evidencias en sindrome regional complejo

8/20/2019 Evidencias en Sindrome Regional Complejo

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R E V I E W A R T I C L E / B R I E F R E V I E W

Treatment of complex regional pain syndrome: a reviewof the evidence

Traitement du syndrome de douleur régionale complexe:une revue des données probantes

De Q. H. Tran, MD • Silvia Duong, BScPhm •

Pietro Bertini, MD • Roderick J. Finlayson, MD

Received: 27 August 2009 / Accepted: 15 November 2009 / Published online: 7 January 2010

Canadian Anesthesiologists’ Society 2010

Abstract

Purpose This narrative review summarizes the evidencederived from randomized controlled trials pertaining to the

treatment of complex regional pain syndrome (CRPS).

Source Using the MEDLINE (January 1950 to April

2009) and EMBASE (January 1980 to April 2009) dat-

abases, the following medical subject headings (MeSH)

were searched: ‘‘Complex Regional Pain Syndrome’’,

‘‘Reflex Sympathetic Dystrophy’’, and ‘‘causalgia’’ as well

as the key words ‘‘algodystrophy’’, ‘‘Sudeck’s atrophy’’,

‘‘shoulder hand syndrome’’, ‘‘neurodystrophy’’, ‘‘neuro-

algodystrophy’’, ‘‘reflex neuromuscular dystrophy’’, and

‘‘posttraumatic dystrophy’’. Results were limited to ran-

domized controlled trials (RCTs) conducted on human

subjects, written in English, published in peer-reviewed

journals, and pertinent to treatment.

Principal findings The search criteria yielded 41 RCTs

with a mean of 31.7 subjects per study. Blinded assessment

and sample size justification were provided in 70.7% and

19.5% of RCTs, respectively. Only biphosphonates appear

to offer clear benefits for patients with CRPS. Improvement

has been reported with dimethyl sulfoxide, steroids, epi-

dural clonidine, intrathecal baclofen, spinal cord

stimulation, and motor imagery programs, but further tri-

als are required. The available evidence does not support

the use of calcitonin, vasodilators, or sympatholytic and

neuromodulative intravenous regional blockade. Clear

benefits have not been reported with stellate/lumbar

sympathetic blocks, mannitol, gabapentin, and physical/

occupational therapy.

Conclusions Published RCTs can only provide limited

evidence to formulate recommendations for treatment of

CRPS. In this review, no study was excluded based on

factors such as sample size justification, statistical power,

blinding, definition of intervention allocation, or clinical

outcomes. Thus, evidence derived from ‘‘weaker’’ trials

may be overemphasized. Further well-designed RCTs are

warranted.

Résumé

Objectif Ce compte-rendu narratif ré sume les donné es

probantes dé rivé es d’é tudes randomisé es contrô lé es

portant sur le traitement du syndrome de douleur

ré gionale complexe (SDRC).

Source Les termes MeSH suivants ont é té recherché s dans

les bases de donné es MEDLINE (janvier1950 à avril 2009)et

EMBASE (janvier 1980 à avril 2009): « Complex Regional

Pain Syndrome », « Reflex Sympathetic Dystrophy », et

« causalgia » ainsi que les mots-clé s « algodystrophy »,

« Sudeck’s atrophy », « shoulder hand syndrome »,

« neurodystrophy », « neuroalgodystrophy », « reflex

neuromuscular dystrophy », et « posttraumatic dystrophy »,

soit : « syndrome de douleur ré gionale complexe »,

« dystrophie sympathique ré flexe », et « causalgie », ainsi

que les mots-clé s « algodystrophie », « syndrome de

Sü deck », « syndrome é paule-main », « neurodystrophie »,

« neuro-algodystrophie », « dystrophie neuromusculaire

ré flexe » et « dystrophie post-traumatique », respectivement.

Nous avons limité les ré sultats aux é tudes randomisé es

contrô lé es (ERC) ré alisé es chez l’humain, é crites en anglais

dans des revues avec comité s de pairs et portant sur le

traitement.

D. Q. H. Tran, MD (&) P. Bertini, MD R. J. Finlayson, MD

Department of Anesthesia, Montreal General Hospital, McGill

University, Montreal H3G 1A4, Quebec, Canada

e-mail: [email protected]

S. Duong, BScPhm

Faculty of Pharmacy, University

of Toronto, Toronto, Ontario, Canada

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Can J Anesth/J Can Anesth (2010) 57:149–166

DOI 10.1007/s12630-009-9237-0


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Constatations principales Les critères de recherche ont

permis d’extraire 41 ERC avec en moyenne 31,7 sujets par

é tude. Une é valuation en aveugle et une justification de la

taille d’é chantillonnage é taient disponibles pour 70,7 % et

19,5 % des ERC, respectivement. Seuls les biphosphonates

semblent procurer des bienfaits é vidents aux patients

souffrant de SDRC. On a rapporté une diminution de la

douleur avec le dimé thylsulfoxyde, les sté roı̈ des, laclonidine pé ridurale, le baclofen intrathé cal, la stimulation

de la moelle é pinière, et les programmes d’imagerie

motrice, mais d’autres é tudes sont né cessaires. Les

donné es probantes disponibles n’appuient pas l’utilisation

de la calcitonine, de vasodilatateurs, ou de bloc ré gional

intraveineux sympatholytique et neuromodulateur. On n’a

pas rapporté de bé né fices clairs lors de l’utilisation de

blocs sympathiques stellaires/lombaires, de mannitol, de

gabapentine et du recours à la physiothé rapie ou à

l’ergothé rapie.

Conclusion Les ERC publié es ne fournissent que des

donné es limité es quant à la formulation de recommandations pour le traitement du SDRC. Dans ce compte-rendu, aucune

é tude n’a é té exclue sur la base de facteurs tels que la

justification de la taille de l’é chantillonnage, la puissance

statistique, la mé thode en aveugle, la dé finition de l’attribution

de l’intervention ou les devenirs cliniques. Dès lors, trop

d’importance peutavoir é té accordé e aux donné esdé rivé es des

é tudes « plus faibles ». D’autres ERC bien conçues sont

né cessaires.

