CLINICAL CONTEXT: Treatments are not very effective
A systematic review of therapeutic options found 18 randomized controlled studies evaluating possible therapies for CRPS.6 The overall quality of data was low. The authors concluded there was little to no evidence for sympathetic blockade (either via stellate ganglion block or RIS block), radical scavenging with DMSO, prednisolone, acupuncture, or manual lymph drainage. Bisphosphonates and calcitonin, as well as qigong exercises, did show some potential, but data were too limited to draw a firm conclusion.
Guidelines recommend early intervention with physical and psychological therapy, as well as adequate pain control.7
The systematic review also identified 2 studies of preventive interventions. A pilot study of vitamin C (by the authors of the trial that is the subject of this PURL) showed some efficacy.8 An RCT of IV guanethidine found no benefit compared with saline.6
STUDY SUMMARY: Vitamin C reduced the rate of CRPS
This randomized, multicenter, dose-ranging, placebo-controlled trial was performed at 3 hospitals in the Netherlands.1 Any adult (>18 years of age) with a fracture of one or both wrists treated in the emergency departments of these hospitals was invited to participate. During 2001–2004, there were 2137 patients with wrist fractures. Of these, 416 (19.5%) patients (with 427 fractures) were enrolled in the study. The study was double-blinded, and allocation was adequately concealed. There was 100% follow-up of all patients. Of enrolled patients, 82.4% were women, and the average age of all subjects was 62.4 years.
Patients were randomized into 1 of 4 groups: placebo, vitamin C 200 mg daily, vitamin C 500 mg daily, or vitamin C 1500 mg daily for 50 days. Other fracture therapy was undertaken at the discretion of the treating physician. Patients were evaluated at 1 week, 4 or 5 weeks (or cast removal), 6 or 7 weeks, 12 weeks, and 26 weeks. After 1 year, patients were contacted by phone or mail to confirm their status using Veldman’s criteria (TABLE 1).8
TABLE 1
Veldman’s criteria for diagnosis of complex regional pain syndrome, type 1
| Must have 4 of the 5 symptoms below, at the affected hand or wrist, or during activity with that wrist: |
|---|
|
10% of the placebo group had CRPS after 1 year
One year after the fracture, 10% of placebo patients had a diagnosis of CRPS. Rates of CRPS were 4%, 2%, and 2% in the 200 mg, 500 mg, 1500 mg daily dosing of vitamin C, respectively (TABLE 2).
There was no association between the development of CRPS and site of fracture, whether the fracture was displaced or intraarticular, or whether surgical therapy was chosen (although 90% of the fractures were treated with casting). Of note: all of the patients who developed CRPS were female; however, only 75 men were enrolled (18%).
Older patients were at increased risk, and patients with complaints about their cast were substantially more likely to have CRPS (number needed to harm [NNH]=2.6; odds ratio [OR]=5.73; 95% confidence interval [CI], 2.11–15.57).
TABLE 2
Rates of complex regional pain syndrome at 1 year: 10% placebo, 2.4% vitamin C
| TREATMENT GROUP | PERCENT WITH CRPS | RR (95% CI ) | ARR | NNT |
|---|---|---|---|---|
| Placebo | 10% | |||
| Vitamin C | ||||
| All doses combined | 2.4% | 0.24 (0.10–0.60) | 0.076 | 13 |
| 200 mg | 4% | 0.41 (0.13–1.27) | 0.06 | 17 |
| 500 mg | 2% | 0.17 (0.04–0.77) | 0.08 | 13 |
| 1500 mg | 2% | 0.17 (0.04–0.75) | 0.08 | 13 |
| CRPS, complex regional pain syndrome; RR, relative risk; CI, confidence interval; ARR, absolute risk reduction; NNT, number needed to treat. | ||||
| Source: Zollinger et al, 2007.1 | ||||
WHAT’S NEW?: Effective dose: 500 mg/d vitamin C for 50 days
Vitamin C at a dose of at least 500 mg/day for 50 days reduced the rate of CRPS from 10% to 2% (number needed to treat [NNT]=13). This is the second study undertaken by the same investigators to demonstrate risk reduction.8 The previous study enrolled only 129 patients, but found an absolute risk reduction of 15% (NNT=7; P<.05) for patients taking 500 mg of vitamin C.
Patients who complained about their casts were at substantially higher risk of being diagnosed with CRPS (OR=10.0; 95% CI, 2.9–33), suggesting that cast complaints may be a harbinger.
The more recent study was also designed to determine the effective dose for vitamin C. Doses of 200 mg daily reduced the risk, but the effect was not statistically significant. The effect size for the 500 mg and 1500 mg doses, on the other hand, were essentially identical, and both statistically and clinically significant.1
