Overview of Reviews

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Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews

  1. Neil E O'Connell1,*,
  2. Benedict M Wand2,
  3. James McAuley3,
  4. Louise Marston4,
  5. G Lorimer Moseley5

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 30 APR 2013

Assessed as up-to-date: 1 MAR 2013

DOI: 10.1002/14651858.CD009416.pub2


How to Cite

O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD009416. DOI: 10.1002/14651858.CD009416.pub2.

Author Information

  1. 1

    Brunel University, Centre for Research in Rehabilitation, School of Health Sciences and Social Care, Uxbridge, Middlesex, UK

  2. 2

    The University of Notre Dame Australia, School of Physiotherapy, Fremantle, West Australia, Australia

  3. 3

    Neuroscience Research Australia, Moseley Group, Randwick, New South Wales, Australia

  4. 4

    University College London, Research Department of Primary Care & Population Health, London, UK

  5. 5

    University of South Australia, School of Health Sciences, Adelaide, South Australia, Australia

*Neil E O'Connell, Centre for Research in Rehabilitation, School of Health Sciences and Social Care, Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK. neil.oconnell@brunel.ac.uk.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 30 APR 2013

SEARCH

 
Table 1. The Budapest clinical diagnostic criteria for CRPS

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

2. Must report at least one symptom in three of the four following categories

  • Sensory: reports of hyperaesthesia and/or allodynia
  • Vasomotor: reports of temperature asymmetry and/or skin colour changes and/or skin colour asymmetry
  • Sudomotor/oedema: reports of oedema and/or sweating changes and/or sweating asymmetry
  • Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

3. Must display at least one sign at time of evaluation in two or more of the following categories

  • Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement)
  • Vasomotor: evidence of temperature asymmetry and/or skin colour changes and/or asymmetry
  • Sudomotor/oedema: evidence of oedema and/or sweating changes and/or sweating asymmetry
  • Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)

4. There is no other diagnosis that better explains the signs and symptoms

 
Table 2. AMSTAR tool: Quality assessment criteria

CriteriaSpecific requirements

1. Was an 'a priori' design provided?The research question and inclusion criteria should be established before the conduct of the review.

2. Was there duplicate study selection and data extraction?There should be at least two independent data extractors and a consensus procedure for disagreements should be in place.

3. Was a comprehensive literature search performed?At least two electronic sources should be searched. The report must include years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the search strategy should be provided. All searches should be supplemented by consulting current contents, reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the references in the studies found.

4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?The authors should state that they searched for reports regardless of their publication type. The authors should state whether or not they excluded any reports (from the systematic review), based on their publication status, language etc.

5. Was a list of studies (included and excluded) provided?A list of included and excluded studies should be provided.

6. Were the characteristics of the included studies provided?In an aggregated form such as a table, data from the original studies should be provided on the participants, interventions and outcomes. The ranges of characteristics in all the studies analysed e.g. age, race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be reported.

7. Was the scientific quality of the included studies assessed and documented?'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to include only randomised, double-blind, placebo controlled studies, or allocation concealment as inclusion criteria); for other types of studies alternative items will be relevant.

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?The results of the methodological rigor and scientific quality should be considered in the analysis and the conclusions of the review, and explicitly stated in formulating recommendations.

9. Were the methods used to combine the findings of studies appropriate?For the pooled results, a test should be done to ensure the studies were combinable, to assess their homogeneity (i.e. Chi squared test for homogeneity, I2). If heterogeneity exists a random effects model should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is it sensible to combine?).

10. Was the likelihood of publication bias assessed?An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other available tests) and/or statistical tests (e.g. Egger regression test).

11. Was the conflict of interest stated?Potential sources of support should be clearly acknowledged in both the systematic review and the included studies.

Total Score

 Each criterion judged as 'Yes' (score one point), 'No' (score no point), 'Can't answer' (score no point) or 'not applicable' (score one point). Total score summed out of a maximum 11 points.
 
