Abstract
Background
It is proposed that vitamin C administration can reduce disproportionate pain and stiffness after distal radius fracture; however, randomized trials that tested this hypothesis have had inconsistent results.
Questions/purposes
(1) Is administering vitamin C after distal radius fracture associated with better ROM, patient-reported upper extremity function, and pain scores? (2) What factors are associated with post-fracture finger stiffness and worse upper extremity function?
Methods
This is a double-blind, randomized, placebo-controlled, noncrossover study. Between August 2014 and July 2017, we approached 204 consecutive patients, of which 195 were eligible, and 134 chose to participate. Participants were randomized to receive once-daily 500 mg vitamin C (67 participants) or placebo (67 participants) within 2 weeks after distal radius fracture. All patients received usual care at the discretion of their surgeon. The mean age of participants was 49 ± 17 years, 99 patients (74%) were women, and 83 (62%) were treated nonoperatively. The primary outcome was the distance between the fingertip and distal palmar crease 6 weeks after fracture. This measure is easy to obtain and previously has been shown to correlate with aggregate ROM of all finger joints. The secondary outcomes were total active finger motion, total active thumb motion, upper extremity-specific limitations, and pain intensity.
An a priori power analysis suggested 126 patients would provide 80% power to detect a difference of 2 cm (SD 4.0) fingertip distance to palmar crease with α set at 0.05 using a two-tailed Student's t-test. Accounting for 5% lost to followup, we included 134 patients.
All analyses were intention-to-treat. Ten participants of the intervention group and five of the placebo group were lost to followup. Their missing data were addressed by multiple imputation, after which we performed linear regression analysis for our outcome variables.
Results
Administration of vitamin C was not associated with ROM, function, or pain scores at 6 weeks (distance to palmar crease: β -0.23; 95% CI -1.7 to 1.2; p = 0.754; finger ROM: β 4.9; 95% CI, -40 to 50; p = 0.829; thumb ROM: β 0.98; 95% CI, -18 to 20; p = 0.918, Patient-Reported Outcomes Measurement Information System [PROMIS] score: β 0.32; 95% CI, -2.6 to 3.2; p = 0.828; pain score: β -0.62; 95% CI, -0.62 to 0.89; p = 0.729) nor at 6 months (PROMIS score: β -0.21; 95% CI, -3.7 to 3.3; p = 0.904; pain score: β 0.31; 95% CI, -0.74 to 1.4; p = 0.559). At 6 weeks, we found that more finger stiffness was mildly associated with greater age (β -1.5; 95% CI, -2.8 to -0.083; p = 0.038). Thumb stiffness was mildly associated with greater age (β -0.72; 95% CI, -1.3 to -0.18; p = 0.009) and strongly associated with operative treatment (β -32; 95% CI, -50 to -13; p = 0.001). Greater pain interference was modestly associated with greater functional limitations at 6 weeks (β -0.32; 95% CI, -0.52 to -0.12; p = 0.002) and 6 months (β -0.36; 95% CI, -0.60 to -0.11; p = 0.004).
Conclusions
Vitamin C does not seem to facilitate recovery after distal radius fracture, but amelioration of maladaptation to nociception (pain interference) merits greater attention.
Level of Evidence
Level I, therapeutic study.
Introduction
The percentage of patients who have disproportionate pain and disability after a distal radius fracture varies widely from lower than 1% to as high as 37% [2, 3, 5-7, 29, 28]. Disproportionate pain and disability are often conceptualized as a categorical and physiological problem such as complex regional pain syndrome (CRPS). However, current diagnosis of a CRPS diagnosis relies on subjective criteria, and a direct pathophysiologic basis has not been established [4, 8, 11, 19, 24]. Some have proposed that in CRPS, oxygen-free radicals contribute to stiffness during recovery from injury [17, 27]. This led to two randomized controlled trials from one research group to determine if vitamin C prophylaxis (a natural antioxidant and free radical scavenger) helps avoid CRPS [29, 28].