Introduction

First described more than 100 years ago, Complex Regional

Pain Syndrome (CRPS) still remains a medical challenge

today, with a natural history characterized by chronicity and

relapses that can result in significant disability over time.1

Women are affected more frequently than men, but the

overall incidence is unknown. Fractures and surgical insult

are often the precipitating events, but CRPS can also develop

after a seemingly benign trauma. Adding to this confusion

was the myriad of names used to describe the syndrome,

such as ‘‘Reflex Sympathetic Dystrophy’’, ‘‘causalgia’’,

‘‘Sudeck’s atrophy’’, ‘‘algodystrophy’’, ‘‘neurodystrophy’’,

and ‘‘post-traumatic dystrophy’’. To standardize the taxon-

omy, the term CRPS was adopted in 1995 by the

International Association for the Study of Pain (IASP).2 This

revision was deemed necessary because previous names,

such as Reflex Sympathetic Dystrophy, were misleading.

The underlying pathophysiology is poorly understood, and

patients often do not respond to sympathetic blockade.

Diagnostic criteria were also proposed by the IASP.2 In

contrast, treatment of CRPS remains a controversial topic.

While the literature is replete with reports advocating the use

of various clinical treatments for CRPS (from physiotherapy

to spinal cord stimulation), the levels of supportive evidence

are quite variable and sometimes limited. Accordingly, a

literature search for level 1 evidence (from randomized

controlled trials) was undertaken to determine the benefits

associated with these therapeutic modalities. For the purpose

of this review, no distinction was made between CRPS type 1(formerly Reflex Sympathetic Dystrophy) and 2 (formerly

causalgia).

Methods

Search strategy and selection criteria

The literature search for this review was conducted during

the second week of April 2009 using the MEDLINE

(January 1950 to the 2nd week of April 2009) and EM-BASE (January 1980 to the 15th week of 2009) databases.

The following MeSH terms were searched: ‘‘Complex

Regional Pain Syndrome’’, ‘‘Reflex Sympathetic Dystro-

phy’’, and ‘‘causalgia’’ as well as the key words

‘‘algodystrophy’’, ‘‘Sudeck’s atrophy’’, ‘‘shoulder hand

syndrome’’, ‘‘neurodystrophy’’, ‘‘neuroalgodystrophy’’,

‘‘reflex neuromuscular dystrophy’’, and ‘‘post-traumatic

dystrophy’’. Results were limited to studies conducted on

human subjects, written in English, and published in peer-

reviewed journals. Only randomized controlled trials

(RCTs) pertaining to the treatment of CRPS were considered

for analysis. We excluded trials that investigated the impact

of interventions on parameters measured in vitro (skin

resistance, temperature, vasodilation, thresholds of pain to

different stimuli, mapping of allodynic area) but did not

assess the clinical response of patients. Furthermore, RCTs

needed to deal exclusively with CRPS to be retained for

analysis. We also excluded trials that enrolled a heteroge-

neous mix of patients suffering from CRPS and neuropathic

pain (diabetic neuropathy, post herpetic neuralgia, phantom

limb pain, trigeminal neuralgia, nerve root injury/

radiculopathy, peripheral nerve injury/lesion/neuroma) or

postsurgical pain (sustained after thoracotomy, mastectomy,

inguinal hernia repair) and indiscriminately pooled results

from all subjects. However studies that provided data spe-

cific to CRPS were included in this review. Randomized

controlled trials (RCTs) published in the form of abstracts or

correspondence were also excluded. After selecting the ini-

tial articles, we examined the reference lists as well as our

personal files for additional material. No RCTs were exclu-

ded based on factors such as definition of intervention

allocation or primary and secondary (clinical) outcomes.

However, non-randomized studies, observational case

150 D. Q. H. Tran et al.

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reports, and cohort studies were excluded to avoid potential

biases introduced by institutional practices.

Results

Our search yielded 50 RCTs pertaining to the treatment of

CRPS. Seven of these were excluded because they inves-tigated treatments requiring consultants (acupuncturists, qi

gong masters) or modalities (electromagnetic field, trans-

cranial magnetic stimulation, occlusive splinting, and

hyperbaric oxygen therapy) that are not readily available to

most practitioners. One identified trial was excluded as it

had recently been retracted;A another RCT was excluded

because both groups received the same treatment (graded

in vivo exposure) (Appendix 1). Eighteen of the remaining

41 RCTs studied pharmacological treatment (Table 1) and

18 investigated intravenous regional blockade or central

and peripheral nerve blocks (Table 2). Spinal cord stimu-

lation and adjuvant therapy were addressed in one and fourstudies, respectively (Tables 3 and 4). Overall, the quality

of the 41 RCTs was variable. The average enrolment was

31.7 subjects per study. The IASP definition of CRPS was

used in 30.0% of trials. Blinded assessment and sample

size justification were provided in 70.7% and 19.5% of

RCTs, respectively. The duration of CRPS prior to enrol-

ment was provided in 70.7% of studies and varied from

50 days to 13 yr. Pain was the most common endpoint

studied (78.1% of trials); patient follow up varied from two

weeks to five years.

Pharmacological therapy

Calcitonin

Calcitonin has received considerable interest in the man-

agement of CRPS because of its analgesic properties

through release of ß-endorphin as well as its inhibition of

bone resorption.3 To date, four RCTs have investigated the

use of calcitonin in CRPS.

Bickerstaff et al.3 randomized 38 patients with upper

extremity CRPS to a four-week regimen of nasal calcitonin

or placebo. The authors observed no differences between

the two groups in terms of pain, hand volume, stiffness,

grip strength, and vascular/sudomotor changes. Further-

more, radiographic, densitometric, and scintigraphic

evaluations of the metacarpal bones were also similar.

