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Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures?A Randomized, Controlled, Multicenter Dose-Response Study
P.E. Zollinger, MD1; W.E. Tuinebreijer, MD, PhD, MSc, MA2; R.S. Breederveld, MD, PhD3; R.W. Kreis, MD, PhD3
1 Department of Orthopaedic Surgery, Ziekenhuis Rivierenland, President Kennedylaan 1, 4002 WP Tiel, The Netherlands. E-mail address: PE.Zollinger@tiscali.nl
2 Relweg 59, 1949 EC Wijk aan Zee, The Netherlands
3 Departments of Surgery (R.S.B., R.W.K.) and Burn Wounds (R.W.K.), Red Cross Hospital, Vondellaan 13, 1942 LE Beverwijk, The Netherlands
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Stichting Achmea Slachtoffer en Samenleving (SASS). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Department of Surgery, Red Cross Hospital, Beverwijk, The Netherlands; the Department of Orthopaedics and Surgery, Haga Hospital (Leyenburg), The Hague, The Netherlands; and the Department of Orthopaedics and Surgery, Reinier de Graaf Group, Delft, The Netherlands

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Jul 01;89(7):1424-1431. doi: 10.2106/JBJS.F.01147
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Abstract

Background: Complex regional pain syndrome type I is treated symptomatically. A protective effect of vitamin C (ascorbic acid) has been reported previously. A dose-response study was designed to evaluate its effect in patients with wrist fractures.

Methods: In a double-blind, prospective, multicenter trial, 416 patients with 427 wrist fractures were randomly allocated to treatment with placebo or treatment with 200, 500, or 1500 mg of vitamin C daily for fifty days. The effect of gender, age, fracture type, and cast-related complaints on the occurrence of complex regional pain syndrome was analyzed.

Results: Three hundred and seventeen patients with 328 fractures were randomized to receive vitamin C, and ninety-nine patients with ninety-nine fractures were randomized to receive a placebo. The prevalence of complex regional pain syndrome was 2.4% (eight of 328) in the vitamin C group and 10.1% (ten of ninety-nine) in the placebo group (p = 0.002); all of the affected patients were elderly women. Analysis of the different doses of vitamin C showed that the prevalence of complex regional pain syndrome was 4.2% (four of ninety-six) in the 200-mg group (relative risk, 0.41; 95% confidence interval, 0.13 to 1.27), 1.8% (two of 114) in the 500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.77), and 1.7% (two of 118) in the 1500-mg group (relative risk, 0.17; 95% confidence interval, 0.04 to 0.75). Early cast-related complaints predicted the development of complex regional pain syndrome (relative risk, 5.35; 95% confidence interval, 2.13 to 13.42).

Conclusions: Vitamin C reduces the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

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    Paul E. Zollinger, M.D.
    Posted on September 06, 2007
    Dr. Zollinger et al. respond to Dr. Rogers.
    Ziekenhuis Rivierenland, Tiel, The Netherlands

    We thank Drs. Rogers and Ricketts for their attention and comments. They are right about the citation of Kearns et al.(1) that rats were used in their study. However, in the discussion, the steady state level of vitamin C in humans is mentioned. We wanted to combine the article of Kearns et al.(1) with his citation of the earlier results from Levine et al.(2), but it would have been better to mention them separately. Furthermore it does not give the credit Levine at al.(2) deserve. We do apologize for this.

    Monitoring plasma levels is a very good suggestion, but it would introduce an invasive component to our study, which might frighten volunteers to participate. It is difficult to take blood samples for the analysis of the placebo blood counts. The intention to treat principle stands, even if patients do not take their trial medicine, and these results have to be valued as input to the study as well. We believe that non-compliance gives an underestimation of the vitamin C effect!

    The criteria to diagnose CRPS are under debate all over the world, but not any more in the Netherlands. Here a multidisciplinary scientific committee(3) chose the criteria of Veldman(4) (and for research purposes in addition those of the IASP and Bruehl(5). This means that the studies and results of Atkins et al.(6,7) are not taken into account here. We appreciate Atkins’ liberal way of diagnosing CRPS and this would even give more strength to our own study, but the trend in the Netherlands is to use the criteria of the world’s largest described population (N=829) by Veldman and Goris.(4).