Table 3. Reasons for review or paper exclusion

Reason for exclusionPapers excluded

Not a systematic review*Athie-Garcia 1992; Baidya 2011; Ezendam 2009; Harden 2005; Harden 2006, Hassantash 2003; Johnson 2011; Koltzenburg 1998; Kouroukli 2010; Bal 2010; Leite 2000; Manchikanti 2011; Martinez 1993; Neira 1988; Nilsagard 2004*; North 2010; Schestasky 2008; Williams 2008

Insufficient CRPS exclusivityAttal 2010; Beckerman 1990; Bekkering 2011; Bernstein 2001; Bittar 2005; Blonk 2010; Blum 2008; Bronfort 2010; Campbell 2001; Cao 2010; Covarrubias-Gomez 2008; del Pozo 2011; Derry 2009; Duhmke 2004; Dworkin 2007; Eccles 2005; Eisenberg 2006; Ellis 2008; Finnerup 2005; Finnerup 2007; Finnerup 2010; Florez 2010; Claydon 2010; Fulop 2010; Gill 2011; Haroutiunian 2010; Gottschild 2003; Linde 2001; Lord 2002; McHardy 2008; Moore 2009; Moulin 2007; Namaka 2004; Namaka 2009; Nnoaham 2008; Noble 2010; Pappagallo 2008; Patel 2009; Pittler 2007; Pittler 2008; Plested 2010; Rauck 2009; Rehberg 2010; Saarto 2010; So 2008; Seidel 2008; Trescott 2008; Vlassakov 2011; Watson 2010; Wetering 2010; Wiedemann 1997; Wiffen 2009; Saarto 2010a; Wiffen 2011; Zaccara 2011

No novel coverage in addition to existing Cochrane reviews or more recently published included reviews**Albazaz 2008; Cepeda 2002; Geertzen 2006; Goodyear-Smith 2009; Kingery 1997; Perez 2010; Prescrire 2009; Vergne-Salle 2009; Van den Berg 2002

Duplicate to included reviewMcQuay 1997 (duplicate of included review by Jadad 1995)

Not measuring relevant outcomes to this overviewGranot 2007

No RCTs identifiedHocking 2003; Motsch 1997

 *Nilsagaard - Norwegian translators judgement (sole reviewer). Also lack of detail in report meant data extraction not possible.
** Where reviews considered all interventions for CRPS or 2 reviews compared the same intervention each review was compared to the most recent. Where an older review identified no RCTs that had not already been identified in a more recent review and the data were adequately reported in the more recent review, the older review was excluded. Similarly where more than one review investigated the same intervention or class of interventions, the equivalent process was followed.
 
Table 4. List of reviews, interventions and trials that contributed to the overview

Intervention Review Unique trials contributed and sample size (n)

Pharmacotherapies

BisphosphonatesBrunner 2009Adami 1997 (20)

Manicourt 2004 (39)

Robinson 2004 (27)

Varenna 2000 (32)

Chauvineau 2005Cohen 1998 (14)

CalcitoninTran 2010Bickerstaff 1991 (38)

Gobelet 1986 (24)

Gobelet 1992 (66)

Sahin 2006 (35)

Perez 2001

 
Cherot 1983 (95)

Friez 1982 (55)

CorticosteroidsFischer 2010Braus 1994 (36)

Christensen 1982 (23)

Kalita 2006 (60)

Lukovic 2006 (60)

Taskaynatan 2004 IVRB (22)

Epidural clonidineTran 2010Rauck 1993 (26)

NMDA antagonistsCollins 2010Schwartzman 2009 (19)

Sigtermans 2009 (60)

Free radical scavengersFischer 2010Geertzen 1994 (26)

Goris 1987 (20)

Perez 2003 (146)

Perez 2008 (41)

Zuurmond 1996 (30)

GabapentinMoore 2011(C)van de Vusse 2004 (58)

Sarpogrelate hydrochlorideTran 2010Ogawa 1998 (30)

Systemic local anaesthetic agentsChallapalli 2005 (C)Wallace 2000 (16)

TadalafilTran 2010Groeneweg 2008 (24)

Interventional and surgical procedures

Epidural clonidineTran 2010Rauck 1993 (26)

IVRB atropineTran 2010Glynn 1993 (30)

IVRB bretyliumJadad 1995Hord 1992 (7)

IVRB dropiredol + heparinJadad 1995Kettler 1988 (6)

IVRB guanethidineJadad 1995Blanchard 1990 (21)

Bonelli 1983 (19)

Jadad 1995 (9)

Rocco 1989 (10)

Dhar 1992 (15)

Tran 2010Livingstone 2002 (56)

Ramamurthy 1995 (57)

IVRB ketanserinJadad 1995Hanna 1989 (16)

 

Forouzanfar 2002Bounameaux 1984 (9)

Local anaesthetic sympathetic blockadeCepeda 2005Price 1998 (7)

Verdugo 1995 (16)

Tran 2010Carroll 2009 (7)

SympathectomyStraube 2010 (C)Manjunath 2008 (20)