Gobelet et al.4 randomized 24 patients suffering from hand

or foot CRPS to physiotherapy alone (eight-week course)

or the same physiotherapy regimen combined with a three-

week course of subcutaneous calcitonin. At eight weeks,

there were no intergroup differences in terms of pain,

edema, range of motion, and fitness for work. Bone scin-

tigraphy was also similar. In 66 patients diagnosed with

wrist or ankle CRPS, Gobelet et al.5 combined an intensive

physiotherapy regimen (eight-week course) to a three-week course of nasal calcitonin or nasal placebo spray. At eight

weeks, these authors noted decreased static and dynamic

pain scores (using a four-point pain scale) in the treatment

compared with the placebo group (0.45 ± 0.68 vs

0.69 ± 0.93; P\ 0.007 and 0.77 ± 0.76 vs 1.22 ± 0.91;

P\ 0.04, respectively). Furthermore, range of motion was

also greater in patients receiving calcitonin (P\ 0.04).

However, there were no differences between the two

groups in terms of edema and ability to work. In 2006,

Sahin et al.6 enrolled 35 patients with upper extremity

CRPS and provided them with an exercise and physical

therapy program. In addition, the subjects were randomizedto a two-month regimen of nasal calcitonin or oral para-

cetamol. At two months, Sahin et al.6 observed no

intergroup differences pertaining to pain, range of motion,

allodynia, hyperalgesia, and trophic changes.

Biphosphonates

Bone demineralization often accompanies CRPS. This

observation has prompted many authors to advocate treat-

ment with biphosphonates, which are potent inhibitors of

bone resorption.7 To date, four RCTs have investigated the

role of bisphosphonates in the treatment of CRPS.

In a study by Adami et al.,7 20 patients were randomized

to receive a three-day course of intravenous alendronate or

placebo. After two weeks of treatment, patients receiving

alendronate presented significant improvements in pain,

swelling, and range of motion compared with the control

group (all P\ 0.01). In light of these encouraging results,

Manicourt et al.8 randomized 39 patients with lower limb

CRPS to an eight-week regimen of oral alendronate or

placebo. Participants were excluded if they had received

calcitonin one week prior to study entry; furthermore, they

were encouraged to continue physical therapy and reha-

bilitation on a regular basis. At four, eight, and 12 weeks,

participants receiving alendronate displayed better pain

control and range of motion compared with controls (both

P\ 0.05). Moreover, edema was also improved with

alendronate at four and eight weeks (both P\0.05). In

2000, Varenna et al.9 randomized 31 patients with CRPS to

a ten-day course of intravenous clodronate or placebo. To

assess efficacy, the authors used a visual analogue scale of

pain (VAS, range 0-100), clinical global assessment (CGA,

range 0-3), and an efficacy verbal score (EVS, range 0-3).

A The following article has been retracted: Reuben SS, Rosenthal EA,

Steinberg RB, Faruqi S, Kilaru PA. Surgery on the affected upper

extremity of patients with a history of complex regional pain

syndrome: the use of intravenous regional anesthesia with clonidine.

J Clin Anesth 2004; 16: 517-22.

Treatment of Complex Regional Pain Syndrome 151

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T a b l e 1

R a n d o m i z e d c o n t r o l l e d t r i a l s p e r t a i n i n g t o p h a r m a c o l o g i c a l t r e a t m e n

t

A u t h o r s

( y e a r )

C R P S D e fi n e d

A c c o r d i n g

t o I A S P 2

B l i n d e d

A s

s e s s m e n t /

S a m p l e S i z e

J u s t i fi c a t i o n

D e s c r i p t i o n

N u m b e r o f

P a t i e n t s /

G r o u p s

P r i m a r y O u t c o m e a n d D u r a t i o n

o f F o l l o w u p

M a i n F i n d i n g s

B i c k e r s t a f f

e t a l . 3

( 1 9 9 1 )

N

N / N

D a i l y n a s a l c a l c i t o n i n 4 0 0 u n

i t s v s

p l a c e b o f o r f o u r w e e k s

3 8 / 2

P a i n ( d o l o r i m e t r y r a t i o ) u n t i l

1 2 w e e k s a f t e r s t a r t o f t r e a t m e n t

N o d i f f e r e n c e s i n p a i n ,

h a n d v o l u m e ,

s t i f f n e s s , g r i p

s t r e n g t h ,

v a s c u l a r /

s u d o m o t o r c h a n g e s .

N o d i f f e r e n c e s i n r a d i o g r a p h i c ,

d e n s i t o m e t r i c ,

s c i n t i g r a p h i c e v a l u a t i o n

o f m e t a c a r p a b o n e s .

G o b e l e t

e t a l . 4

( 1 9 8 6 )

N

N / N

D a i l y s u b c u t a n e o u s c a l c i t o n i n 1 0 0 u n i t s

d a i l y f o r t h r e e w e e k s c o m b i n e d w i t h

P T f o r e i g h t w e e k s v s P T a l o n e

2 4 / 2

P a i n , e d e m a , r a n g e o f m o t i o n , a n d

fi t n e s s f o r w o r k u n t i l e i g h t w e e k s

a f t e r e n d o f t r e a t m e n t

N o d i f f e r e n c e .

G o b e l e t

e t a l . 5

( 1 9 9 2 )

N

Y / N

N a s a l c a l c i t o n i n 3 0 0 u n i t s d a

i l y v s

p l a c e b o f o r t h r e e w e e k s i n

c o n j u n c t i o n

w i t h P T f o r e i g h t w e e k s

6 6 / 2

P a i n u n t i l e i g h t w e e k s a f t e r s t a r t o f

t r e a t m e n t

C a l c i t o n i n : b e t t e

r s t a t i c / d y n a m i c p a i n

s c o r e s a n d r a n g e o f m o t i o n a t e i g h t

w e e k s .

N o d i f f e r e n c e s i n e d e m a a n d a b i l i t y t o

w o r k .

