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), Sudecks

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)

Type 1

Type 2

CRPS Subtypes

Most common

No identifiable nerve lesion

present

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

Non-modifiable Risk

Factors Modifiable Risk Factors

Theoretical Constructs: Risk

Factors for CRPS

Ethnicity: Asian and

Caucasian

Age: 50-70

Sex: female

Precipitating Injury: upper

extremity

Premorbid psychological

state: depression or anxiety

Exaggerated inflammatory response to injury

Hypoxia to involved tissues

Continuous pain input in the acute stage

Increased sympathetic response

Psychological distress

Fear of movement

Possible Mechanisms

Exaggerated

inflammatory

response

Continuous pain input in

the acute stage

Hypoxia to involved

tissues

Preserves

capillary

endothelium

Contributes to

production of

Vitamin E

Reduces

Leakage of

Fluid and

Protein

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

Primary Question Secondary Questions

Purpose: Answer Questions

Is Vitamin C effective in the

prevention of CRPS following

trauma in adults?

1. If Vitamin C is effective, what is the most effective 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 a physical trauma P

Vitamin C I

No Vitamin C or placebo C

Receiving a diagnosis of CRPS O

Null Hypothesis Alternate Hypothesis

Hypotheses

Vitamin C does not reduce

the incidence of complex

regional pain syndrome

following trauma

Vitamin C does reduce the

incidence complex regional

pain syndrome following

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:

Age: 18+

s/p traumatic injury,

including surgery

Article available in English

or French

Outcome measure:

presence or absence

meeting diagnostic criteria

for CRPS

Some of subjects have

taken Vitamin C following

traumatic event

Exclusion Criteria:

No traumatic

injury/precipitating event

Study design does not

include control group

Article body unavailable

with pre-paid

student/faculty resources at

UCSF/SFSU

Non-human subjects

Methods: Search Terms and

Databases

Recursive

search

Complex regional

pain syndrome

Algodystrophy

Shoulder-hand

syndrome

Sudecks

syndrome

Reflex sympathetic

dystrophy

Prevention

Vitamin C Ascorbic acid

Statistical Analyses Odds Ratio (OR) and Relative Risk (RR) with

confidence intervals calculated for each study

Q statistic

Combined OR and RR

RESULTS

PR

ISM

A

Results: Primary Articles

Author Design Type of Trauma

Follow

up

N Mean

Age

Dosage

Zollinger et

al., 1999

Double-

blind RCT

(1b)

Wrist

fracture

(conservati

ve tx)

1 year 119 fractures

(Control=65,

Exp=54)

C=60

E=57

C: placebo

E: 500 mg/day

x50 days

Cazeneuve

et al., 2002

Quasi-

experime

ntal (2b)

Surgically

fixated

distal

radius fx

>6

months

195 fractures

(C=100,

E=95)

C=54

E=57

C: nothing

E: 1000

mg/day x45

days

Zollinger et

al., 2007

Double-

blind

dose-

response

RCT (1b)

Wrist

fracture

1 year 427 fractures

(C=99,

E=96/114/118

C=61

E=63

C: placebo

E: 200, 500 or

1500 mg/day

x50 days

Besse et

al., 2009

Quasi-

experime

ntal (2b)

Foot/ankle

surgery

>3

months

420 surgeries

(C=235,

E=185)

C=47

E=51

C: nothing

E: 1000

mg/day x45

days

Results: Homogeneity

Q: 1.86

P-value: 0.87

0 0.2 0.6 0.8 1.0 1.2 1.4 0.4

Besse, 2009

Cazeneuve,

2002

Zollinger,

1999

Zollinger,

2007 (1500 mg)

Combined

Zollinger,

2007 (200 mg)

Zollinger,

2007 (500 mg)

Odds Ratios

0.22 (0.13, 0.37)

Results: Dose Response

Dosage Studies Odds Ratio Relative Risk

200 mg x 50 days Zollinger 2007a 0.39 (0.12, 1.29) 0.41 (0.12, 1.35)

500 mg x 50 days Zollinger 1999, Zollinger 2007b 0.23 (0.09, 0.59) 0.26 (0.10, 0.67)

1000 mg x 45 days Besse 2009, Cazeneuve 2002 0.17 (0.07, 0.42) 0.18 (0.07, 0.45)

1500 mg x 50 days Zollinger 2007c 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)

1 Study

1 Study

2 Studies

2 Studies

0 0.2 0.6 0.8 1.0 1.2 1.4 0.4

200 mg x 50

days

500 mg x 50

days

1000 mg x 45

days

Combined

1500 mg x 50 days

Dosage Odds Ratios

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