Neurostimulation methods

Spinal cord stimulationMailis-Gagnon 2004 (C)Kemler 2000;

Kemler 2001; Kemler 2002 (54)

Simpson 2009Kemler 2004; Kemler 2006

Repetetive transcranial magnetic stimulation (motor cortex)O'Connell 2010Pleger 2004 (10)

Physical and rehablitation interventions

Manual lymph drainageForouzanfar 2002Uher 2000 (35)

Mirror therapy and GMIRothgangel 2011Cacchio 2009 (48)

Cacchio 2009a (24)

Moseley 2004 (15)

Moseley 2006 (37)

Physiotherapy and occupational therapyDaly 2009Oerlemans 1999 (135)

Pulsed electromagnetic frequency therapyDaly 2009Durmus 2004 (40)

Alternative therapies

Acupuncture and QigongLu 2009Chang 2005 (80)

Jin 2007 (72)

Liu 2006 (100)

Smith 2005Ernst 1995 (14)

Fialka 1993 (14)

Kho 1995 (28)

Wu 1999 (26)

Forouzanfar 2002Korpan 1999 (14)

Autogenic relaxation trainingSmith 2005Fialka 1996 (18)

 
Table 5. Characteristics of included reviews

ReviewDate assessed as up to date*PopulationInterventionsComparison InterventionsOutcomes for which data were reported**Review LimitationsϮ

Cochrane reviews

Cepeda 2005November 2003CRPS (formal diagnostic criteria not required)selective sympathetic blockade (excl. somatic nerve blocks, local anaesthetics or sympatholytic drugs)placeboshort and long-term pain relief. Adverse events

Challapalli 2005May 2004patients of any age with neuropathic painlidocaine or its analogues given orally or parenterallyplacebo or other therapyintensity of pain or its relief. Adverse effects

Mailis-Gagnon 2004September 2003adult patients with chronic pain (duration >6 months)spinal cord stimulation (surgically or percutaneously implanted)no stated limitationspain relief, functional status/ disability, well being, satisfaction with treatment, complications, quality of life

Moore 2011January 2011adult patients with chronic neuropathic paingabapentin (any dose)placebo, no intervention or any active comparatorpain intensity or relief. Patient global impression of change. Withdrawal due to lack of efficacy or adverse events, adverse events, function

O'Connell 2010November 2009adult patient with chronic pain (duration > 3 months)non-invasive brain stimulation techniquessham stimulation controlspain intensity/ severity, disability, quality of life, adverse events

Straube 2010May 2010any age, any duration, neuropathic paindestructive surgical or chemical cervicothoracic or lumbar sympathectomyplacebo or other active treatmentpain relief lasting for a minimum of 4 weeks, adverse events and complications, occurrence or persistence of new or expanded pain

non-Cochrane reviews

Brunner 2009April 2007CRPS-I (diagnostic criteria not specified)bisphosphonatesplacebopain, function, quality of life, adverse eventsdetails of meta-analysis insufficient

Chauvineau 20052003CRPS-I (diagnostic criteria not specified)bisphosphonatesplacebo, calcitoninNot specified

Collins 2010October 2009acute or chronic neuropathic painNMDA receptor antagonistsplacebopain, adverse events

Daly 2009September 2007CRPS-I, with stated diagnostic criteriaphysiotherapy (alone or delivered in combination with other therapies)any comparisonpain, function

Fischer 2010December 2009CRPS-I (diagnostic criteria not specified)anti-inflammatory therapiesany comparisonpain, ROM, clinical improvementpositive conclusions influenced by non-randomised studies

Forouzanfar 2002June 2000RSD and CRPS-Iany treatmentany comparisonpain intensity

Jadad 1995May 1993RSD (diagnostic criteria not specified)intravenous regional sympathetic blockadeany comparisonpain intensity

Lu 2009Sept 2008Post-stroke shoulder hand syndromeacupuncturesham or other interventionpain, ROM, ability to conduct daily activitiesinformation extracted via an interpreter

Perez 2001May 2000RSD, CRPS-I (diagnostic criteria not specified)medicinal treatmentsany comparisonpain relief

Rothgangel 2011August 2010all adult patients suffering from stroke, phantom limb pain or CRPS (diagnostic criteria not specified)mirror therapy (more than 2 interventions) in isolation or combination with other types of treatmentany comparisonat least one important clinical outcome

pain, motor function
includes studies that are not pure mirror therapy - therefore effects observed may not be due to mirror therapy component