S a h i n e t a l . 6

( 2 0 0 6 )

N

Y / N

N a s a l c a l c i t o n i n 2 0 0 m g d a i l y v s o r a l

p a r a c e t a m o l 1 , 5 0 0 m g d a i l y i n

c o n j u n c t i o n w i t h P T f o r t h r e e w e e k s

3 5 / 2

P a i n , r a n g e o f m o t i o n , a l l o d y n i a ,

h y p e r a l g e s i a , t r o p h i c c h a n g e s u n t i l

t w o m o n t h s a f t e r s t a r t o f t r e a t m e n t


A d a m i

e t a l . 7

( 1 9 9 7 )

N

Y / N

A l e n d r o n a t e 7 . 5

m g i v d a i l y v s p l a c e b o

f o r t h r e e d a y s

2 0 / 2

P a i n a t t w o w

e e k s a f t e r s t a r t o f

t r e a t m e n t

A l e n d r o n a t e : l e s s p a i n a n d s w e l l i n g ,

m o r e

r a n g e o f m o t i o n .

M a n i c o u r t

e t a l . 8

( 2 0 0 4 )

Y

Y / Y

A l e n d r o n a t e 4 0 m g p o d a i l y v s p l a c e b o

f o r e i g h t w e e k s

3 9 / 2

P r e s s u r e t o l e r a n c e ( d o l o r i m e t r i c r a t i o )

u n t i l 1 2 w e

e k s a f t e r s t a r t o f

t r e a t m e n t

A l e n d r o n a t e : l e s

s p a i n ,

b e t t e r p r e s s u r e

t o l e r a n c e a n d

m o b i l i t y a t f o u r ,

e i g h t ,

a n d 1 2 w e e k s .

A l e n d r o n a t e : l e s s e d e m a a t f o u r a n d e i g h t

w e e k s .

V a r e n n a

e t a l . 9

( 2 0 0 0 )

N

Y / N

C l o d r o n a t e 3 0 0 m g i v v s p l a c

e b o f o r t e n

d a y s

3 1 / 2

P a i n 4 0 d a y s a f t e r e n d o f t r e a t m e n t

C l o d r o n a t e : l e s s

p a i n ,

i m p r o v e d g l o b a l

a s s e s s m e n t ( e v a l u a t e d b y i n v e s t i g a t o r ) ,

a n d h i g h e r p e r c e i v e d e f fi c a c y

( e v a l u a t e d b y

p a t i e n t s ) .

R o b i n s o n

e t a l . 1 0

( 2 0 0 4 )

Y

Y / N

P a l m i d r o n a t e 6 0 m g i v a s a s i n g l e d o s e v s

p l a c e b o

2 7 / 2

P a i n a f t e r t h r e e m o n t h s

P a l m i d r o n a t e : l e

s s p a i n , h i g h e r o v e r a l l

i m p r o v e m e n t

( p a t i e n t ’ s a s s e s s m e n t ) ,

a n d h i g h e r f u n c t i o n a l a s s e s s m e n t

s c o r e s .

Z u u r m o n d

e t a l . 1 1

( 1 9 9 6 )

N

Y / N

5 0 % D M S O c r e a m d a i l y v s p

l a c e b o f o r

t w o m o n t h s

3 1 / 2

P a i n a n d R S D

s c o r e u n t i l t w o m o n t h s

a f t e r s t a r t o

f t r e a t m e n t

S i m i l a r r e d u c t i o n i n R S D s c o r e s .

G r e a t e r r e d u c t i o n i n V A S s c o r e s w i t h

D M S O .

G e e r t z e n

e t a l . 1 2

( 1 9 9 4 )

N

N / N

5 0 % D M S O c r e a m f o u r t i m e s p e r d a y v s

I V R B ( t w i c e p e r w e e k ) f o r

t h r e e w e e k s

2 6 / 2

S c o r e ( b a s e d o n p a i n ,

d a i l y a c t i v i t i e s ,

e d e m a , c o l o r ,

a n d R O M ) u n t i l n i n e

w e e k s a f t e r

s t a r t o f t r e a t m e n t

D M S O : g r e a t e r i m p r o v e m e n t a t s e v e n a n d

n i n e w e e k s .


1 3


5/18


6/18


7/18

T a b l e 2

c o n t i n u e d

A u t h o r s ( y e a r )


A c c o r d i n g t o

I A S P ( 2 )

B l i n d e d

A s s e s s m e n t /

S a m p l e S i z e



N u m b e r o f

P a t i e n t s /

G r o u p s

P r i m a r y O

u t c o m e / D u r a t i o n o f F o l l o w

u p


P r i c e e t a l . 3 3

( 1 9 9 8 )

Y

Y / N

S G B o r L S B : 1 % l i d o c a i n e 1 5 m L f o r

S G B a n d 1 % l i d o c a i n e

1 5 m L p l u s

0 . 2 5 % b u p i v a c a i n e 1 0 m L f o r L S B v s

N S

7 / 2 (

c r o s s o v e r

s t u d y )

P e a k a n a l g e s i c e f f e c t ( V A S 3 0 m i n

a f t e r i n j e c t i o n ) V A S u n t i l s e v e n

d a y s p o

s t t r e a t m e n t

S i m i l a r p e a k

a n a l g e s i c e f f e c t .

L A : l o n g e r a

n a l g e s i c d u r a t i o n .

M a n j u n a t h

e t a l . 3 4

( 2 0 0 8 )

N *

Y / N

L S B : T R F ( t w o l e s i o n s a t

8 0 8 C f o r 9 0 s e c

a t L 2 , L 3 ,

a n d L 4 ) v s n

e u r o l y s i s w i t h

7 % p h e n o l 3 m L / l e v e l a t L 2 , L 3 , a n d

L 4 .

1 9 / 2

P a i n ( V A S ,

s h a r p p a i n ,

d u l l p a i n ,

s u r f a c e

p a i n ,

d e e p p a i n ,

i n t e n s i t y

o f p a i n ,

h o t p a i n ) u n t i l f o u r

m o n t h s

a f t e r t r e a t m e n t


H a y n s w o r t h R F

J r e t a l . 3 5

( 1 9 9 1 )

N

N / N

L S B : T R F ( t w o l e s i o n s a t 7 0 8 C f o r 1 2 0

s e c a t L 2 , L 3 , a n d L 4 )

v s n e u r o l y s i s

w i t h 6 % p h e n o l 3 m L / l e v e l a t L 2 , L 3 ,

a n d L 4

1 7 / 2

D u r a t i o n o f s y m p a t h e c t o m y

( t e m p e r a t u r e ,

s w e a t t e s t

p e r f o r m

e d b i m o n t h l y ) u n t i l

e i g h t w

e e k s a f t e r t r e a t m e n t

P h e n o l : l o n g e r d u r a t i o n .

