Prevention of Complex Regional Pain Syndrome Using Liposomal Encapsulated Vitamin C in Programmed Knee Surgery; A Prospective Randomized Trial
Phase: NA
Conditions: Complex Regional Pain Syndrome I of Lower Limb
Sponsor: Centre Hospitalier de Ham

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Prevention of Complex Regional Pain Syndrome using liposomal encapsulated vitamin C in Programmed 
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Knee Surgery; A Prospective Randomized Trial 
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Short title: “Liposomal encapsulated vitamin C in complex regional pain syndrome” 
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Cazeneuve Jean-François*,1, MD. 
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1Centre Hospitalier de Ham,  56 Rue de Verdun, 80400 Ham, France 
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*Corresponding Author: Cazeneuve Jean-Francois (56 Rue de Verdun, 80400 Ham, France) E-mail : 
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jfc.laon@gmail.com. 
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Date : 15/07/2019 
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NCT04204200 
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Abstract 
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Background 
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Complex regional pain syndrome (CRPS) is a significant complication in operated osteoarticular pathology and may 
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adversely affect patient’s quality of life. Vitamin C is an anti-oxidant and a neuro-modulating agent. Intake of 
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vitamin C appears to be the only preventative factor. The objective of this study seeks to assess the effectiveness of 
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liposomal conditioning of vitamin-C in reducing CRPS and to show evidence that it is more effective than taking 
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vitamin C in its usual form. 
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Methods 
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Three series of patients undergone for identical pathologies the same surgery performed in the same centre by a 
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single surgeon using the same operative techniques and the same implants. The first group took vitamin C in 
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liposomal form. The second one took classical vitamin C tablets while the third one received placebo pills. 
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Comparison was made between both groups which were identical in number and were the same average age. Results 
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were compared and analysed at the end of one-year follow-up. 
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Results 
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After a one-year follow-up, the group taking the liposomal form showed improvement of functional outcome as 
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compared to the classical vitamin C and placebo groups. 
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Conclusions 
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The intake of vitamin C in a liposomal encapsulation represents a breakthrough in the prevention of the occurrence 
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of CRPS particularly on scheduled osteo-articular knee surgery risk areas.  
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Keywords 
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Vitamin C – Complex regional pain syndrome – Prevention – Knee. 
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Level of Evidence: I. 
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Introduction 
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Complex regional pain syndrome (CRPS), formerly called reflex sympathetic dystrophy, algodystrophy, neuro-
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algodystrophy or shoulder-hand syndrome, remains one of the major complications of osteoarticular surgery 
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according to Camelot et al.1. Of note, its occurrence was attributed to the toxic effects of the oxidation of free radicals 
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on the endothelial permeability of the microcirculation, causing protein and fluid losses in animal models2. However, 
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ascorbic acid has the effect of recovering these excess free radicals in the extracellular medium, and acts as a 
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prophylactic antioxidant3. In 2002, in the footsteps of Zollinger et al.4, we had published encouraging results as to 
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the preventive nature of vitamin C upon occurrence of a complex type 1 regional pain syndrome after fracture of the 
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distal radius treated by surgery5. These results were confirmed by a systematic review and a recently published meta-
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analysis6. Only 10% conventional vitamin C is absorbed. Since 2014, we have used liposomal vitamin C in scheduled 
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knee surgery (Goldman® Laboratories LTD, London, UK). Liposomal encapsulation uses European 
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phosphatidylcholine, extracted from natural sunflower lipids and non-GMO cultures; it is also known as lecithin. 
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The active substance is encapsulated in a structured spherical composition of phospholipids. This new matrix 
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assembly called liposome protects the active substance when in direct contact with the gastric juice of the stomach 
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and the digestive enzymes of the intestine. Technology makes it possible to design the optimal size for each liposome 
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to ensure that the active substance is properly released into the cells of the body. Thus, the content of each liposome 
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is fully absorbed when it reaches the level of the gastrointestinal system and it retains all its intrinsic properties. The 
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aim of this prospective and mono-centric comparative study is to find out if the liposomal form represents a 
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breakthrough compared to the form conventionally used in the prevention of the occurrence of a CRPS in 
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programmed knee surgery. 
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Material and Methods 
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Ethical Statement 
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Ethical approval from the I.R.B of C.H.U Montpellier (France) Hospital Research and Ethics committee was sought 
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and granted. Also, the researchers notified the participants about the study and obtained written and oral informed 
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consents. All methods were conducted in accordance with the relevant approved regulations, guidelines, and 
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declaration of Helsinki. The trial was registered at clinicaltrials.gov (ID: 2019_IRB-HTP_07-19). 
