J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

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Case Report

Volume 7, Number 1, January 2016, pages 33-42

Complex Regional Pain Syndrome: Diagnostic and Treatment Conundrum

**Table 1.** Budapest Criteria 2010 [2]
1) Continuing pain, which is disproportionate to any inciting event
2) Must report one symptom in three of the following four categories;
Sensory: hyperesthesia and/or allodynia
Vasomotor: temperature asymmetry and/or changes in skin color
Sudomotor/edema: edema and/or sweating asymmetry or changes
Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes
3) Must display at least one sign out of the following two or more categories;
Sensory: evidence of hyperalgesia (to pinprick) or allodynia (to light touch) and/or joint movement
Vasomotor: evidence of temperature asymmetry and/or changes in skin color
Sudomotor: evidence of edema and/or sweating asymmetry or changes
Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes
4) There is no other condition that explains the signs and symptoms

Table 1. Budapest Criteria 2010 [2]

1) Continuing pain, which is disproportionate to any inciting event

2) Must report one symptom in three of the following four categories;

Sensory: hyperesthesia and/or allodynia

Vasomotor: temperature asymmetry and/or changes in skin color

Sudomotor/edema: edema and/or sweating asymmetry or changes

Motor/trophic: decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes

3) Must display at least one sign out of the following two or more categories;

Sensory: evidence of hyperalgesia (to pinprick) or allodynia (to light touch) and/or joint movement

Vasomotor: evidence of temperature asymmetry and/or changes in skin color

Sudomotor: evidence of edema and/or sweating asymmetry or changes

Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes

4) There is no other condition that explains the signs and symptoms

**Table 2.** Studies Evaluating Bisphosphonates in Complex Regional Pain Syndrome-I
Study	Design	Drug and regimen	Number (n) of patients and duration (D) of follow-up	Pain assessment following treatment	Outcomes	Comments
n: number; D: duration; NRS: numeric rating scale; VAS: visual analogue scale.
Varenna et al, 2013 [12]	Randomized, double blind, placebo-controlled, multicenter trial	Intravenous neridronate-100 mg (four times over 10 days)	n = 82 patients D = 1 year	Decrease in VAS by 46 mm in treatment group vs. 22 mm in placebo group	1) Better quality of life in treatment group 2) At 1 year all patients were asymptomatic	1) In early stage CRPS-1 patients neridronate provides long-term pain relief and quality of life 2) First study showing conclusive evidence of the efficacy
Robinson et al, 2004 [22]	Randomized, double blind, placebo-controlled study	Single dose intravenous pamidronate 60 mgs vs. saline	n = 27 D = 3 months	VAS at 3 months was lower in treatment group (P = 0.043)	1) Reduction in patient’s global assessment of disease severity in the treatment group 2) Higher SF-36 score in treatment group in function at 3 months (P = 0.047)	1) Small study and single dose administration makes generalizability of efficacy harder 2) Nevertheless, this study highlights the place for bisphosphonates in CRPS
Manicourt et al, 2004 [23]	1) Randomized, double blind, placebo-controlled study 2) Posttraumatic CRPS-I patients	Oral alendronate 40 mg for 8 weeks	n = 40 (20 + 20) D = 24 weeks	1) VAS: significant reduction (P < 0.001) during initial 12-week period 2) Mean VAS was 33% of placebo group at 12 weeks	1) Improvement in joint mobility, edema of legs, tolerance to pressure and spontaneous pains 2) Biomarker urinary N-telopeptide was measured	1) One patient dropped out due to upper GI intolerance 2) Reduction in urinary N-telopeptide (NTX) was noted in treatment group
Adami et al, 1997 [24]	Randomized, placebo-controlled study	1) Intravenous alendronate (7.5 mg) or placebo daily for 3 days 2) Two weeks later all patients received 7.5 mg IV alendronate for 3 days	n = 20 D = 12 months	Reduction in spontaneous pain (P < 0.001)	1) Improvement in motion and edema of extremity (P < 0.001) vs. control group (P < 0.01) 2) Control group who received alendronate showed improvement after first 2 weeks while receiving alendronate	1) Reduction in pain by 50-75% was seen in majority of patients in study group 2) At 1 year 9/20 patients were in remission 3) Optimal dose and duration of therapy remains to be established
Varenna et al, 2000 [25]	1) Randomized, double blind, placebo-controlled study 2) Cross-over trial	1) Intravenous clodronate 300 mg daily for 10 days vs. placebo 2) Placebo group received clodronate after initial 10 days	n = 32 D = 6 months	VAS (0 - 100 mm) - treatment group had overall reduction in pain (93.6) at 6 months	1) Clinical global assessment (0 - 3) -decreased (P = 0.001) 2) Efficacy verbal score (0 - 3) - 11/32 patients EVS = 1.6 3) Urinary telopeptide (marker of bone resorption)-significant decreases at 40 days (P = 0.0003)	1) At 6 month, VAS continued to improve 2) No correlation between VAS and telopeptide marker was seen 3) Clodronate infusion was well tolerated-mechanism of action seems to be different when compared to other bisphosphonates

Table 2. Studies Evaluating Bisphosphonates in Complex Regional Pain Syndrome-I

Study

Design

Drug and regimen

Number (n) of patients and duration (D) of follow-up

Pain assessment following treatment

Outcomes

Comments

n: number; D: duration; NRS: numeric rating scale; VAS: visual analogue scale.