    The actual diagnosis of CRPS was not made over telephone but rather in the outpatient clinic according to the described scheme of planned controls. The telephone inquiry after one year was to make sure that not one patient with CRPS type I had escaped from our attention. The telephone inquiry provided no indication that any patient had been missed; no patient had to be called back for extra physical examination (but would have, if necessary).

    Randomization assures that there will be equality of the groups that are compared. Confounding factors might exist but adequacy of fracture reduction is not one of them according to this and our earlier study in the Lancet(8). This point has been mentioned in our previous letter. A difference in compliance is ruled out by the randomization as well.

    Once again we must state that our study did not investigate the effect of physiotherapy in patients with CRPS, but was a search for the incidence and probable prophylaxis of CRPS in trauma patients with a wrist fracture.

    References:

    1. Kearns SR, Moneley D, Murray P, Kelly C, Daly AF. Oral vitamin C attenuates acute ischaemia-reperfusion injury in skeletal muscle. J Bone Joint Surg Br 2001;83:1202-1206.

    2. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci USA, 1996;93:3704-9.

    3. Guidelines Complex Regional Pain Syndrome type I. 2006, The Netherlands Society of Rehabilitation Specialists. ISBN-10: 90-8523-124-8; ISBN-13:978-90-8523-124-0. http://www.posttraumatischedystrofie.nl/ pdf/CRPS_I_Guidelines.pdf

    4. Veldman PH, Reynen HM, Amtz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342:1012-6.

    5. Bruehl S. Harden RN, Galer BS, Saltz S. Bertram M, Backkonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain. 1999;81:147-54.

    6. Atkins RM, Duckworth T, Kanis JA. Algodystrophy following Colles' fracture. J Hand Surg Br. 1989;14:161-4.

    7. Atkins RM, Duckworth T, Kanis JA. Features of algodystrophy after Colles' fracture. J Bone Joint Surg Br. 1990;72:105-10.

    8. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomized trial. Lancet 1999;354:2025-8.

    Benedict A. Rogers, MA, MSc, MRCS
    Posted on August 01, 2007
    Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures?
    The Princess Royal Hospital, Haywards Heath, UK

    To The Editor:

    We read with interest the paper by Zollinger et al. (1) and we would like to make the following points:

    The paper cites Kearns et al.(2) to provide the value of a steady state level of ascorbic acid (vitamin C) with doses of 200mg per day. However, Kearns’ studies used Sprague-Dawley rats. The muscles were analysed after three hours of ischaemia and one hour of re-perfusion. We are not convinced that these data can be used to accurately determine the steady state level of vitamin C in humans.

    Instead, we feel monitoring of plasma vitamin C levels would have been very useful in Zollinger’s study for many reasons. Such monitoring would detect non-compliance in taking the medication. This was likely to have occurred in the elderly female group studied(3). It would also have identified those patients who entered this study with vitamin C deficiency and those patients who achieved above normal serum vitamin C levels.

    The criteria used by the authors to diagnosis complex regional pain syndrome (CRPS) were different from those used in other studies(4,5) Thus, it is not surprising that the incidence of CRPS stated in this study differed from previous studies.

    One symptom (pain) and four signs (skin colour, oedema, skin temperature and limited range of movement) were listed as diagnostic criteria for CRPS. It would have been difficult to assess these signs over the telephone at the final one year assessment as described.

    There are many confounding factors that could have affected the outcomes in the different groups. We suggest the differing groups studied need to be corrected for the following variables: the adequacy of fracture reduction or surgical treatment; the compliance rate, known to be low in the elderly (3); and the different treatment rates for the different groups studied. (Treatment e.g. physiotherapy, pain clinic treatment) improves outcome after CRPS(6&7).