C a r r o l l e t a l . 3 6

( 2 0 0 9 )

Y

Y / N

L S B : 0 . 5 % b u p i v a c a i n e 1

0 m L v s

b u p i v a c a i n e - B T A ( 7 5 u

n i t s )

7 / 2 (

c r o s s o v e r

s t u d y )

P a i n ( V A S ) u n t i l o n e m o n t h

p o s t t r e

a t m e n t o r r e t u r n

o f p a i n

t o i t s b a s e l i n e l e v e l

B u p i v a c a i n e

- B T A : l o n g e r a n a l g e s i c

d u r a t i o n .

T r a n e t a l . 3 7

( 2 0 0 0 )

Y

Y / N

L S B : 2 % l i d o c a i n e 3 m L

w i t h

e p i n e p h r i n e ( 5 l g m L - 1 ) a n d 0 . 2 5 %

b u p i v a c a i n e 1 5 m L : I o h e x o l ( 1 . 5

m L )

v s N S

1 5 / 2

P a i n ( V A S ) u n t i l o n e w e e k a f t e r

b l o c k

I o h e x o l : l o w e r V A S s c o r e s o n e h o u r

a n d t h e fi r s t m o r n i n g a f t e r b l o c k .

N o d i f f e r e n c e s a f t e r w a r d s .

N o d i f f e r e n c e s i n a l l o d y n i a , p e r c e n t o f

p a i n r e l i e f ,

a n d i n t e r f e r e n c e w i t h

d a i l y a c t i v

i t i e s .

R a u c k e t a l . 3 8

( 1 9 9 3 )

N

Y / N

C e r v i c a l o r l u m b a r e p i d u r a l f o r u p p e r a n d

l o w e r l i m b C R P S ,

r e s p e c t i v e l y :

c l o n i d i n e 3 0 0 l g v s 7 0 0 l g v s N S

2 6 / 3 ( c

r o s s o v e r

s t u d y )

P a i n ( V A S ,

M P Q ) u n t i l s i x h o u r s

p o s t t r e

a t m e n t

C l o n i d i n e : b e t t e r a n a l g e s i a t h a n N S .

N o d i f f e r e n c e b e t w e e n t h e t w o

c l o n i d i n e d o s e s .

3 0 0 l g c l o n i d i n e : l e s s s e d a t i o n t h a n

7 0 0 l g .

v a n H i l t e n

e t a l . 3 9

( 2 0 0 0 )

Y

Y / N

I n t r a t h e c a l : b a c l o f e n 2 5 l g v s 5 0 l g v s

7 5 l g v s N S

7 / 4 (

c r o s s o v e r

s t u d y )

D y s t o n i a ( V A S ) u n t i l e i g h t h o u r s

a f t e r e a

c h i n j e c t i o n

5 0 l g a n d 7 5

l g o f f e r m o s t r e d u c t i o n s

i n d y s t o n i a .

N o d i f f e r e n c e b e t w e e n 2 5 l g a n d N S .

B T A =

b o t u l i n t o x i n t y p e A ; C R P

S =

c o m p l e x r e g i o n a l p a i n s y n d r o m e ; I A S P =

I n t e r n a t i o n a l A s s o c i a t i o n f o r t h e S t u d y o f P a i n ; I V R B =

i n t r a v e n o u s r e g i o n a l b l o c k a d e ; L S B =

l u m b a r

s y m p a t h e t i c b l o c k ; M P Q =

M c G i l l p a i n q u e s t i o n n a i r e ; N =

n o ; N S = n o r m a l s a l i n e ; R O M =

r a n g e o f m o t i o n ;

S G B =

s t e l l a t e g a n g l i o n b l o c k ; T R F =

t h e r m a l r a d i o f r e q u e n c y ;

V A S =

v i s u a l a n a l o g u e s c a l e ; Y =

y e s

* C R P S d i a g n o s e d a c c o r d i n g t o m o d i fi e d I A S P d e fi n i t i o n

5 8


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Forty days after treatment, subjects receiving clodronate

displayed significantly improved VAS (22.3 ± 20.2 vs56.4 ± 31.4; P\0.001), CGA (0.9 ± 0.6 vs 1.9 ± 0.7;

P\ 0.001), and EVS scores (1.6 ± 0.7 vs 0.2 ± 0.4;

P\ 0.001) compared with controls. In 2004, Robinson

et al.10 randomized 27 patients to a single intravenous

dose of palmidronate 60 mg or placebo. At the three-

month evaluation, subjects who had received biphospho-

nates reported lower pain scores (P = 0.043), a greater

overall improvement (P = 0.026), and higher functional

assessment scores pertaining to physical function

(P = 0.047).

Free radical scavengers

An excessive inflammatory reaction can lead to the over-

production of free radicals, resulting in the destruction of

healthy tissue and possibly leading to CRPS. Thus, free

radical scavengers have been proposed to curtail the dis-

ease process.11 To date, three free radical scavengers

(dimethyl sulfoxide, N -acetylcysteine [NAC], and manni-

tol) have been investigated for the treatment of CRPS.

In 1996, Zuurmond et al.11 randomized 31 patients to a

daily application of a fatty cream containing 50% dimethyl

sulfoxide (DMSO) or a placebo. In addition, all subjects

received physiotherapy. After two months of treatment, theauthors observed that patients in the study group displayed

a greater improvement in the Reflex Sympathetic Dystro-

phy score (based on the presence of pain, edema, decrease

range of motion, altered colour and temperature, as well as

use-dependent worsening of symptoms) (3 vs 4; P\ 0.01).

However, the reductions in subjective pain were similar for

the two groups. In 26 patients with a new diagnosis for

CRPS (\three months), Geertzen et al.12 compared a three-

week course of 50% DMSO to intravenous regional

blockade with ismelin (twice a week for three weeks).