Simpson 2009August 2007adults with chronic neuropathic or ischaemic pain with inadequate response to medical or surgical treatmentspinal cord stimulation (incl. implantable pulse generator systems (rechargeable and non-rechargable) and radiofrequency receiver systemsmedical or surgical treatment that does not include spinal cord stimulationpain, health-related quality of life, function, anxiety and depression, complications and adverse effects

Smith 2005November 2004CRPS-I (diagnostic criteria not specified)physiotherapy modalities (one or more)any comparisonpain, function, patient subjective success, sickness impact profile, depression, anxietyreporting of methodology limited

Tran 2010April 2009CRPS (diagnostic criteria not specified)any interventionany comparisonany clinical outcomesonly English language trials included

 * For non-Cochrane reviews the final month/year that the search included
** of interest to this overview
Ϯ not clearly covered by AMSTAR assessment (see  Table 6)
 
Table 6. Results of AMSTAR quality assessment

AMSTAR Item


Review ID1234567891011Score /11

Cochrane reviews

Cepeda 2005YNYYYYYYYNAN9

Challapalli 2005YYYYYYYYNAYN10

Mailis-Gagnon 2004YYYYYYYYNANAN10

Moore 2011YYYYYYYYYYN10

O'Connell 2010YYYYYYYYNAYN10

Straube 2010YYYNYYYYNANAN9

non-Cochrane reviews

Brunner 2009YYNNNYYYCANN5

Chauvineau 2005CANYNNYYYNANN5

Collins 2010CANNNNYYYYNN4

Daly 2009CANYNNYYYNANN5

Fischer 2010CANNNNYYYNANAN5

Forouzanfar 2002CAYYNNYYYNANAN7

Jadad 1995CANNNNYNYNANN3

Lu 2009CAYYNNYYYNANAN5

Perez 2001CANNNNYYYYNANA4

Rothgangel 2011CAYYNYYYYNANN7

Simpson 2009CANYYYYYYNANAN8

Smith 2005CANYNNYNYNANN4

Tran 2010CANNNYYNYNANAN5

 Y = Yes - criteria met (score 1 point), n = No - criteria not met (score 0 points), CA = Can't answer (score 0 points)
NA = not applicable (score 1 point)
 
Table 7. Overview of reviews

OutcomeIntervention and comparison interventionContributing reviewsRelative effect?Number of participants (studies)Quality of the evidence (GRADE)Comments

Pain

Pharmacotherapy


Anti-inflammatory treatments

Corticosteroids (Oral)Fischer 2010

Oral prednisolone

5mg/day + diverse physical agents versus placebo + same
Outcome: 0-10 pain VAS

no statistically significant difference
60 (1)Very low

Topical free radical scavengersFischer 2010

DMSO 50% in fatty cream versus placebo fatty cream over 2 monthsOutcome 0-10 pain VAS

No significant difference
31 (1)Very low

IVRB corticosteroids

IVRB methylprednisolone 40mg with lidocaine10ml 2% once a week versus 100ml saline x3 in totalOutcome pain VAS

No significant difference
22 (1)Very low

Intravenous free range scavengersFischer 2010

Mannitol 10% versus placebo every day for 5 daysOutcome pain VAS 0-100

No significant improvement
41 (1)Very low

Bisphosphonates

Brunner 2009; Chauvineau 2005

Bisphosphonates (IV, oral) versus placeboOutcome pain

VAS 0-100

Pooled estimates:

4 weeks -22.4 (95%CIs not available)

12 weeks -21.6 (95% CIs not available)
66 (2)LowPooled estimates obtained using data from 2 out of 4 identified trials. Minimal detail given re: statistical approach to pooling. No precision estimates available. Remaining two trials also positive.

Calcitonin

Calcitonin *(varied delivery and dosage) versus placeboPerez 2001Effect size (Glass Δ adjusted for sample size) 0.444, SD 0.362, P<0.002118 (3)Low

Nasal Calcitonin versus oral paracetamolTran 2010Pain, no significant difference35 (1)Very low

Nasal calcitonin versus IV pamidronateChauvineau 2005Pain, no significant difference14 (1)Very low

Gabapentin


Gabapentin 1800mg/day orally versus placeboMoore 2011Pain.

