BEVERWIJK, The Netherlands—A daily 500 mg dose of vitamin C given for 50 days after wrist fracture can significantly reduce the risk of subsequent complex regional pain syndrome (CRPS) type I (formerly known as reflex sympathetic dystrophy), Dutch researchers report in The Journal of Bone and Joint Surgery.1

 

"[W]e recommend the administration of 500 mg of vitamin C daily for 50 days after a wrist fracture because we believe that such treatment may prevent complex regional pain syndrome. Whether vitamin C can also be used as a treatment for complex regional pain syndrome should be the subject of further study," writes lead author P. E. Zollinger, MD, with the department of orthopaedic surgery at Ziekenhuis Rivierenland, in Tiel, The Netherlands. Three hospitals in The Netherlands participated in the study.

Double-blind, prospective, multicenter trial

The investigators randomized 317 patients with 328 fractures to receive vitamin C 200 mg (n = 96), 500 mg (n = 114), or 1500 mg (n = 118), and 99 patients with 99 fractures to receive a placebo. Treatment began on the day of fracture and continued for 50 days. Patients were evaluated after 1 week, at the time of cast removal, and at 6 or 7, 12, and 26 weeks. After 1 year patients were interviewed by telephone or letter.

The primary endpoint was the presence of CRPS at any time within 1 year after the fracture. CRPS was defined as four of the following five symptoms present at the wrist, hand, or fingers, and occurring or increasing after activity: unexplained diffuse pain, a difference in skin color relative to the other hand and wrist, diffuse edema, a difference in skin temperature relative to the other hand and wrist, or limited range of motion of the wrist and fingers unrelated to the stage of fracture treatment [Table 1].


Table 1. Diagnostic Criteria for CRPS Following Wrist Fracture

CRPS is diagnosed if the patient meets four of the following five criteria:

l        Unexplained diffuse pain not normal in relation to the stage of fracture treatment

l        A difference in skin color relative to the other hand and wrist

l        Diffuse edema

l        A difference in skin temperature relative to the other hand and wrist

l        Limited range of motion of the wrist and fingers unrelated to the stage of fracture treatment
Source: Adapted from Zollinger et al.1

At 1 year, the prevalence of CRPS was 10.1% in the placebo group, 4.2% in the 200-mg vitamin C group (P = NS), 1.8% in the 500-mg group (P = .007), and 1.7% in the 1500-mg group (P = .005). "Overall, there was a significant difference between the vitamin C group and the placebo group (relative risk, 0.24; 95% confidence interval, 0.10-0.60; P = .002)," Dr. Zollinger reports [Table 2].

 

Table 2. Effect of Postfracture Vitamin C or Cast Complaints on Risk of CRPS After Wrist Fracture

 

Intervention or Symptom

Odds Ratio for CRPS

P

Vitamin C overall

0.22

0.020

Vitamin C 200 mg

0.38

0.122

Vitamin C 500 mg

0.14

0.014

Vitamin C 1500 mg

0.16

0.022

Cast-related complaints

5.73

0.001

The investigators also found that early complaints related to the plaster cast predicted the occurrence of CRPS. "We found that complaints related to the use of the plaster cast were strongly predictive of the development of complex regional pain syndrome. This finding has been described in previous studies and should alert physicians who treat fractures with a plaster cast."

"The present study confirms that vitamin C can have an inhibiting effect on the occurrence of complex regional pain syndrome after wrist fractures," the researchers conclude.

According to Dr. Zollinger, this trial was inspired by research in patients who have suffered major trauma or burns. In such cases, it is thought that the ability to sustain homeostasis can be overwhelming, leading to a syndrome of systemic inflammatory response and multiple-organ distress. There may be a parallel between the inflammatory reaction and microangiopathy of CRPS that develops after burns and wrist fractures. "Complex regional pain syndrome and burn wounds may involve a cascade of deterioration and exaggeration of a similar process," the investigators say. Attempts to right this balance have included ascorbic acid given during the first 24 hours of burn resuscitation, which significantly reduces resuscitation fluid volume requirements and wound edema, according to Dr. Zollinger.

The underlying mechanism is thought to involve increased vascular permeability. "Vitamin C reduces lipid peroxidation, scavenges hydroxyl radicals, protects the capillary endothelium, and inhibits vascular permeability," Dr. Zollinger explains.

Little downside, worth trying

"This is definitely worth trying. The downside is minimal," Scott S. Reuben, MD, with the department of anesthesiology at Baystate Medical Center, in Springfield, Massachusetts, told CIAOMed. "This study as well as the studies published previously2,3 have documented the efficacy of vitamin C for preventing complex regional pain syndrome. The hypothesis is that toxic oxygen radicals are produced, resulting in an increased incidence of complex regional pain syndrome."

References

1. Zollinger PE, Tuinebreijer WE, Breederveld RS, et al. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007;89:1424-1431.
2. Zollinger PE, Tulnebreijer WE, Kreis RW, et al. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999;354:2025-2028.
3. Yilmaz C, Erdemli E, Selek H, et al. The contribution of vitamin C to healing of experimental fractures. Arch Orthop Trauma Surg. 2001;121:426-428.