Varenna et al, 2013 [12]

Randomized, double blind, placebo-controlled, multicenter trial

Intravenous neridronate-100 mg (four times over 10 days)

n = 82 patients
D = 1 year

Decrease in VAS by 46 mm in treatment group vs. 22 mm in placebo group

1) Better quality of life in treatment group
2) At 1 year all patients were asymptomatic

1) In early stage CRPS-1 patients neridronate provides long-term pain relief and quality of life
2) First study showing conclusive evidence of the efficacy

Robinson et al, 2004 [22]

Randomized, double blind, placebo-controlled study

Single dose intravenous pamidronate 60 mgs vs. saline

n = 27
D = 3 months

VAS at 3 months was lower in treatment group (P = 0.043)

1) Reduction in patient’s global assessment of disease severity in the treatment group
2) Higher SF-36 score in treatment group in function at 3 months (P = 0.047)

1) Small study and single dose administration makes generalizability of efficacy harder
2) Nevertheless, this study highlights the place for bisphosphonates in CRPS

Manicourt et al, 2004 [23]

1) Randomized, double blind, placebo-controlled study
2) Posttraumatic CRPS-I patients

Oral alendronate 40 mg for 8 weeks

n = 40 (20 + 20)
D = 24 weeks

1) VAS: significant reduction (P < 0.001) during initial 12-week period
2) Mean VAS was 33% of placebo group at 12 weeks

1) Improvement in joint mobility, edema of legs, tolerance to pressure and spontaneous pains
2) Biomarker urinary N-telopeptide was measured

1) One patient dropped out due to upper GI intolerance
2) Reduction in urinary N-telopeptide (NTX) was noted in treatment group

Adami et al, 1997 [24]

Randomized, placebo-controlled study

1) Intravenous alendronate (7.5 mg) or placebo daily for 3 days
2) Two weeks later all patients received 7.5 mg IV alendronate for 3 days

n = 20
D = 12 months

Reduction in spontaneous pain (P < 0.001)

1) Improvement in motion and edema of extremity (P < 0.001) vs. control group (P < 0.01)
2) Control group who received alendronate showed improvement after first 2 weeks while receiving alendronate

1) Reduction in pain by 50-75% was seen in majority of patients in study group
2) At 1 year 9/20 patients were in remission
3) Optimal dose and duration of therapy remains to be established

Varenna et al, 2000 [25]

1) Randomized, double blind, placebo-controlled study
2) Cross-over trial

1) Intravenous clodronate 300 mg daily for 10 days vs. placebo
2) Placebo group received clodronate after initial 10 days

n = 32
D = 6 months

VAS (0 - 100 mm) - treatment group had overall reduction in pain (93.6) at 6 months

1) Clinical global assessment (0 - 3) -decreased (P = 0.001)
2) Efficacy verbal score (0 - 3) - 11/32 patients EVS = 1.6
3) Urinary telopeptide (marker of bone resorption)-significant decreases at 40 days (P = 0.0003)

1) At 6 month, VAS continued to improve
2) No correlation between VAS and telopeptide marker was seen
3) Clodronate infusion was well tolerated-mechanism of action seems to be different when compared to other bisphosphonates