No significant effect
58 (1)Very low

NMDA receptor antagonists

IV ketamine (variable dosage) versus placeboCollins 2010Pain 0-10 NRS

mean difference post-treatment

-2.63 (95% CI -3.39-1.88) I2=21%, P=0.00001
79 (2)Low

Sarpogrelate hydrochloride


oral sarpogrelate hydrochloride (300mg/day) plus conventional treatment versus conventional treatment alone for 3 monthsTran 2010Pain 0-100 VAS

No significant difference observed
30 (1)Very low

Systemic local anaesthetic agents


IV lidocaine infusion targeted to deliver a stepped increase in plasma concentrations of 1,1.5, 2 or 3 µg/ml versus "placebo" IV diphenhydramine (70-80mg)Challapalli 2005Spontaneous pain 0-100 VAS

high dose lidocaine may have a small short-term effect (immediately post-infusion)
Very low

Tadalafil

Oral tadalafil (10mg/day for four weeks followed by 20mg/day for 8 weeks) versus placeboTran 2010Pain 0-100 VAS

Study report: 14% improvement versus placebo

Our analysis:

-4.20mm (95% CI -16.61 to 8.21) (not significant)
24 (1)Very low

Interventional procedures


Epidural clonidine


Epidural clonidine versus placeboTran 2010300

or 600μg clonidine reduced pain VAS greater than placebo (saline). 6 hours post-treatment

No numeric data presented

No long-term follow up
26 (1)Very low

Intravenous regional anaesthetic blocks (IVRB)


Atropine (0.6mg) versus placeboTran 2010Pain VAS

No effect
33 (1)Very low

Bretylium (1.5mg/kg) + lidocaine (200-300mg) versus lidocaine (200-300mg)Jadad 1995Duration of ≥30% pain relief

active group mean (SD) 20.0 (17.5) days

control group mean 2.7 (3.7) days
Very low

Dropiredol (2.5mg) + heparin (500-1000U) versus heparin (500-1000U)Jadad 1995Pain VAS

No effect observed
6 (1)Very low

Guanethidine (varied dose) versus placeboJadad 1995; Tran 2010Pain (miscellaneous)

No effect in any study
189 (6)Moderate

Ketanserin (10mg) versus placeboJadad 1995weekly pain VAS

Demonstrated a significant effect (no effect size available)
9 (1)Very low

Local Sympathetic Blockade

Local anaesthetic sympathetic blockade (lidocaine or bupivacaine) versus placeboCepeda 2005Short-term pain relief

RR 1.17 (95% CI 0.80 to 1.72)

(no significant effect)
23 (2)Very low

Botulinum toxin A (75 units) plus bupivacaine (10ml of 0.5%) with just bupivacaine (10ml of 0.5%)Tran 2010Median time to analgesic failure

71 days (95% CI 12-253) with botulinum toxin versus bupivacaine compared to <10 days (95% CI 0-12) with bupivacaine alone P<0.02
7 (1)Very low

Sympathectomy


Straube 2010PainNo evidence

Neurostimulation methods

High frequency repetitive transcranial magnetic stimulation (single session) versus sham stimulationO'Connell 2010Pain VAS

SMD -0.14 (95% CI -0.57 to 0.29) P=0.52
9 (1)Very low

Spinal cord stimulation (SCS) + physical therapy versus physical therapy aloneMailis-Gagnon 2004; Simpson 2009Pain 0-10 VAS mean difference

6 months

(-3.40 (95% CI -4.82 to -1.98)
54 (1)Very low

Physiotherapy/ Occupational Therapy

Physiotherapy (PT) versus occupational therapy (OT) versus social work (SW)Daly 2009; Smith 2005One year follow up: pain 0-100 VAS

PT vs OT mean difference 4.5 (95% CI -10.1 to 19.1)

PT vs SW 5.2 (-3.3 to 7.1)
135 (1)Low

Manual lymph drainage massage and exercise versus exercise aloneForouzanfar 2002Pain verbal rating scale

No significant difference
35 (1)Very low

Pulsed electromagnetic field plus calcitonin and exercise versus sham EMF plus calcitonin and exerciseDaly 2009Pain VAS

No significant difference
40 (1)Very low

Graded motor imagery programme versus conventional physiotherapyDaly 2009; Rothgangel 2011Pain VAS 0-100

pooled mean difference:

end of treatment: -14.45 (95% CI -23.02 to -5.57, P=0.001)

at 3-6 month follow up: -21.64 (95% CI -30.02 to -13.27, P<0.001)
49 (2)Low

Mirror therapy versus covered mirror therapy.

(post stoke CRPS)
Rothgangel 2011Pain at rest 0-10 VAS

Both studies report positive effects.