Using a scoring system based on pain, disability, edema,colour, and range of motion, these authors observed a

greater improvement at seven and nine weeks in subjects

randomized to DMSO.

Subsequently, Perez et al.13 compared 50% DMSO with

NAC. One hundred twelve patients, who were recently

diagnosed with CRPS (\one year) and did not undergo

prior sympathectomy, were randomized to a 17-week

course of 50% DMSO or NAC. All subjects also received

paracetamol, naproxen, tramadol, and occupational and

physical therapy. The primary outcome measurement was

the Impairment Level SumScore (ISS), which incorporates

pain, temperature, volume, and active range of motion of the affected extremity. Perez et al.13 also assessed the

effect of treatment on the disability level and the quality of

life. After 17 weeks, no differences were found between

the two groups. However, subgroup analysis revealed that

patients with cold CRPS, defined as a –0.4C difference

between the affected and healthy extremity, showed a

greater improvement in ISS with NAC compared with

DMSO (P = 0.04). In contrast, subjects with warm CRPS,

defined as a ?0.4C difference between the affected and

healthy extremity, displayed more improvement in the

quality of life with DMSO (P = 0.001). Follow up at

52 weeks again revealed no major differences between thetwo groups.

van Dieten et al.14 performed a cost analysis using a

pharmacoeconomic evaluation conducted in parallel to

Perez et al.’s trial. Total costs were defined as the sum of

direct costs within the healthcare system (visits to health-

care providers, prescribed medication, occupational

devices, and home care), direct costs outside the healthcare

system (travel expenses, costs of alternative treatment,

over-the-counter medication, and family care), and indirect

Table 3 Randomized controlled trials pertaining to spinal cord stimulation

Authors (year) CRPS

Defined

According

to IASP (2)

Blinded

Assessment/

Sample Size

Justification

Description Number of

Patients/

Group

Primary Outcome and

Duration of Follow up

Main Findings

Kemler et al.40-42

(2000)

N* N/Y SCS and PT

vs PT alone

54/2 Pain (VAS), GPE,

functional status, and

quality of life until fiveyears after start of

treatment

SCS and PT: significant

improvement in VAS

and GPE at six monthsand two years.

No differences in

functional status and

quality of life.

SCS: 42% cumulative

incidence of side

effects at five years.

CRPS = complex regional pain syndrome; GPE = global perceived effect; IASP = International Association for the Study of Pain; N = no;

PT = physiotherapy; SCS = spinal cord stimulation; VAS = visual analogue scale; Y = yes

* CRPS defined according to the IASP with two additional criteria: impaired function and symptomatology beyond the area of trauma


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T a b l e 4

R a n d o m i z e d c o n t r o l l e d t r i a l s p e r t a i n i n g t o a d j u v a n t t h e r a p y

A u t h o r s ( y e a r )


A c c o r d i n g t o

I A S P ( 2 )

B l i n d e d

A s s e s s m e n t /

S a m p l e S i z e



N u m b e r o f

P a t i e n t s /

G r o u p s

P r i m a r y O u t c

o m e a n d D u r a t i o n

o f F o l l o w u p


O e r l e m a n s

e t a l . 4 3 - 4 5

( 1 9 9 9 )

N

Y / N

P T v s O T v s C T

1 3 5 / 3

P a i n ( V A S a n

d M P Q - D

L V ) , R O M ,

i m p a i r m e n t ( G E P I r a t i n g a n d I S S ) ,

d i s a b i l i t y ( R a b o u d S k i l l s

Q u e s t i o n n a

i r e , m o d i fi e d G r e e n t e s t ,

R a b o u d D e

x t e r i t y T e s t ) ,

a n d

h a n d i c a p ( S I P ) u n t i l o n e y e a r a f t e r

i n c l u s i o n i n t h e s t u d y

N o d i f f e r e n c e i n

V A S .

A t o n e y e a r ,

f e w

e r t o t a l a n d s e n s o r y

w o r d s c h o s e n

o n t h e M P Q - D

L V b y P T

c o m p a r e d w i t h O T ( p e r p r o t o c o l

a n a l y s i s ) .

A t o n e y e a r ,

i m p r o v e d t h u m b R O M w i t h

P T c o m p a r e d

w i t h O T a n d C T ( p e r

p r o t o c o l a n a l y

s i s ) .

A t o n e y e a r ,

n o

d i f f e r e n c e s i n I S S a n d

G E P I r a t i n g ( p e r p r o t o c o l a n a l y s i s ) .

A t o n e y e a r ,

n o

d i f f e r e n c e s i n R a b o u d

S k i l l s Q u e s t i o

n n a i r e ,

m o d i fi e d

G r e e n t e s t ,

a n d

S I P s c o r e s ( p e r p r o t o c o l

a n a l y s i s ) .

L e e e t a l . 4 7

( 2 0 0 2 )

N

Y / Y

S i x - w e e k r e g i m e n o f

P T i n

c h i l d r e n w i t h L E C

R P S : o n e v s

t h r e e t i m e s p e r w e e k

2 5 / 2

P a i n ( V A S ) u

n t i l s i x - 1 2 m o n t h s a f t e r

e n d o f t r e a t m e n t

N o i n t e r g r o u p d i f f e r e n c e s i n V A S ,

g a i t ,

a n d s t a i r c l i m

b i n g a b i l i t y .

M o s e l e y

4 8

( 2 0 0 4 )

N *

Y / N

M I P v s c o n v e n t i o n a l

t h e r a p y f o r

s i x w e e k s

1 3 / 2

P a i n ( N P S ) u n t i l 1 2 w e e k s a f t e r s t a r t

o f t r e a t m e n

t

M I P : d e c r e a s e d

N P S s c o r e s a n d s w e l l i n g

a t s i x a n d 1 2

m o n t h s .

M o s e l e y

4 9

( 2 0 0 5 )

N *

Y / N

R e c I m M i r v s I m R e c I m v s

R e c M i r R e c f o r s i x

w e e k s

2 0 / 3

P a i n ( N P S ) u n t i l 1 2 w e e k s a f t e r s t a r t

o f t r e a t m e n

t

R e c I m M i r : g r e a t e r d e c r e a s e s i n N P S a n d

t a s k - s p e c i fi c N

R S s c o r e s a t 1 2 m o n t h s .