These initial trials found that vitamin C prophylaxis has a benefit, but a subsequent trial by independent investigators could not reproduce these findings [9]. Each of these trials used different and subjective diagnostic criteria to categorize people with disproportionate pain and disability [1]. We propose that it is more helpful to measure disproportionate pain and disability on the continuous scale that it naturally occurs on–instead of dichotomizing this outcome–using objective outcome measures.
Therefore, we asked: (1) Is administering vitamin C after distal radius fracture associated with better ROM, upper extremity function, and pain scores? (2) What factors are associated with post-fracture finger stiffness and worse upper extremity function?
Patients and Methods
Our institutional review board approved this single-center, double-blind, randomized, placebo-controlled, noncrossover study under protocol number 2014P000561. Additionally, our independent institutional human research quality improvement committee, under the supervision of the senior vice presidents of research of our hospital and another affiliated Level I trauma center in our region, oversaw this study and conducted mandatory audits at random points to ensure that this study was conducted in accordance with federal regulations, institutional policies, and good clinical practice. Lastly, this trial was prospectively registered on clinicaltrials.gov under protocol number NCT02216812. No changes were made to methods after the trial began.
Study Design
Patients were enrolled at outpatient offices of an urban level-1 trauma center between August 2014 and July 2017. We approached 204 patients, of whom 61 declined participation and nine did not meet our inclusion criteria, resulting in our final cohort of 134 participants (Fig. 1). Patients were recruited at their index visit to the outpatient office of one of five experienced fellowship-trained orthopaedic hand and upper extremity or trauma surgeons. The treating surgeon determined eligibility based on predefined inclusion criteria for participation in this trial. All patients received the usual care at the discretion of their surgeon; participation in this study did not influence the treatment of their distal radius fracture. After obtaining both oral and written informed consent for participation in this study, we recorded the patients’ demographics (age, sex, race, BMI, years of education, employment status, marital status, tobacco use, and supplement use) and injury and treatment characteristics (dominant extremity injured, type of treatment, carpal tunnel release), performed standardized baseline measurements (distance to palmar crease of the injured and uninjured hands, total active finger motion of the injured and uninjured hands, and total active thumb motion of the injured and uninjured hands), and asked patients to complete the Patient-Reported Outcome Measurement Information System – Pain Interference (PROMIS-PI, version 1.1) questionnaire, the PROMIS-Upper Extremity (PROMIS-UE, version 1.2) questionnaire, and the numeric rating scale for pain (NRS-pain).
Fig. 1.
A flow diagram of enrollment, intervention, allocation, followup, and data analysis is shown; DTPC = distance to palmar crease; PROMIS-UE = Patient-Reported Outcomes Measurement Information System – Upper Extremity.
Randomization
Patients were randomly assigned in a 1:1 allocation to one of two parallel noncrossover groups to receive either 500 mg capsule of vitamin C or an inert control capsule of lactose.
The pharmacist involved in preparing the study capsules, who was not involved with any other aspects of this study, numbered the bottles by block randomization (33 blocks of four bottles and one block of two), all of which were computer generated. The block size was unknown to anyone but the pharmacist, and the pharmacist was the only person with the access code until the trial ended. Capsule boxes containing pills of either 500 mg of vitamin C or placebo were independently dispensed by the pharmacist to the research coordinator.
Allocation Concealment and Blinding
There was no difference in shape, size, or color between the vitamin C and placebo capsules. The capsules were prepared in identical boxes and consecutively numbered based on the randomization schedule. Participants, healthcare providers, data collectors, outcome assessors, and data analysts were all blinded to the allocation. Blinding was maintained until completion of the final analyses.
Study Pathway
Six weeks after fracture (mean, 6.6 ± 1.1 weeks, range, 4.7–12 weeks), a research assistant (SÖ, WvL, IS, TT) measured the distance to the palmar crease of the injured hand, total active finger motion of the injured hand, and total active thumb motion of the injured hand. Patients also completed the PROMIS-UE and the NRS-pain questionnaires. If this followup interval was missed or if the clinical appointment was outside the 5- to 8-week timeframe, we contacted patients by email and/or telephone (maximum of three attempts) to complete the 6-week questionnaires.
