injury and ranges from simple decompression, neuroma resection, nerve graft or joint denervation. Jupiter et al. also advocated for coverage of the injured nerve with vascular tissue in the form of a local vascular flap.
The Role of Local Anesthetic Sympathetic Blockade for Treatment of CRPS
Local and intravenous anesthetic has been used for the treatment of CRPS in patients with DRFs. Early results from small case series appeared promising. Paraskevas et al. reported treating 17 patients with CRPS with intravenous regional sympathetic block (Bier’s block) sessions with guanethidine and lidocaine. All of the patients had complete disappearance of pain and return to normal function and movement of the extremity.
However, Livingstone et al. performed a randomized control trial of 57 patients with CRPS 9 weeks following DRF. Patients received either intravenous regional blockade with 15 mg of guanethidine, a local anesthetic, or intravenous saline. They found no significant difference in finger tenderness, stiffness, or grip strength between the two groups. However, the guanethidine group experienced more pain in the affected hand ( P = 0.025) and at 6 months, had more vasomotor instability ( P < 0.0001). The authors concluded that intravenous regional blockade with guanethidine is not effective and may even delay the resolution of vasomotor instability.
Livingstone et al. finding are further supported by a recent Cochrane review of CRPS treatment with local anesthetic. Twelve studies with 461 patients with CRPS, not confined to DRF patients, were reviewed. The authors found no evidence to support the effectiveness of local anesthetic blockade in the treatment of CRPS and therefore, did not endorse its use.
What Is the Role of Physical Therapy and Behavioral Therapy for Treatment of CRPS in Patients With DRFs?
There is a large variety of physiotherapy interventions recommended as part of the multimodal treatment of CRPS; however, very little evidence exists to support their use. The following interventions have been described for the treatment of CRPS and may be used as stand-alone treatments or in combination: manual therapy (e.g., mobilization, manipulation, massage, desensitization), therapeutic exercise and progressive loading regimens (including hydrotherapy), adjunctive modalities [e.g., contrast baths, transcutaneous electrical nerve stimulation (TENS), therapeutic ultrasound, shortwave diathermy, laser], physiotherapist-administered education (e.g., pain neuroscience education), as well as cortically directed sensory-motor rehabilitation strategies [e.g., graded motor imagery (GMI), mirror therapy (MT), sensory motor retuning, tactile discrimination training].
Mirror therapy is based on the mirror image of the healthy extremity being seen in place of the affected extremity while exercises are performed in both extremities. Graded motor imagery (GMI) is a multidimension movement representation technique that includes three interventional phases: (1) Limb laterality recognition; (2) Explicit motor imagery; and (3) Mirror therapy ( Fig. 3 ). These physical therapy approaches are the only approaches supported by prospective controlled studies. Moseley et al. published two small prospective trials on treatment of CRPS following DRF with GMI. In his 2004 paper, Moseley et al. randomized 13 patients with chronic CRPS following DRF to receive either 6 weeks of GMI or 12 weeks or physiotherapy. He reported statistically significant improvement in pain at 6 weeks follow-up with three patients needed to treat to obtain a 50% reduction in pain (NNT = 3).