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Study Design 
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From 2014 to 2017, we treated 66 patients divided into three identical groups in number and whose average age was 
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44 years, ranging from 30 to 55 years for planned knee surgery also divided into five transpositions of the anterior 
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tibial tuberosity, five ligamentoplasties of the Kenneth-Jones type, six unicompartmental internal prostheses for 
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centralized osteoarthritis and six total prostheses for eccentric osteoarthritis. All of them benefited from a truncular 
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block associated with general anaesthesia performed thirty times or with spinal anaesthesia performed in thirty-four 
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cases. The treatment was performed in a single centre by a single surgeon using the same pathways, the same surgical 
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techniques and the same implants. In each group, there was no history of CRPS. The first took a capsule of liposomal 
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vitamin C at 500 mg, in the morning and evening, one week before surgery, one during the day of surgery and lastly, 
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during the first 21 post operation days. In the second group, the surgery was performed under the standard vitamin 
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C framework with a daily intake of 500 mg in the morning and evening for 28 days (starting 7 days before the 
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operative procedure, on the day of the surgery and ending twenty-one days after surgery). In the third group, the 
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placebo was taken daily in the morning and the evening for 28 days (7 days before surgery, on the day of surgery 
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and twenty-one days after the surgical procedure). Patients were reviewed monthly during the first trimester and 
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then every three months during the first postoperative year. The main objective was to monitor whether CRPS 
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developed and to document the one-year follow-up. The diagnosis of CRPS was established according to the 
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Budapest criteria for screening cases developing algodystrophy, moreover scans were only requested in case of 
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positive Budapest criteria validated in 2010 by Harden et al.7 (Appendix 1). Of note, each time the scintigraphy was 
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done it confirmed the clinical diagnosis (Figure 1). 
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Statistical Analysis 
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The skewness and kurtosis tests were used for testing the normal distribution of continuous variables8,9. Descriptive 
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statistics, including mean/median and standard deviation (SD)/interquartile range (IQR), were provided for 
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continuous variables. Frequencies and percentages were used to summarize categorical variables. χ2 test was used 
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for categorical data while Student’s t-test (or one-way ANOVA test for > two groups comparisons) was used for 
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continuous variables normally distributed while Mann–Whitney test (Kruskal-Wallis H test for > two groups 
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comparisons) was used for continuous variables not normally distributed. The statistical significance was considered 
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when the P-value was < 0.05. Data were analysed using MedCalc version 14.8.1, SPSS version 23, and RStudio 
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software version 3.2.4. 
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Results 
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We have included 22 patients in each intervention group (Figure 2). The mean age was 43.9 (±9.25) years with a 
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mean BMI of 21.69 (±2). Moreover, we have noted no difference between the three groups regarding the covariates 
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like age, BMI, surgery, complications, or scintigraphy (Table 1, and Figures 3 and 4). 
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For the first group, there was no discontinuation of liposomal vitamin C due to intolerance. The one-year follow-up 
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showed no CRPS (P-value <0.05). Moreover, we did not find any major loco-regional complications such as 
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hematoma, deep infection, post-fall fracture, dislocation or general thromboembolic or cardio neurovascular type. 
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Two-thirds of the patients who had undergone anterior tibial tubercle transposition admitted feeling no improvement 
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during the long follow-up. No instability or anteroposterior laxity was observed on patients who received a 
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ligamentoplasty in compliance with Kenneth-Jones, but half of them showed patellar signs. Patients who received 
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unicompartmental joint replacement surgery had good X-rays and clinical results at the end of the one-year follow-
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up. Lastly, one third of the patients who benefited from a total prosthesis of the knee presented a stiffness, whereas 
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a second third showed moderate mechanical pain chart. 
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The scintigraphy requested for this first group have never revealed occurrence of CRPS. The results analysis of the 
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second group reveals the occurrence of three CRPS with one pain syndromes confirmed by scintigraphy. One case 
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occurred on a follow-up of a transposition of the anterior tibial tuberosity, one case during a ligamentoplasty carried 
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out according to Kenneth-Jones and finally one cases during the implantation of a total knee prosthesis. The other 
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complications were in line with and proportionally the same as the first group. The analysis of the third group shows 
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five CRPS also confirmed by scintigraphy. Two cases occurred after a transposition of the anterior tibial tuberosity 
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and two cases after implantation of total knee arthroplasty. The other complications were in line too with and 
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proportionally the same as the first group (Table 2). 