Six months after the fracture (mean, 6.4 ± 0.91 months, range, 5-9 months) we emailed patients to invite them to complete the PROMIS-UE and NRS-pain questionnaires. If the patients did not respond to email, we made a maximum of three attempts to contact each patient via telephone or email to complete the 6-month questionnaires.
We collected and managed study data using Research Electronic Data Capture (REDCap, Vanderbilt University, Nashville, TN, USA) tools hosted at our institution, which is a secure, Health Insurance Portability and Accountability Act (HIPAA)-compliant, web-based application designed to support data capture for research studies [12].
Participants and Interventions
Eligible participants were patients aged 18 or older who presented to our hospital within 2 weeks after having a distal radius fracture. The exclusion criteria were kidney failure, current or prior diagnosis of kidney stones, known vitamin C allergy, pregnancy, ipsilateral wrist fracture within the last year before the new fracture, or lack of fluency in either English or Spanish.
Patients assigned to the intervention group took 500 mg of vitamin C orally once a day for 6 weeks, whereas patients assigned to the control group took a placebo capsule consisting of lactose once per day for 6 weeks. The mean age of our patients was 49 ± 17 years, and most of our study cohort were women (n = 99, 74%). Most of the fractures (n = 83, 62%) were treated nonoperatively (Table 1). We found no gross differences in baseline characteristics. Patients unavailable for measurement at 6 weeks after injury had more finger motion and were treated nonoperatively more often than patients who were available (see Appendix, Supplemental Digital Content 1, http://links.lww.com/CORR/A188). This is a common problem in fracture studies. Due to randomization, we do not expect this to affect our primary study question. There were no adverse events because of the administration of vitamin C or the placebo.
Table 1.
Baseline characteristics of the study cohort
Outcome Measures
The primary outcome measure of this study was the distance to the palmar crease after 6 weeks. The secondary outcome measures were total active finger motion 6 weeks after fracture, total active thumb motion 6 weeks after fracture, and the PROMIS-UE score and NRS-pain (an 11-point ordinal measure of pain intensity) score at 6 weeks and 6 months after fracture. We also assessed the distance to the palmar crease, total active finger motion, and total active thumb motion at enrollment.
Finger Stiffness
To measure the distance to palmar crease, we asked patients to make a fist and measured the distance in centimeters between the finger pulp and the corresponding most distal palmar crease with a ruler. The distance to the palmar crease is a commonly used metric to describe digital motion among hand surgeons and therapists. We performed these measurements for each of the index, long, ring, and small fingers individually, and then calculated the total distance to the palmar crease by adding the values of these four digits. A previous study found a high correlation (r -0.74, p < 0.001) between the distance to the palmar crease and index-to-small finger ROM [25]. We did not assess the inter- and intraobserver variability of distance to palmar crease measure.
We measured the total active finger motion with a handheld goniometer.
Questionnaires
The PROMIS-PI (minimal clinically important difference [MCID] 7.1) is a computer adaptive test that measures the degree to which a person limits activity because of pain, and the PROMIS-UE (MCID 9.0) questionnaire quantifies upper extremity-specific limitations [13, 26].
The NRS-pain (MCID 1.0) is an 11-point ordinal measure of pain intensity from 0 (no pain) to 10 (worst pain imaginable) [14, 22].
Sample Size and Interim Analysis
Based on previous research, an a priori power analysis suggested that 126 patients would provide 80% power to detect a difference of 2 cm (SD 4.0) fingertip distance to the palmar crease with α set at 0.05 using a two-tailed Student's t-test. After accounting for 5% lost to followup, we included 134 patients. [28]. There is no known clinically important difference for the distance of the fingertip to the palmar crease or finger ROM [25].
Per protocol, we assessed the rate of followup halfway through the study to adjust the sample size to account for the number of patients lost to followup. Since the 6-week followup rate was greater than 80%, we did not adjust our sample size. This evaluation was done without unblinding or reviewing any of the values of any of the parameters in this study, and no interim analyses were performed. In all, 98 patients (73%) completed questionnaires 6 months after having a fracture. Of those, one patient completed the pain questionnaire but not the PROMIS-UE questionnaire (Fig 1).