C R P S =

c o m p l e x r e g i o n a l p a i n s y n d r o m e ; C T =

c o n v e n t i o n a l t h e r a p y ; G E P I

=

g u i d e s t o t h e e v a l u a t i o n o f p e r m a n e n t i m p a i r m e n t ; I A S P =

I n t e r n a t i o n a l A s s o c i a t i o n f o r t h e S t u d y o f P a i n ;

I m =

i m a g i n e d m o v e m e n t s ; I S S =

i m p a i r m e n t l e v e l s u m s c o r e ; M I P =

m o t o r i m a g e r y p r o g r a m ; M i r =

m i r r o r m o v e m e n t s ; N =

n o ; M P Q - D

L V =

M c G i l l p a i n q u e s t i o n n a i r e ( D u t c h

L a n g u a g e V e r s i o n ) ; N P S =

n e u r o p

a t h i c p a i n s c a l e ; N R S =

n u m e r i c a l r a t i n g s

c a l e ; O T =

o c c u p a t i o n a l t h e r a p y ; P T = p h

y s i o t h e r a p y ; R e c =

r e c o g n i t i o n o f h a n d l a t e r a l i t y ; R O M =

r a n g e o f

m o t i o n ; V A S =

v i s u a l a n a l o g u e s c

a l e ; Y =

y e s

* C R P S d i a g n o s e d a c c o r d i n g t o m o d i fi e d I A S P d e fi n i t i o n

5 8


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costs (absenteeism, loss of productivity). Over the course

of the 52 weeks, van Dieten et al.14 observed that DMSO

resulted in lower total direct costs than NAC (2852 € vs

3934 €; P\0.05).

Mannitol has also been investigated in the treatment of

CRPS. Perez et al.15 randomized 41 patients to receive

10% mannitol intravenously or placebo, each to be

administered on five consecutive days. These authors foundno intergroup differences in pain (assessed daily during

nine weeks). Furthermore, the levels of impairment, dis-

ability, and handicap were also similar between the two

groups at two, six, and nine weeks.

Steroids

Biopsy studies showing tissue inflammation in CRPS have

led many authors to use steroids.16 To date, three RCTs

have investigated the role of steroids in the treatment of

CRPS.

Christensen et al.16 randomized 23 patients with upperextremity CRPS to prednisone or placebo. The medication

was continued until a clinical response was obtained, but for

no more than 12 weeks. Using a scale based on pain, edema,

volar sweating, and finger-knitting ability, the authors

observed 75% improvement rates of 100% and 20% in the

treatment and control groups, respectively (P\ 0.01).

Braus et al.17 enrolled 34 patients suffering from upper limb

CRPS secondary to cerebral infarct. The subjects were

randomized to a four-week course of methylprednisolone or

placebo. After treatment, the steroid group presented a

decreased shoulder-hand syndrome (SHS) score (based on

pain/hyperalgesia, distal edema, and passive humeral

abduction/external rotation). When patients in the placebo

group were crossed over to the treatment arm, these benefits

persisted. Furthermore benefits were still present at six

months (SHS score\ 3/14). Using a similar population,

Kalita et al.18 randomized 60 patients to a five-week course

of prednisolone or piroxicam. After treatment, the pred-

nisolone group displayed lower SHS scores (4.27 ± 2.83 vs

9.37 ± 2.89; P\ 0.001). In both groups, no changes were

detected in activities of daily living.

Gabapentin

Because neuropathic pain can be a prominent feature in

CRPS, gabapentin, an anticonvulsant with proven analgesic

effect in various neuropathic pain syndromes, has been

investigated.19

van de Vusse et al.19 undertook a double-blind ran-

domized crossover study in 46 patients with long standing

CRPS that was refractory to sympathetic blocks, mannitol

infusions, and transcutaneous modulation. At first, the

subjects were randomized to receive a three-week course of

gabapentin or placebo. This was followed by a two-week

washout period. Subsequently, the patients were crossed

over. Overall, there were no differences in pain scores

between treatment and control groups. However, using

global perceived pain relief, more patients receiving

gabapentin reported an improvement in pain control (43%

vs 17% of patients; P = 0.002). Subjects receiving gaba-

pentin also reported more side effects (dizziness,somnolence, lethargy) (all P B 0.003).

Tadalafil

During the chronic phase of CRPS, impaired microcircu-

lation can lead to tissue hypoxia and metabolic tissue

acidosis. Tadalafil is a vasodilator that inhibits phospho-

diesterase 5, used to treat erectile dysfunction and

pulmonary arterial hypertension.20

Groeneweg et al.20 randomized 24 patients suffering

from cold CRPS of a lower limb to a 12-week course of

placebo or tadalafil. In addition, all subjects continuedphysiotherapy. After treatment, patients in the tadalafil

group experienced a greater reduction in VAS scores (15%

vs 0%; P = 0.004). However temperature changes, muscle

strength, and activity level were similar between the two

groups.

Sarpogrelate hydrochloride

Sarpogrelate hydrochloride, a selective 5-HT2 antagonist,

has been shown to improve peripheral blood circulation

through inhibition of serotonin-induced platelet aggrega-

tion and vasoconstriction.21

Ogawa et al.21 randomized 30 patients with CRPS to

conventional treatment (sympathetic blocks, analgesics,

antiepileptics, antidepressants, sedatives, physical therapy)

or a three-month course of sarpogrelate combined with

conventional therapy. At the end of treatment, no differ-

ences in pain were observed between the two groups.

However, with sarpogrelate, a greater proportion of

patients reported improvement in burning pain sensation

(70% vs 0%; P\ 0.05).

