Vitamin C is Effective in Preventing Complex Regional Pain Syndrome in Adults Following Trauma: An Evidence Based Review - Brianna Pickering, MS, DPTc

Vitamin C is Effective in Preventing
Complex Regional Pain Syndrome in
Adults Following Trauma: An Evidence
Based Review

 Brianna Pickering, MS, DPTc

Complex Regional Pain Syndrome
(CRPS)
 A disabling condition affecting 1 or more extremities
  precipitated by any physical injury

 Vast array of sensory, vasomotor, sudomotor, motor and
  trophic symptoms
     Sensory: hyperalgesia, allodynia
     Vasomotor: decreased skin temperature, altered bloodflow
     Sudomotor: altering of sweat gland function
     Motor: atrophy, dystonias
     Trophic: thickening of nails, localized osteopenia

  Alternate names: reflex sympathetic dystrophy (RSD), Sudeck’s
  syndrome, algodystrophy, causalgia, and peripheral trophoneurosis

Diagnostic Criteria for CRPS
1. Four of the following five must be present:
  1.   Unexplained diffuse pain
  2.   Difference in skin color relative to contralateral extremity
  3.   Diffuse edema
  4.   Difference in skin temperature relative to contralateral
       extremity
  5.   Limited active range of motion
2. Occurrence of or increase in the aforementioned signs and
   symptoms following activity
3. Aforementioned signs and symptoms must be present in
   an area larger than the original injury

(Veldman et al., 1993)

CRPS Subtypes

Type 1
 Most common
 No identifiable nerve lesion
  present

Type 2
 Identifiable nerve lesion
  present

Background: Significance
 Incidence: 26.2 per 100,000 person-years (de Mos et al.,
 2010)

 10% prevalence following wrist fracture (Zollinger et al., 1999)

 Cost over life time varies
   $6,000/year for physical therapy (Taylor et al., 2011)
   $10,000 initial costs for spinal cord stimulator
    implantation

Background: Current Treatments
 Pharmacologic agents (Tran et al., 2010)
    Most ineffective except membrane stabilizers (Neurontin)

 Mirror therapy
    positive results (Moseley et al., 2011)

 Spinal cord stimulator
    positive but fading results

 Extreme measures
    amputation of involved extremity: mixed results (Bode et al., 2011)

Background: Clinical Problem

6 years after receiving CRPS diagnosis:
 64% still met diagnostic criteria
 31% unable to work

De Mos et al., 2009

Vitamin C
 Low risk dietary supplement (Zollinger et al., 1999)
 Decreases duration of the common cold
 Effective in the prevention and treatment of pneumonia
 Antioxidant

Background: Relevance to PT
 CRPS historically difficult to treat from both a medical and
  rehabilitative perspective

 If Vitamin C is shown to be effective, it would stop the
  disabling condition before it begins

 PTs can make patients aware of the possible efficacy of
  Vitamin C and recommend that they discuss it further with
  their physician or dietician

Theoretical Constructs

Theoretical Constructs: Risk
Factors for CRPS
Non-modifiable Risk
Factors                          Modifiable Risk Factors

 Ethnicity: Asian and            Exaggerated inflammatory
  Caucasian                        response to injury
                                  Hypoxia to involved tissues
 Age: 50-70
                                  Continuous pain input in the
 Sex: female                      acute stage
 Precipitating Injury: upper     Increased sympathetic
  extremity                        response
 Premorbid psychological         Psychological distress
  state: depression or anxiety    Fear of movement

Possible Mechanisms
Exaggerated
                                          Hypoxia to involved
inflammatory
                                               tissues
  response

                      Reduces to
                    Contributes
                      Preserves
                     Leakage
                       capillaryofof
                    production
                      Fluid and
                     endothelium
                      Vitamin  E
                        Protein

               Continuous pain input in
                  the acute stage

GAP
 Some studies have been published which address the
  efficacy of Vitamin C following wrist fractures, wrist surgeries
  and ankle surgeries (Zollinger et al., 1999; Zollinger et al., 2008; Cazeneuve et al., 2002; Besse et
  al., 2009)

 NO evidence-based reviews or meta-analyses have been
  published

 NO studies evaluating use of Vitamin C any trauma

Purpose: Answer Questions

Primary Question                Secondary Questions
Is Vitamin C effective in the   1. If Vitamin C is effective,
prevention of CRPS following       what is the most effective
trauma in adults?                  dose?
                                2. Are there documented
                                   adverse effects in the
                                   utilization of Vitamin C to
                                   prevent CRPS?
                                3. Are there patient or injury
                                   characteristics which are
                                   more highly correlated
                                   with successful use of
                                   Vitamin C to prevent
                                   CRPS?

• Adults who have experienced
P     a physical trauma

I   • Vitamin C

C   • No Vitamin C or placebo

    • Receiving a diagnosis of
O     CRPS

Hypotheses
 Null Hypothesis            Alternate Hypothesis

Vitamin C does not reduce   Vitamin C does reduce the
the incidence of complex    incidence complex regional
regional pain syndrome      pain syndrome following
following trauma            trauma

Expected Findings

7-10 RCTs and quasi-experimental studies
 of moderate to high quality

Strong evidence that Vitamin C reduces the
 incidence of CRPS following trauma

Methods: Selection Criteria
Inclusion Criteria:              Exclusion Criteria:
 Age: 18+                        No traumatic
 s/p traumatic injury,            injury/precipitating event
  including surgery               Study design does not
 Article available in English     include control group
  or French                       Article body unavailable
 Outcome measure:                 with pre-paid
  presence or absence              student/faculty resources at
  meeting diagnostic criteria      UCSF/SFSU
  for CRPS                        Non-human subjects
 Some of subjects have
  taken Vitamin C following
  traumatic event