Funding Source
No external funds were received for this study, which was departmentally funded. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Statistical Methods
After multiple linear imputation for missing values, we identified differences in outcome measures between patients using vitamin C or the placebo through a multiple linear regression analysis. We did not include any other variables in the models.
Factors Associated with the Distance to the Palmar Crease, Total Active Motion of the Fingers or Thumb, PROMIS-UE, and NRS-Pain
For each outcome variable, we separately performed an exploratory bivariate analysis (data not shown). Associations between continuous, dichotomous, or categorical data and our outcome variables were assessed with a Pearson correlation, the t-test, and ANOVA, respectively. For each outcome variable, after multiple imputations, we then entered variables with p values smaller than 0.10 into a multiple linear regression model. We reported the adjusted R2 and the partial R2 for each of these multivariable analyses. The adjusted R2 measures the amount of variability accounted for by the whole model, whereas the partial R2 measures the amount of variability accounted for by the respective variable.
The same statistical methodology was used for our unplanned tertiary analysis. All our prespecified analyses were intention-to-treat, and none of the randomized patients were excluded from the study.
Missing Values
We accounted for missing values through multiple linear imputations, with the number of imputations set to 40. At the 6-week evaluation, there were 15 missing distance to the palmar crease measurements (11%), total active finger motion, and total active thumb motion; 13 missing (10%) PROMIS-UE scores, and 14 (10%) NRS-pain scores. Eleven patients cancelled or rescheduled their 6-week appointment, two patients received care closer to home, and two patients declined to participate. At the 6-month evaluation there were 37 (28%) missing PROMIS-UE scores and 36 (27%) NRS-pain scores.
Patients with missing data at the 6-week evaluation (see Appendix, Supplemental Digital Content 4, http://links.lww.com/CORR/A189) were more likely to use tobacco (20% versus 4.2%; p = 0.045) or have nonoperative treatment (87% versus 59%; p = 0.047) than those with complete data and had less distance to the palmar crease (3.6 ± 3.5 cm versus 7.3 ± 6.1 cm; p = 0.023) and more thumb ROM at enrollment (206 ± 48° versus 152 ± 52°; p < 0.001). There were no differences between patients who did and did not complete the 6-month questionnaires.
Results
Administration of vitamin C was not associated with ROM, self-reported upper extremity function, or pain at 6 weeks (distance to palmar crease: β -0.23; 95% CI, -1.7 to 1.2; p = 0.754; finger ROM: β 4.9; 95% CI, -40 to 50; p = 0.829; thumb ROM: β 0.98; 95% CI, -18 to 20; p = 0.918, PROMIS: β 0.32; 95% CI, -2.6 to 3.2; p = 0.828; pain score: β -0.62; 95% CI, -0.62 to 0.89; p = 0.729) nor at 6 months (PROMIS: β -0.21; 95% CI, -3.7 to 3.3; p = 0.904; pain score: β 0.31; 95% CI, -0.74 to 1.4; p = 0.559, Table 2). A sensitivity analysis without any imputed data (see Appendix, Supplemental Digital Content 2, http://links.lww.com/CORR/A190) showed similar results.
Table 2.
Effect of vitamin C on outcomes after distal radius fracture
At 6 weeks, we found that more finger stiffness was mildly associated with greater age (β -1.5; 95% CI, -2.8 to -0.083; p = 0.038). Thumb stiffness was mildly associated with greater age (β -0.72; 95% CI, -1.3 to -0.18; p = 0.009) and strongly associated with operative treatment (β -32; 95% CI, -50 to -13; p = 0.001; see Appendix, Supplemental Digital Content 3, http://links.lww.com/CORR/A191). Greater pain interference was modestly associated with greater functional limitations at 6 weeks (β -0.32; 95% CI, -0.52 to -0.12; p = 0.002) and 6 months (β -0.36; 95% CI, -0.60 to -0.11; p = 0.004; Table 3). No other factors were associated with self-reported measures after fracture (see Appendix, Supplemental Digital Content 4, http://links.lww.com/CORR/A189).