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    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. Kearns SR, Moneley D, Murray P et al. Oral vitamin C attenuates acute ischaemia-reperfusion injury in skeletal muscle. J Bone Joint Surg Br 2001;83:1202-1206.

    3. McElnay JC, McCallion CR, al-Deagi F et al. Self-reported medication non-compliance in the elderly. Eur J Clin Pharmacol 1997;53:171-178.

    4. Atkins RM, Duckworth T, Kanis JA. Algodystrophy following Colles' fracture. J Hand Surg [Br] 1989;14:161-164.

    5. Atkins RM, Duckworth T, Kanis JA. Features of algodystrophy after Colles' fracture. J Bone Joint Surg Br 1990;72:105-110.

    6. Burton AW, Hassenbusch SJ, III, Warneke C et al. Complex regional pain syndrome (CRPS): survey of current practices. Pain Pract 2004;4:74- 83.

    7. Mak PH, Irwin MG, Tsui SL. Functional improvement after physiotherapy with a continuous infusion of local anaesthetics in patients with complex regional pain syndrome. Acta Anaesthesiol Scand 2003;47:94- 97.

    Paul E. Zollinger, M.D.
    Posted on July 15, 2007
    Dr. Zollinger et al. respond to Dr. Frolke.
    Ziekenhuis Rivierenland, Tiel, The Netherlands

    We read the letter of our colleague, Dr.Frölke, with great interest. First, we do not agree with the title of his letter; on the basis of our study, we believe that Vitamin C does prevent CRPS! Unfortunately most of his comments do not apply to our study.

    The number of enrolled patients in our study in relation to the eligible patients was mentioned in the Discussion of our article. The quality of reduction was studied in this paper and in our publication in Lancet(1) as well. In both studies there was no relation between the occurrence of CRPS and the need to undergo fracture reduction. Moreover, the quality of reduction did not influence the chance of developing CRPS. We performed the current study because, to our knowledge, there have been no published studies since 1999 (1) that either confirm or refute our original findings.

    To our knowledge, no prospective study has ever demonstrated an association between the prevalence of CRPS and the quality of reduction. Retrospective studies do not have the level of evidence which is needed. Frölke et al. make a misjudgement by citing the article of Arora et al.(2). Arora et al. found 5 patients with CRPS type I out of 114 patients studied for 1 year and 3 patients with a CRPS type II. Thus, the incidence for CRPS type I in their study is 4.38% (and not the 3.5% as stated in Dr. Frolke's letter)and is higher than our overall prevalence of 4.2%; it stands in contrast with the 2.4% for all of our vitamin C treated patients. The difference is even more striking with the prevalence of only 1.8% for the group receiving 500 mg of Vitamin C and 1.7% for the 1500 mg group.

    Why the articles of Rowbotham (3), Oerlemans(4) and Sherry(5) are cited is unclear to us. Our study is about the possible prevention of CRPS after a wrist fracture in adults with a prophylactic dose of vitamin C and not about the therapy of CRPS itself. The endpoint of our study was defined as the presence of CRPS at any time within one year of the fracture (see study design). The article of Rowbotham et al(3). deals with pharmacotherapy in patients with CRPS.

    The article of Oerlemans et al(4). is a very well respected trial of adjuvant physical therapy versus occupational therapy in patients with CRPS. So here lies the difference with our fracture patients. If we had treated our patients with physical therapy as well, we would have created our own confounding factor. Skeptics would have challenged our conclusions and pointed to the positive effect of the physical therapy rather than to the effect of vitamin C, as Dr. Frölke does now.

    When patients who sustain a wrist fracture develop CRPS, they are, of course, treated with physical therapy and medication, if necessary.(6) The article by Sherry et al (5). deals with the outcome in children with CRPS after exercise therapy. However, we believe that CRPS in children is a completely different entity than CRPS in adults, and so is the approach to its treatment. This was confirmed by Wilder et al.(7) who reminded us that in children, CRPS most often involves the lower extremity (61/70=87%) in contrast to adults who have more upper extremity CRPS. The therapies used by Sherry et al.(5) consisted of aerobic functionally directed exercises, hydrotherapy, and desensitization. Which therapy achieved the desired outcome? Can it get more confounding than this?