Interpretation

In all placebo-controlled RCTs, biphosphonates have been

shown to decrease pain and swelling as well as to increase

range of motion for patients with CRPS. In most trials per-

taining to calcitonin, benefits associated with its

administration were not detected. The effect of free radical

scavengers may be drug dependent; while mannitol is no

better than placebo, DMSO seems to provide a mild

improvement in range of motion and vasomotor instability

in patients with CRPS. Owing to its costs, NAC is best


1 3


11/18

reserved for a subgroup of patients with cold CRPS. A short

course of oral steroids (prednisolone or methylprednisolone)

may help with pain control, edema, and mobility in CRPS

patients with or without cerebral infarcts. In light of the

marginal benefits or limited supportive evidence, tadalafil,

sarpogrelate, and gabapentin should be used with caution.

Intravenous regional blockade and nerve blocks

Intravenous regional blockade (IVRB)

Since CRPS has been traditionally associated with a dys-

function of the sympathetic nervous system, many authors

have advocated treatment with sympathetic blockade,

achieved using an IVRB consisting of local anesthetics,

guanethidine (an inhibitor of the presynaptic release of

norepinephrine), reserpine (an agent inhibiting norepineph-

rine synthesis and depleting norepinephrine stores), and/or

droperidol (an alpha adrenergic antagonist). Ketanserin

(a serotonin type 2 receptor antagonist) and atropine havealso been used, although the beneficial effects with these

agents were thought to occur through neuromodulation.

Currently, there are seven RCTs comparing IVRB

therapy with placebo; another four RCTs compare various

therapeutic agents for IVRB.

Randomized controlled trials comparing treatment with

placebo

In 1990, Blanchard et al.22 randomized 21 patients with

CRPS to IVRB with guanethidine, reserpine, or normal

saline (NS). Both guanethidine and reserpine were diluted

in NS. Pain scores measured at weekly intervals during

12 weeks were not significantly different between the three

groups. Subsequently, Jadad et al.23 enrolled nine patients

with CRPS who were known to be responsive to sympa-

thectomy with guanethidine. In each subject, one low dose

of guanethidine (10 and 20 mg for the upper and lower

limb, respectively) diluted in NS, one high dose of gua-

nethidine (30 mg for both upper and lower limbs) diluted

in NS, and one dose of plain NS were tested on three

occasions separated by intervals of one week. The order of

the solutions was random. Jadad et al.23 observed no

intergroup differences in terms of pain intensity and relief,

mood, and duration of analgesia. In 2002, Livingstone

et al.24 randomized 56 patients with upper extremity CRPS

to IVRB with NS or guanethidine (diluted in 0.5% prilo-

caine). Based on the clinical response, further blocks, to a

maximum of four, were administered at weekly intervals.

Assessments (pain, vasomotor instability, digital tender-

ness, and stiffness) were carried out at 24 hr, 48 hr, and one

week after each block. Compared with the control group,

Livingstone et al.24 found no benefits associated with

guanethidine. In fact, long term analysis at 15 weeks

revealed that patients receiving guanethidine were more

likely to have persistent alterations in hand color

(P = 0.015); the colour and temperature of their hands also

exhibited more sensitivity to ambient thermal changes

(P = 0.003). Moreover, at 30 weeks, more subjects com-

plained of altered hand temperature (69% vs 14%;

P\ 0.001) and digital swelling (P = 0.04).Although guanethidine is the most commonly used drug

for IVRB, some authors have investigated alternative

agents, such as droperidol, ketanserin, atropine, and

methylprednisolone. Kettler et al.25 enrolled six patients

with CRPS who had previously obtained a significant but

transient relief with a local anesthetic sympathetic block.

The subjects were randomized to IVRB with droperidol/

heparin/NS or placebo (heparin/NS). Pain was monitored

daily. After two weeks, the procedure was repeated with

the alternate solution. Droperidol was not associated with

any analgesic benefits; however, in three patients, akithe-

sia, dysphoria, or nausea occurred. Hanna et al.26

randomized nine patients to a series of two IVRB with

ketanserin followed by two IVRBs with placebo or vice

versa. Treatments were provided at weekly intervals. No

differences in pain scores were seen. However, ketanserin

was associated with more drowsiness, faintness, and

shakiness (all P\ 0.05). In 1993, Glynn et al.27 recruited

14 patients with CRPS that was confirmed by pain relief

after a guanethidine IVRB. The subjects were randomized

to IVRB with atropine diluted in NS or NS alone. Patients

could receive up to two treatments at a weekly interval

before crossing over to the alternate solution. There were

no differences in pain, pain relief, and mood. Taskaynatan

et al.28 recruited 22 patients with upper limb CRPS who

did not undergo sympathetic blockade in the prior month.

Treatment was randomized to IVRB with methylprednis-

olone and 2% lidocaine (diluted in NS) or NS. A series of

three treatment sessions was carried out at weekly inter-

vals. Pain, range of motion, edema, and patient satisfaction,

measured on each occasion one hour after tourniquet

release, revealed no differences between the two groups.

These variables were still similar at 1.5 months.

Randomized controlled trials comparing therapeutic

modalities

Rocco et al.29 recruited 12 patients with CRPS that pre-

sented temporary relief with either stellate or lumbar

sympathetic block. IVRB was achieved using guanethidine

diluted in 0.5% lidocaine, reserpine diluted in 0.5% lido-

caine, or plain 0.5% lidocaine. Every subject underwent

treatment with all three solutions in a randomized fashion

at weekly intervals. Pain scores were evaluated over

90 min after each block, and patients maintained an hourly


1 3


12/18

pain log during the week following treatment. There were

no differences between the three groups.

In 1995, Ramamurthy et al.30 attempted to determine the

optimal number of blocks for an IVRB with guanethidine.

Fifty-seven patients with a recent history of CRPS (\three

months), who had not undergone prior IVRB, were ran-

domized to receive one, two, or four IVRBs. The blocks

were carried out at four-day intervals using guanethidinediluted in 0.5% lidocaine. Pain, global evaluation (per-

ceived improvement), and range of motion measured after

each session and at one, three, and six months, were similar

after one, two, or four block s.

In 1983, Bonelli et al.31 compared IVRB and stellate

ganglion blockade. Nine patients were randomized to a

series of four IVRBs with guanethidine performed every

four days or to a sequence of eight stellate ganglion blocks

(0.5% bupivacaine) carried out every other

evidencias en sindrome regional complejo

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