CRPS series: Vitamin C a look at the evidence.

Complex Regional Pain Syndrome (CRPS) is commonly associated with an injury of the extremities. In CRPS type I, the most common is a fracture of the hand or foot complex. In the upper limb (which has a higher prevalence of CRPS) an uncomplicated radial fracture would normally take around 6-8 weeks to heal (if no pre-morbid factors such as smoking were apparent). Some individuals go on to develop CRPS and whilst some see a resolution in their symptoms and function within a year, a portion continue to live with (worsening) symptoms beyond one year (Bean, Johnson, Heiss-Dunlop, & Kydd, 2016). There appears to be clinical consensus that early intervention is the key to treatment for CRPS, and that reductions in visible symptoms in the first 6 months from diagnosis show people tend to recover better overall (Bean et al., 2016; Miller, Williams, Heine, Williamson, & O ’connell, 2017).

In the case where CRPS develops following a fracture or surgery, prevention is an attractive idea and trials using Vitamin C have been conducted. A CRPS type I task force has developed evidence based guidelines identifying that Vitamin C could reduce CRPS incidence if treated from the date of injury (Perez et al., 2010). Interestingly, this may be difficult to determine as we don’t know who will go on to develop CRPS. Well that might not be entirely true. There is only one piece of research that I am aware of by Moseley et al., (2013). His team found that intense pain soon after wrist fracture was a strong predictor for developing CRPS. To date, I am not aware of any replication studies and so the recommendations are equivocal.

The evidence based guidelines recommend a 500mg dose of Vitamin C for 50 days to see an improvement in prevention of developing CRPS type I (Perez et al., 2010; Zollinger, Tuinebreijer, Breederveld, & Kreis, 2007). So, the next question on all your lips, “why aren’t we prescribing Vitamin C to all wrist fracture patients and early diagnosis CRPS?” What a great question that is. Before I attempt to answer it I want to discuss what, the reasoning for use and mechanisms behind Vitamin C.

Get your lab coats on it’s time for biochemistry

Vitamin C is an essential nutrient involved in tissue repair and for the development of neurotransmitters. So kinda important.  It is also an antioxidant and antioxidants are molecules that inhibit oxidation of other molecules. Oxidation or Reactive Oxygen Species (ROS) is a chemical reaction that produces free radicals, kind of like the emissions that come from our cars. An antioxidant supports the removal of free radicals by mopping them up.

Ok stay with me on the biochemistry lesson. Vitamin C was first introduced as a potential treatment for CRPS following investigations into its use with burns patients. Similarities were identified in the inflammatory mechanisms between burns patients and CRPS patients. Vitamin C was shown to stop vascular permeability (blood vessels become more leaky in the presence of inflammatory mediators or tissue damage), reduce lipid peroxidation (oxidative degeneration of lipids – lipids and proteins are what make up our cell membranes), and mop up free radicals protecting important cells for tissue healing (Zollinger et al., 2007).

One of the many mechanisms that occur with CRPS is hypoxia (a reduction or deficieny of oxygen to the tissues). This is an example of a ‘stress’ or ‘load’ in the perfusion of tissue. This leads to oxidative stress and oxidative stress results in an imbalance between oxidant and antioxidant levels, increasing the abundance of free radicals. As a result an increase in the abundance of free radicals over prolonged periods can lead to damage of cell structures and the development of chronic disease (Katch, McArdle, & Katch, 2011; Moylan & Reid, 2007). Thus, the understanding behind the use of vitamin C for CRPS is to address the accumulation of free radicals and reduce the permeability of blood vessels thus reducing inflammatory mediators to the injured tissue.

Phew! Here endeth the biochemistry lesson.

So back to that earlier question –

“Why aren’t we prescribing Vitamin C to all wrist fracture patients and early diagnosis CRPS?”

Well, I suspect some of you clever people reading this may have noted that much of the research for Vitamin C into CRPS was around the time the Budapest criteria was being proposed. Interestingly, the paper by Zollinger et al., (2007) entitled ‘Can Vitamin C Prevent Complex Regional Pain Syndrome in Patients with Wrist Fractures?’ is the paper that is referenced in more recent papers about Vitamin C’s efficacy on CRPS (Perez et al., 2010; Shibuya, Humphers, Agarwal, & Jupiter, 2013). Zollinger et al’s paper concluded that ‘Vitamin C reduces the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended.’ Further appraisal of Zollinger’s paper identifies a number of flaws including no indication of the use of Budapest criteria, patients in the intervention group had been taking vitamin supplements prior to the fracture and were not excluded (Vitamin E is an antioxidant) and highlighted in the limitations:

The strength of our conclusion is limited by two issues. First, our two vitamin C studies yielded relative risks with wide confidence intervals, which must be interpreted as a lack of precision, limiting the validity of our conclusion. Second, with vitamin C, we prevented a group of symptoms defined by us as complex regional pain syndrome. Due to the lack of precision with this diagnosis, we cannot be sure that we actually prevented complex regional pain syndrome.