Table 3.
Factors independently associated with ROM and upper extremity function after distal radius fracture
Unplanned Analyses: Finger Stiffness Within Two Weeks of Fracture
In the unplanned analysis for factors independently associated with finger ROM, being retired (β 105; 95% CI, 3.5–206; p = 0.043) and lower pain interference (β -4.8; 95% CI, -8.3 to -1.3; p = 0.007) were associated with more finger ROM within 2 weeks of fracture, whereas operative treatment (β -77; 95% CI, -130 to -23; p = 0.006) was associated with less finger motion. Patients who were divorced (β -40; 95% CI, -70 to -9.8; p = 0.010) or had lower pain interference (β -1.5; 95% CI, -2.8 to -0.21; p = 0.023) had lower thumb ROM (see Appendix, Supplemental Digital Content 5, http://links.lww.com/CORR/A192).
Operative treatment was associated with a larger distance to the palmar crease (more stiffness) within 2 weeks of fracture (β 4.5; 95% CI, 2.3–6.6; p < 0.001). Being separated, divorced, or widowed (β -40; 95% CI, -70 to -9.8; p = 0.010) and greater pain interference (β -1.5; 95% CI, -2.8 to -0.21; p = 0.023) were both independently associated with less thumb motion within 2 weeks after fracture (see Appendix, Supplemental Digital Content 5, http://links.lww.com/CORR/A192).
Six weeks after fracture, no factors were independently associated with the distance to the palmar crease. Greater age was independently associated with less finger motion (β -1.5; 95% CI, -2.8 to -0.083; p = 0.038) and less thumb motion (β -0.72; 95% CI, [-1.3 to -0.18; p = 0.009). Greater pain interference was associated with a greater magnitude of upper extremity-specific limitations (β -0.32; 95% CI, -0.52 to -0.12; p = 0.002). No factors were independently associated with greater pain intensity (Table 3).
Six months after injury, greater pain interference was associated with reduced upper extremity function (β -0.36; 95% CI, -0.60 to -0.11; p = 0.004). No factors were independently associated with pain intensity (Table 3).
Discussion
The idea that a safe and inexpensive intervention such as vitamin C might ease recovery is appealing. Prior studies categorized the recovery process using subjective and relatively unreliable criteria that have been criticized as internally inconsistent [29, 28]. We tried to reproduce the finding that vitamin C can limit pain and limitations after upper extremity injury using a double-blind, placebo controlled, randomized trial evaluating an objectively measurable outcome for the primary study question and avoiding categorization of continuous variables. We found that vitamin C did not facilitate recovery in our study.
It is important to consider the limitations of this study. First, patients unavailable for measurement at 6 weeks after injury had more motion and were treated nonoperatively more often than patients who were available (see Appendix, Supplemental Digital Content 1, http://links.lww.com/CORR/A188). This may somewhat limit the generalizability of our findings at 6 weeks. Second, we performed a pragmatic trial and did not measure actual medication adherence, such as measuring the blood levels of those with vitamin C. While this is a limitation to testing the efficacy of vitamin C, it is an advantage because it mimics actual clinical practice. Third, PROMIS-Pain Interference was designed more as a measure of the magnitude of physical limitations. Although it correlates well with coping strategies in response to pain [15], it might have been helpful to measure catastrophic thinking or pain self-efficacy directly [9, 16, 18, 20, 25]. Fourth, we used the distance of the fingertip to the palmar crease as our primary outcome. There are relative differences when considering a large and small hand. But, due to randomization, such differences are divided equally among groups. Fifth, the effect of vitamin C on a specific subgroup cannot be determined from this study because the sample size is too small for subgroup analysis. Although to our knowledge there is no known difference in metabolism of vitamin C based on sex or age.