**Table 3.** Studies Evaluating the Role of Spinal Cord Stimulation in Complex Regional Pain Syndrome
Author	Study design	Number of patients and duration of follow-up	Pain score	Comments
n: number; D: duration; NRS: numeric rating scale; VAS: visual analogue scale; PT: physical therapy; PTSD: post-traumatic stress disorder.
Geurts et al, 2013 [26]	Prospective cohort study on CRPS-I	n = 84 D = 12 years	30% reduction in VAS in 40% of patients	Overall reduction in pain was less than 50% At 12 years follow up 60% patients continue to use the implant
Kemler et al, 2008 [27]	Randomized controlled trial-5 year follow-up	n = 36 (SCS + PT) 18 patients PT only D = 2 year *24 patients received permanent implant	SCS + PT was similar to PT only in terms of pain relief	1) In subgroup analysis global perceived effect and pain relief was superior in patients who had SCS 2) SCS efficacy decreases with time but patient satisfaction remains high
van Eijis et al, 2012 [28]	Prospective	n = 6 (out of 74 patients) received early SCS D = 12 months	35% reduction in mean pain relief	Improvement in mental component of SF-36 No functional improvement was noted in any patient SCS beneficial in early stage CRPS
Moriyama et al, 2012 [29]	Prospective, open label, multicenter study	n = 14 (CRPS) D = 6 months	Reduction in mean VAS (79 to 22 mm) and QOL from 0.4 to 0.1 at 6 months	Although shorter follow results are presented, significant reduction in pain and improvement in QOL was noted
Sears et al, 2011 [30]	Prospective evaluation of patients who had SCS (1997 - 2008)	n = 35 D = 4.4 years	More than 50% pain reduction in CRPS patients	Greater patient satisfaction at 4 years
Kemler et al, 2004 [31]	Randomized controlled trial-2 year follow up	n = 36 (SCS + PT) 18 patients PT only D = 2 year *24 patients received permanent implant n = 18 (PT only)	Significant improvement in SCS group (P = 0.001)	1) Global perceived effect was superior in SCS group (43% vs. 6%) 2) Improvement in health related QOL in SCS group 3) No improvement in functional status 4) High initial costs are offset by low overall healthcare costs compared to controls ($60,000 cheaper/patient)
Kumar et al, 2011 [32]	Retrospective review of CRPS patients	n = 25 D = 88 months Follow-ups at entry, 3, 12 and 88 months	VAS: baseline 8.4, at 3 months (4.8) and at 88 months (5.6)	Regression in effect but beneficial (P < 0.01) at last follow-up SCS is beneficial in early stage of CRPS (< 1 year) Reduction in analgesic consumption by 25% Improvements noted in disability, SF-36 and functional status
Reig et al, 2009 [33]	Retrospective 20 year analysis of SCS	n = 260 CRPS-I = 40 patients	VAS in CRPS was 77 ± 13	5% did not have pain relief; 48% had good pain relief; 7.5 % had excellent pain relief; 40% had poor pain relief; Overall complication rate was 28%.
Bennett et al, 1999 [34]	Retrospective, multicenter study on CRPS-1 patients. Two different systems were implanted	n = 101 D = 3 years	Significant reduction in pain (P = 0.0001) in patients who received dual octrode system	High frequency stimulation and multi-electrode stimulation is superior
Kumar et al, 1997 [35]	Retrospective	n = 12 D = 41 months Upper limb injury = 5 patients Lower limb injuries = 7 patients	VAS and McGill questionnaire showed 75% (n = 8) and 50% (n = 4) reduction in pain	Early stage CRPS and younger patients respond better with SCS implantation
Verdolin et al, 2007 [36]	Retrospective, observational study in veterans	1) n = 10 (7 LE pain and 3 UE pain) 2) Symptom duration was less than 1 year	1) Mean NRS 1.6 (pre-SCS NRS 7.6) 2) Reduction in morphine equivalent consumption in CRPS (P = 0.006) patients	1) SCS improved PT efforts 2) Early stage SCS is useful in both CRPS-I and II 3) Co-existing PTSD does not affect SCS efficacy 4) Long-term follow results needs to be seen

Table 3. Studies Evaluating the Role of Spinal Cord Stimulation in Complex Regional Pain Syndrome

Author

Study design

Number of patients and duration of follow-up

Pain score

Comments

n: number; D: duration; NRS: numeric rating scale; VAS: visual analogue scale; PT: physical therapy; PTSD: post-traumatic stress disorder.

Geurts et al, 2013 [26]

Prospective cohort study on CRPS-I

n = 84
D = 12 years

30% reduction in VAS in 40% of patients

Overall reduction in pain was less than 50%
At 12 years follow up 60% patients continue to use the implant

Kemler et al, 2008 [27]

Randomized controlled trial-5 year follow-up

n = 36 (SCS + PT)
18 patients PT only
D = 2 year
*24 patients received permanent implant

SCS + PT was similar to PT only in terms of pain relief

1) In subgroup analysis global perceived effect and pain relief was superior in patients who had SCS
2) SCS efficacy decreases with time but patient satisfaction remains high

van Eijis et al, 2012 [28]

Prospective

n = 6 (out of 74 patients) received early SCS
D = 12 months

35% reduction in mean pain relief

Improvement in mental component of SF-36
No functional improvement was noted in any patient
SCS beneficial in early stage CRPS

Moriyama et al, 2012 [29]

Prospective, open label, multicenter study

n = 14 (CRPS)
D = 6 months

Reduction in mean VAS (79 to 22 mm) and QOL from 0.4 to 0.1 at 6 months

Although shorter follow results are presented, significant reduction in pain and improvement in QOL was noted

Sears et al, 2011 [30]