Those are pretty big issues! I would go as far to add that Zollinger’s group may not even have been sure that they were actually treating CRPS!

Prior to the development of the current diagnostic criteria a high percentage of CRPS was being diagnosed, frequently misdiagnosed, which lead to many issues around appropriate treatment and even as far as legal ramifications. As such a revision of the old criteria lead to the updated and current diagnostic criteria for CRPS, the Budapest criteria.

Furthermore, the current understanding of CRPS includes more than one mechanism. Vitamin C is proposed to only have a local effect on the inflammatory component of CRPS. An excellent review by Packham & Holly, (2018) discusses the proposed mechanisms and recommendations for management. Janet Holly recently submitted a guest post here on her paper she co-authored with Tara Packham identifying the mechanisms involved in CRPS.

CRPS is still somewhat of an enigma due to the various mechanisms and the lack of understanding of those mechanisms. There is still ongoing debate as to whether it should be classed as a neuropathic pain condition (Bruehl, 2015). The complex interaction of the mechanisms means that it is a challenging condition to treat. So, it is fair to suggest and all to commonly expressed nowadays that “one size does not fit all” when treating complex pain conditions.

A recent paper by Birklein & Dimova, (2017) has recommended that treatment should be individually tailored based upon the predominant pathophysiology. So, whilst I’m not recommending that we should all rush out and get Vitamin C, it may be that the supplement could have indications if hypoxia and the inflammatory component are the predominant features. In addition, there’s nothing wrong with having a little extra Vitamin C in our diets!

Thanks for having a read.

TNP

References

Bean, D. J., Johnson, M. H., Heiss-Dunlop, W., & Kydd, R. R. (2016). Extent of recovery in the first 12 months of complex regional pain syndrome type-1: A prospective study. European Journal of Pain (United Kingdom), 20(6), 884–894. https://doi.org/10.1002/ejp.813

Birklein, F., & Dimova, V. (2017). Complex regional pain syndrome-up-to-date. PAIN Reports, (e624), 1–8. https://doi.org/10.1136/bmj.h2730

Bruehl, S. (2015). Complex regional pain syndrome. British Medical Journal, 350. https://doi.org/10.1136/bmj.h2730

Katch, V. L., McArdle, W. D., & Katch, F. I. (2011). Training the Anaerobic and Aerobic Energy Systems. In Essentials of Exercise Physiology(4th Editio, pp. 409–442). Lippincott Williams & Wilkins.

Miller, C., Williams, M., Heine, P., Williamson, E., & O ’connell, N. (2017). Current practice in the rehabilitation of complex regional pain syndrome: a survey of practitioners. Disability & Rehabilitation. https://doi.org/10.1080/09638288.2017.1407968

Moseley, G. L., Herbert, R. D., Parsons, T., Lucas, S., Van Hilten, J. J., & Marinus, J. (2013). Intense pain soon after wrist fracture strongly predicts who will develop complex regional pain syndrome: Prospective cohort study. Journal of Pain, 15(1), 1–8. https://doi.org/10.1016/j.jpain.2013.08.009

Moylan, J. S., & Reid, M. B. (2007). Oxidative stress, chronic disease, and muscle wasting. Muscle & Nerve, 35(4), 411–429. https://doi.org/10.1002/mus.20743

Packham, T., & Holly, J. (2018). Mechanism-specific rehabilitation management of complex regional pain syndrome: Proposed recommendations from evidence synthesis. Journal of Hand Therapy, 16–19. https://doi.org/10.1016/j.jht.2018.01.007

Perez, R. S., Zollinger, P. E., Dijkstra, P. U., Thomassen-Hilgersom, I. L., Zuurmond, W. W., Rosenbrand, K. C. J., & Geertzen, J. H. (2010). Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurology, 10(May 2014). https://doi.org/10.1186/1471-2377-10-20

Shibuya, N., Humphers, J. M., Agarwal, M. R., & Jupiter, D. C. (2013). Efficacy and Safety of High-dose Vitamin C on Complex Regional Pain Syndrome in Extremity Trauma and Surgery-Systematic Review and Meta-Analysis. Journal of Foot and Ankle Surgery, 52(1), 62–66. https://doi.org/10.1053/j.jfas.2012.08.003

Zollinger, P. E., Tuinebreijer, W. E., Breederveld, R. S., & Kreis, R. W. (2007). Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. Journal of Bone and Joint Surgery – Series A, 89(7), 1424–1431. https://doi.org/10.2106/JBJS.F.01147