We found that vitamin C did not affect objective measurements of finger motion (distance to the palmar crease and total active finger or thumb motion) during recovery from distal radius fracture. One prior randomized trial found that vitamin C did not influence finger motion in patients with distal radius fracture [9]. Their finding of worse wrist flexion and pinch strength 6 weeks after a nondisplaced fracture among patients taking vitamin C is likely spurious given the many statistical tests performed in their study. This study also measured similar constructs to our study but used different questionnaires (the DASH questionnaire [26] and VAS for pain [14]) and found no effect of vitamin C [9]. In light of that, we are confident that vitamin C has no clinically important effect on pain intensity and upper-extremity limitations. However, due to our sample size a small effect–smaller than in previous published trials [29, 28]–cannot be excluded. In addition, if CRPS is pathophysiologically distinct and occurs very rarely after distal radius fracture, our study would not be able to detect a difference.
Finger stiffness was associated with operative treatment and pain interference at enrollment and age and operative treatment at 6 weeks and 6 months after fracture, and upper extremity-specific limitations were associated with greater pain interference at 6 weeks and 6 months after fracture. Older age was associated with less motion 6 weeks after fracture. Although we did not assess for osteoarthritis directly, we speculate that this is because of underlying osteoarthritis in older people. Our finding is consistent with a recent prospective cohort study that found finger stiffness correlated with catastrophic thinking during recovery from volar plate fixation [25]. The Pain Catastrophizing Questionnaire and PROMIS-Pain Interference scores have a notable correlation [15]. Aspects of normal human illness behavior (particularly coping strategies in response to nociception) seem to account for most variations in recovery. Demographic and injury characteristics are factors of long-term, patient-reported upper extremity function and pain after distal radius fracture [10, 16, 21, 23], but the influence of psychological traits may be comparable or greater [9, 16, 18, 20, 25].
Vitamin C does not facilitate recovery from distal radius fracture, and we do not recommend prescribing it after distal radius fracture. Attention to reducing pain interference by stimulating more adaptive coping strategies to help recovery from injury seems merited. Surgeon awareness and patient education are important in everyday management, and implementation of formal interventions such as cognitive behavioral therapy or mindfulness-based cognitive therapy are considerations if a patient demonstrates a concerning postoperative course; this is something future research can address. Adaptive coping strategies can be facilitated by conveying in a respectful and empathetic way that stiffness and pain are normal aspects of recovery and assuring patients that they can use their affected limbs–in spite of pain–for everyday tasks.
Acknowledgments
We thank Ilse Schol BSc, and Wouter van Leeuwen MD, for their assistance with enrollment and data collection. We also thank Catherine Huynh, medical assistant; Kimda Tran, medical assistant; and Adam Nazzal MD, for their help with logistics and followup communication. Lastly, we thank our colleague surgeons who allowed us to invite their patients to enroll: Jesse Jupiter MD, Sang-Gil Lee MD, and Chaitanya Mudgal MD.
Footnotes
Sezai Özkan has no potential conflicts of interest.
One of the authors (DR) received royalties from Tornier (formerly Wright Medical; Memphis, TN, USA) for elbow plates in the amount of less than USD 10,000 per year and from Skeletal Dynamics (Miami, FL, USA) for an internal joint stabilizer elbow in the amount of less than USD 10,000 per year. One of the authors certifies that he (DR) is a Deputy Editor for Hand and Wrist, Journal of Orthopaedic Trauma, and Clinical Orthopaedics and Related Research® and has received or may receive payments or benefits in an amount of USD 5000 per year. One of the authors certifies that he (DR) received honoraria from meetings of AO North America (Wayne, PA, USA), AO International (Davos, Switzerland), and various hospitals and universities.
One of the authors certifies that he (TT) received payments in the amount of less than USD 10,000 per year from AO Trauma (Dubendorf, Switzerland), DePuy Synthes (West Chester, PA, USA), and PATIENT+ (The Hague, The Netherlands).
One of the authors certifies that he (NCC) has received less than USD 10,000 for consulting for Miami Device Solutions (Miami, FL, USA). One of the authors (NCC) is the program director for a fellowship that received support from OMeGA and Acumed.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
Each author certifies that his institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
The work was performed at the Hand and Upper Extremity Service, Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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