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Discussion 
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CRPS remains a frequent postoperative complication1. It is distributed differently according to the different series10-
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13. Its frequency can reach 37 percent14. Contrary to commonly accepted notions, psychological and constitutional 
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factors cannot explain its occurrence2,14-16. In fact, the experimental study of Van der Laan et al.2 shows the toxicity 
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of free radicals released during soft-tissue contusion that increase the vascular permeability of striated muscle to 
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macromolecules thereby decreasing circulating proteins and fluids17. Matsuda et al.3 observed the beneficial effect 
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of vitamin C in high doses, which reduces leakage of liquids and proteins thanks to its antioxidant and protective 
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action against capillary endothelium, red blood cells and leucocytes18. Regarding prevention efficacy, a systematic 
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review of the literature associated with a meta-analysis performed by Aïm et al.6 found only three randomized 
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controlled trials. Two series are in favour of the preventive character of vitamin C intake to offset the occurrence of 
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the CRPS4,19 whereas one study shows no benefit from administration of vitamin C as a preventive measure20. 
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Chronologically, in 1999, Zollinger et al.4 showed in a study on two series of patients that vitamin C administration 
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in the event of reduced and immobilized distal radius fracture prevented the development of CRPS. In 2002, we 
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reported in a retrospective sequenced study that daily intake of one gram of vitamin C for 45 days in distal radius 
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trauma enabled reducing the rate of CRPS from 10 to 2.1%5. In 2004, Reuben et al.21 concluded that only vitamin C 
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has proven its effectiveness in preventing the development of CRPS, in scheduled orthopaedic surgery. To conclude, 
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in 2009, Besse et al.22 confirmed the preventive effect of vitamin C in CRPS, on ankle and foot surgery. These again 
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are retrospective studies. Regarding the dosage to be prescribed, in 2007, Zollinger et al.19 showed that intake of 
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doses below 500 mg are ineffective. In 2013, Shibuya et al.23 demonstrated through a meta-analysis the beneficial 
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effects and non-toxicity of high-dose vitamin C in the prevention of CRPS for lower limb trauma. In 2017, Aïm et 
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al.6 using a systematic review and a meta-analysis of only placebo-controlled randomized trials, concluded that 
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taking 500 mg of vitamin C daily for 50 days tended to reduce pain syndrome by half. This refers to oral intake of 
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vitamin C, as only 10% of the ingested dose is absorbed. With reference to the usefulness of liposomal encapsulation: 
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in 2017, Sabesan et al.24 indicated that liposomal encapsulation used in shoulder surgery anaesthesia to deliver 
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constant doses of bupivacaine for 72 hours provided excellent control of postoperative pain by drastically reducing 
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opioid consumption. Our study has shown that vitamin C in its liposomal form seems even more effective than the 
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vitamin C usually and the placebo administered to prevent the occurrence of the CRPS and no case was found 
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throughout the one-year follow-up with p < 0.05 (Table 3). The liposomal envelope provides protection against 
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acidic gastric juices and intestinal enzymes thus allowing almost complete absorption, without denaturing the active 
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ingredient. 
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Our study shows new interesting results regarding prevention of CRPS using the liposomal encapsulating vitamin 
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C, however, it is limited by the small sample size in each group, moreover we had few different diagnoses. So, future 
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studies need to have a larger sample and a single diagnosis to have a homogenous analysis. 
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Conclusions 
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This prospective comparative study demonstrates that over one-year liposomal encapsulation form of vitamin C 
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provides better prevention for the CRPS in programmed knee surgery rather than the conventionally used form and 
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the placebo. This liposomal conditioning does not cause intolerance leading to a prescription. Currently and 
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systematically, we prescribe the intake of a 500 mg capsule of liposomal vitamin C, in the morning and the evening, 
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seven days before the operation, the day of the operation and for twenty-one days afterwards. 
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Funding 
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None. 
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Acknowledgment 
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None. 
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Figure Legends 
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Figure 1. Scintigraphy, Gamma scan, for confirming diagnosis of CRPS. 
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Figure 2. The flow chart of patients’ enrolment. (Statistical Analysis Plan) 
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Figure 3. Age comparison across the three groups of treatments. The y-axis represents the age in years. 
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Figure 4. BMI comparison across the three groups of treatments. The y-axis represents the BMI in kg/m2. 
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References 
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Figure 1. Scintigraphy, Gamma scan, for confirming diagnosis of CRPS. 
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Figure 2. The flow chart of patients’ enrolment. (Statistical Analysis Plan) 
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Figure 3. Age comparison across the three groups of treatments. The y-axis represents the age in years. 
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Figure 4. BMI comparison across the three groups of treatments. The y-axis represents the BMI in kg/m2. 
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