Prospective evaluation of patients who had SCS (1997 - 2008)

n = 35
D = 4.4 years

More than 50% pain reduction in CRPS patients

Greater patient satisfaction at 4 years

Kemler et al, 2004 [31]

Randomized controlled trial-2 year follow up

n = 36 (SCS + PT)
18 patients PT only
D = 2 year
*24 patients received permanent implant
n = 18 (PT only)

Significant improvement in SCS group (P = 0.001)

1) Global perceived effect was superior in SCS group (43% vs. 6%)
2) Improvement in health related QOL in SCS group
3) No improvement in functional status
4) High initial costs are offset by low overall healthcare costs compared to controls ($60,000 cheaper/patient)

Kumar et al, 2011 [32]

Retrospective review of CRPS patients

n = 25
D = 88 months
Follow-ups at entry, 3, 12 and 88 months

VAS: baseline 8.4, at 3 months (4.8) and at 88 months (5.6)

Regression in effect but beneficial (P < 0.01) at last follow-up
SCS is beneficial in early stage of CRPS (< 1 year)
Reduction in analgesic consumption by 25%
Improvements noted in disability, SF-36 and functional status

Reig et al, 2009 [33]

Retrospective 20 year analysis of SCS

n = 260
CRPS-I = 40 patients

VAS in CRPS was 77 ± 13

5% did not have pain relief;
48% had good pain relief;
7.5 % had excellent pain relief;
40% had poor pain relief;
Overall complication rate was 28%.

Bennett et al, 1999 [34]

Retrospective, multicenter study on CRPS-1 patients.
Two different systems were implanted

n = 101
D = 3 years

Significant reduction in pain (P = 0.0001) in patients who received dual octrode system

High frequency stimulation and multi-electrode stimulation is superior

Kumar et al, 1997 [35]

Retrospective

n = 12
D = 41 months
Upper limb injury = 5 patients
Lower limb injuries = 7 patients

VAS and McGill questionnaire showed 75% (n = 8) and 50% (n = 4) reduction in pain

Early stage CRPS and younger patients respond better with SCS implantation

Verdolin et al, 2007 [36]

Retrospective, observational study in veterans

1) n = 10 (7 LE pain and 3 UE pain)
2) Symptom duration was less than 1 year

1) Mean NRS 1.6 (pre-SCS NRS 7.6)
2) Reduction in morphine equivalent consumption in CRPS (P = 0.006) patients

1) SCS improved PT efforts
2) Early stage SCS is useful in both CRPS-I and II
3) Co-existing PTSD does not affect SCS efficacy
4) Long-term follow results needs to be seen

**Table 4.** Studies Showing Effectiveness of Cognitive Behavior Therapy in Chronic Pain Conditions
Authors	Techniques	Conditions	Results
Lee et al, 2002 [48]	CBT/ physical therapy Children and adolescents	CRPS	89% improvement in functional status No need for assistive devices No severe atrophy and contractures
Van Hoof et al, 2012 [50]	Short intensive CBT Pain management	Chronic low back pain	> 65% significant difference 73% reduction of health care use 57% reduction in analgesic consumption 14% decrease in opioid use
Monticone et al, 2014 [51]	Multidisciplinary CBT Disability/kinesiophobia	Chronic low back pain	61% improvement in disability 100% returned to activities/work 100% discontinued medications
Knox et al, 2014 [52]	CBT - compliance and effectiveness	Lumbar pain	Increased compliance predicted greater effect size and decrease in pain/disability
Heutink et al, 2014 [53]	Multidisciplinary CBT	Spinal cord injury/neuropathic pain	9 - 12 months decrease in pain intensity and pain related disability and anxiety levels Increase in activity

Table 4. Studies Showing Effectiveness of Cognitive Behavior Therapy in Chronic Pain Conditions

Authors

Techniques

Conditions

Results

Lee et al, 2002 [48]

CBT/ physical therapy
Children and adolescents

CRPS

89% improvement in functional status
No need for assistive devices
No severe atrophy and contractures

Van Hoof et al, 2012 [50]

Short intensive CBT
Pain management

Chronic low back pain

> 65% significant difference
73% reduction of health care use
57% reduction in analgesic consumption
14% decrease in opioid use

Monticone et al, 2014 [51]

Multidisciplinary CBT
Disability/kinesiophobia

Chronic low back pain

61% improvement in disability
100% returned to activities/work
100% discontinued medications

Knox et al, 2014 [52]

CBT - compliance and effectiveness

Lumbar pain

Increased compliance predicted greater effect size and decrease in pain/disability

Heutink et al, 2014 [53]

Multidisciplinary CBT

Spinal cord injury/neuropathic pain

9 - 12 months decrease in pain intensity and pain related disability and anxiety levels
Increase in activity