    References:

    1. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomized trial. Lancet 1999;354:2025-8.

    2. Arora R, Lutz M, Hennerbichler A, Krappinger D, Espen D, Gabl M. Complications following internal fixation of unstable distal radius fracture with a palmar locking-plate. J Orthop Trauma. 2007;21:316-22.

    3. Rowbotham MC. Pharmacologic management of complex regional pain syndrome. Clin J Pain. 2006;22:425-9.

    4. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999;83:77–83.

    5. Sherry DD, Wallace CA, Kelley C, Kidder M, Sapp L. Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain. 1999;15:218-23.

    6. Guidelines Complex Regional Pain Syndrome type I. 2006, The Netherlands Society of Rehabilitation Specialists. ISBN-10: 90-8523-124-8; ISBN-13:978-90-8523-124-0. http://www.posttraumatischedystrofie.nl/ pdf/CRPS_I_Guidelines.pdf

    7. Wilder RT, Berde CB, Wolohan M, Vieyra MA, Masek BJ, Micheli LJ. Reflex sympathetic dystrophy in children. Clinical characteristics and follow-up of seventy patients. J Bone Joint Surg Am. 1992;74:910-9.

    Jan Paul M. Frölke
    Posted on July 11, 2007
    Vitamin C does not prevent CRPS
    University Medical Center St Radboud Nijmegen, The Netherlands

    To The Editor:

    In the article "Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study," Zollinger et al.(1) studied the prophylactic effect of vitamin C on the incidence of complex regional pain syndrome (CRPS) in 416 patients with wrist fractures. They concluded that vitamin C is indeed effective and they recommend giving 500 mg of vitamin C daily for fifty days to each patient with a wrist fracture to prevent CRPS.

    Some limitations of this study mentioned in the article include a large selection bias (2137 eligible patients of which 416 enrolled) and a low event rate due to an unexpected low prevalence of CRPS (4,2% against 22%). This means that only 18 (8/328 in the treatment group and 10/99 in the placebo group) fulfilled the criteria for CRPS. One patient with fractures of both wrists developed CRPS on one side where the fracture turned out to be badly reduced. The other side healed without complications. This example points out dramatically how this study demonstrates a strong confounder: although the number of fractures needing reduction is equal in both groups, the quality of the reduction has not been mentioned.

    Wrist fractures treated with open reduction and internal fixation generally achieve a better reduction than closed reduction and casting. Retrospective studies of surgically treated wrist fractures therefore report a lower incidence rate of CRPS of around 3,5%(2). No prospective study has ever demonstrated an association between the incidence of CRPS and the quality of reduction, but pain syndromes in general occur more frequently when fractures are not adequately reduced.

    Much scientific effort has been invested in prophylaxis and treatment for CRPS by pharmacological means in the past, not leading to clinical recommendations(3). Conservative physical therapy has added some benefit to patients with CRPS(4). Since the introduction of functional and time-contingent ‘pain-exposure’ physical therapy by Sherry in 1999, more reports are to be expected with this approach(5).

    A difference is therefore to be expected in patients with CRPS who are treated by the physical therapist and who are not. In this paper(1) the use of any form of physical therapy is not mentioned, which introduces more doubt about the effectiveness of vitamin C in preventing CRPS.

    The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the author, or a member of his immediate family, is affiliated or associated .

    References:

    1. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999;354:2025-8.

    2. Arora R, Lutz M, Hennerbichler A, Krappinger D, Espen D, Gabl M. Complications following internal fixation of unstable distal radius fracture with a palmar locking-plate. J Orthop Trauma. 2007;21:316-22.

    3. Rowbotham MC. Pharmacologic management of complex regional pain syndrome. Clin J Pain. 2006;22:425-9.

    4. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999;83:77–83.

    5. Sherry DD, Wallace CA, Kelley C, Kidder M, Sapp L. Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain. 1999;15:218-23.

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