Data extracted from one study mean difference -2.9 (95% CI -1.57 to -4.23) at end of treatment

mean difference -3.4(95%CI -2.09 to -4.71) at 6 months
72 (2)Low

Alternative therapies

Acupuncture and rehab versus rehabilitation alone (post-stroke CRPS_Lu 2009;Various pain/ outcome scores

All conclude in favour of acupuncture
252 (3)Very low

Acupuncture versus shamSmith 2005Pain VAS, no significant differences in any study70 (4)Very Low

Qigong therapy versus sham QigongForouzanfar 2002; Smith 2005% participants who reported a reduction in pain. 91% in Qigong group versus 36% in sham group26 (1)Very low

Relaxation therapy added to multi-modal care versus multi-modal care alone.Smith 2005Pain - no significant difference18 (1)Very low

Composite clinical CRPS and RSD scores

Anti-inflammatory treatments

Corticosteroids (oral)Fischer 2010

Oral prednisolone

40mg/day prednisolone versus piroxicam 20mg/day
Outcome: 0-14 composite CRPS score

mean difference -5.10 (95% CI -6.55 to -3.65)
60 (1)Very low

methylprednisolone 32mg/day versus placeboOutcome: relevant improvement in composite shoulder-hand syndrome score (<4/14)

No data given for between group comparisonS for drug versus placebo, Graphs appear not to demonstrate a difference
36 (1)Very lowUnblinded study

prednisolone 30mg/day versus placebo up to 12 weeksOutcome: "75% clinical improvement" within 12 week period.

Relative risk 4.24 (95% CI 1.42 to 12.67)

NNT 1
23 (1)Unblinded study

Topical free radical scavengersFischer 2010

DMSO 50% in fatty cream versus placebo fatty cream over 2 monthsRSD score (0-5)

A statistically significant improvement seen with DMSO versus placebo Inadequate data to determine effect size
31 (1)Very low

DMSO 50% lotion applied x3 daily for 3 weeks versus regional IV Ismelin (guanethidine) blocks x2 weekly for 3 weeksComposite score based on pain, oedema, discolouration, ROM (0-70 scale)

Data not available "patients improved more" with DMSO cream
26 (1)Very lowUnblinded study

DMSO 50% cream x5 daily versus N-Acetylcysteine (NAC) 600mg x3 dailyISS composite CRPS score (5-50) based on pain temperature, volume differences and function. No difference between the groups.146 (1)Low

5-HT2 receptor antagonists

IV ketanserin (10mg) versus placeboForouzanfar 2002Subjective pain score (not clearly defined). No effect observed9 (1)Very low

Function/ Disability


Neurostimulation methods


Spinal cord stimulation (SCS) + physical therapy versus physical therapy aloneMailis-Gagnon 2004; Simpson 2009Jebsens test. No difference at any time point54 (1)Very low

Physiotherapy/ Occupational Therapy

Physiotherapy (PT) versus occupational therapy (OT) versus social work (SW)Daly 2009; Smith 20051 year follow up:

Impairment score (0-50 scale)

PT vs OT mean difference 1.6 (95% CI 1 to 2.2)

PT vs SW mean difference 5.1 (95% CI 4.6 to 5.6)
135 (1)Low

Graded motor imagery versus usual careDaly 2009; Rothgangel 2011Patient-specific functional scale (0-11 NRS), mean difference 1.90 (95% CI 1.26 to 2.54) at end of treatment,

2.69 (95% CI 1.80 to 3.58) at 3 to 6 month follow up
49 (2)Low

Adverse Events? BisphosphonatesBrunner 2009

Quality of life

Neurostimulation methodsSpinal cord stimulation (SCS) + physical therapy versus physical therapy aloneMailis-Gagnon 2004; Simpson 2009Pain component of Nottingham Health Profile significant improvement with SCS54 (1)Very lowEffect not maintained in an intention-to-treat analysis

Anti-inflammatory treatments

Topical free radical scavengers


Topical 50% DMSO in water versus placebo water x5 daily for 1 weekFischer 2010Outcome subjective evaluation of clinical improvement by patient.

Insufficient data
20 (1)Very low

Neurostimulation methods


Spinal cord stimulation (SCS) + physical therapy versus physical therapy aloneMailis-Gagnon 2004; Simpson 2009Global perceived effect

More participants in SCS group considered themselves "much improved" at 6 months (P<0.01) and at two years (P<0.001)
54 (1)Very low

 Unless specifically stated, otherwise comparisons refer to outcomes measured at the end of the intervention period.