Methods: Search Terms and
 Databases

            Complex regional     Algodystrophy
            pain syndrome
            Shoulder-hand        Sudeck’s
            syndrome             syndrome
            Reflex sympathetic   Prevention
            dystrophy
            Vitamin C            Ascorbic acid
Recursive
 search

Statistical Analyses
 Odds Ratio (OR) and Relative Risk (RR) with
  confidence intervals calculated for each study

 Q statistic

 Combined OR and RR

…RESULTS

PRISMA

Results: Primary Articles
   Author       Design       Type of    Follow         N         Mean      Dosage
                             Trauma       up                     Age

Zollinger et   Double-   Wrist          1 year   119 fractures   C=60   C: placebo
al., 1999      blind RCT fracture                (Control=65,    E=57   E: 500 mg/day
               (1b)      (conservati             Exp=54)                x50 days
                         ve tx)
Cazeneuve      Quasi-      Surgically   >6       195 fractures   C=54   C: nothing
et al., 2002   experime    fixated      months   (C=100,         E=57   E: 1000
               ntal (2b)   distal                E=95)                  mg/day x45
                           radius fx                                    days
Zollinger et   Double-     Wrist        1 year   427 fractures   C=61   C: placebo
al., 2007      blind       fracture              (C=99,          E=63   E: 200, 500 or
               dose-                             E=96/114/118           1500 mg/day
               response                                                 x50 days
               RCT (1b)
Besse et       Quasi-      Foot/ankle   >3       420 surgeries   C=47   C: nothing
al., 2009      experime    surgery      months   (C=235,         E=51   E: 1000
               ntal (2b)                         E=185)                 mg/day x45
                                                                        days

Results: Homogeneity

Q: 1.86

P-value: 0.87

Odds Ratios
 Besse, 2009

 Cazeneuve,
      2002

    Zollinger,
         1999
    Zollinger,
2007 (200 mg)

    Zollinger,
2007 (500 mg)

   Zollinger,
  2007 (1500
          mg)

Combined                     0.22 (0.13, 0.37)

                 0   0.2   0.4   0.6    0.8      1.0   1.2   1.4

Results: Dose Response

Dosage              Studies                            Odds Ratio        Relative Risk
200 mg x 50 days    Zollinger 12007a
                                  Study                0.39 (0.12, 1.29) 0.41 (0.12, 1.35)
500 mg x 50 days    Zollinger21999,
                                Studies
                                     Zollinger 2007b   0.23 (0.09, 0.59) 0.26 (0.10, 0.67)
1000 mg x 45 days           2 Studies
                    Besse 2009,   Cazeneuve 2002       0.17 (0.07, 0.42) 0.18 (0.07, 0.45)
1500 mg x 50 days   Zollinger 12007c
                                  Study                0.15 (0.13, 0.41) 0.17 (0.036, 0.79)
Combined                                               0.22 (0.13, 0.37) 0.24 (0.14, 0.41)

Dosage Odds Ratios

      200 mg x 50
            days

      500 mg x 50
            days

    1000 mg x 45
           days

1500 mg x 50 days

    Combined

                    0   0.2   0.4   0.6   0.8   1.0   1.2   1.4

Discussion: Adverse Effects
None reported in studies

Recommended Daily Allowance: 75-90 mg/day
Tolerable Upper Intake Level: 2000 mg/day (USDA
 guidelines)

Discussion: Cost
Not directly addressed in studies

Retail price: $10/100 capsules (1000 mg)

Dietary Sources (USDA):
   Oranges (130 mg)
   Potatoes (200 mg)
   Red or yellow peppers (120 mg)

Discussion

     Vitamin C does reduce the
    incidence of CRPS in adults
          following trauma

If Vitamin C is effective, what is the
   most effective dose?

   Unclear

   Likely > 1000 mg/day for 45 days

Are there documented adverse
 effects in the utilization of Vitamin
 C to prevent CRPS?

                 NO

Are there patient or injury characteristics
 which are more highly correlated with
 successful use of Vitamin C to prevent
 CRPS?

 Unable to determine
 Not adequately reported in studies

Discussions: Limitations
 Few databases searched
 Non-medical expert translator used for French translation
 Inadequate data reporting for patient or injury characteristics
  on some studies
 Some studies not blinded
 Same primary author for multiple studies

Directions for future research
 Determining the efficacy of Vitamin C for treating CRPS

 Determining what patient or injury characteristics impact the
  effectiveness of Vitamin C in preventing CRPS

 More injury types

Scope of Practice
CA Physical Therapy Business and Professions Code
2620.

(a) “Physical therapy means the art and science of physical or
  corrective rehabilitation or of physical or corrective treatment
  of any bodily or mental condition of any person …and shall
  include physical therapy evaluation, treatment planning,
  instruction and consultative services….”

Recommendations for PT

Following a traumatic injury or extremity surgery,
 PTs should recommend a patient consult with a
 dietician or physician to discuss the possibility of
 implementing Vitamin C into their daily regimen
 during the recovery process.

Conclusion
Vitamin C is effective in the prevention of complex regional
 pain syndrome in adults following trauma.

Following a traumatic injury or extremity surgery, PTs should
 recommend a patient consult with a dietician or physician to
 discuss the possibility of implementing Vitamin C into their
 daily regimen during the recovery process.

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Acknowledgements
 Jessica Manley, MS, DPTc
 Justin Trumbull, MS, DPTc
 Christine Zampach, PT, DPT, MEd
 Jet Lee, PT, PhD
 Diane Allen, PT, PhD
 Kristal Andersen, Esq.
 UCSF/SFSU Physical Therapy Class