Intervention Review

You have free access to this content

Non-invasive brain stimulation techniques for chronic pain

  1. Neil E O'Connell1,*,
  2. Benedict M Wand2,
  3. Louise Marston3,
  4. Sally Spencer4,
  5. Lorraine H DeSouza1

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 11 APR 2014

Assessed as up-to-date: 24 JUL 2013

DOI: 10.1002/14651858.CD008208.pub3


How to Cite

O'Connell NE, Wand BM, Marston L, Spencer S, DeSouza LH. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008208. DOI: 10.1002/14651858.CD008208.pub3.

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, W, Australia

  3. 3

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

  4. 4

    Lancaster University, Faculty of Health and Medicine, Lancaster, Lancashire, UK

*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: New search for studies and content updated (conclusions changed)
  2. Published Online: 11 APR 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Ahmed 2011

MethodsParallel, quasi-randomised controlled trial


ParticipantsCountry of study: Egypt

Setting: Dept of Neurology, hospital-based

Condition: chronic phantom limb pain

Prior management details: unresponsive to various pain medications

n = 27, 17 active and 10 sham

Age, mean (SD): active group 52.01 (12.7), sham group 53.3 (13.3)

Duration of symptoms, mean (SD) months: active group 33.4 (39.3), sham group 31.9 (21.9)

Gender distribution: active group 13 M, 4 F; sham group 6 M, 4 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 20 Hz; coil orientation not specified, no. of trains 10; duration of trains 10 sec; ITI 50 sec; total no. pulses 2000

Stimulation location: M1 stump region

Number of treatments: x 5, daily

Control type: sham - coil angled away from scalp


OutcomesPrimary: pain VAS (anchors not reported), LANNS

When taken: post-stimulation session 1 and 5 and at 1 month and 2 months post-treatment

Secondary: none relevant


NotesAdverse events: not reported

Conflict of interest: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskComment: not true randomisation

Quote: "patients were randomly assigned to 2 groups depending on the day of the week on which they were recruited"

Allocation concealment (selection bias)High riskComment: given method of randomisation allocation concealment not viable

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: levels of drop-out not reported

Selective reporting (reporting bias)Low riskComment: primary outcomes presented in full

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Low riskQuote: "The second author evaluated these measures blindly, without knowing the type of TMS"

Adequate blinding of participants?Unclear riskComment: sham credibility assessment - sub-optimal. Coil angled away from scalp. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow risk> 8 weeks follow-up

André-Obadia 2006

MethodsCross-over randomised controlled trial; 3 conditions


ParticipantsCountry of study: France

Setting: laboratory

Condition: neuropathic pain (mixed central, peripheral and facial)

Prior management details: refractory to drug management, candidates for invasive MCS

n = 14

Age: 31 to 66; mean 53 (SD 11)

Duration of symptoms: mean 6.9 years (SD 4)

Gender distribution: 10 M, 4 F


InterventionsStimulation type: rTMS figure of 8 coil

Stimulation parameters:

Condition 1: frequency 20 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 20; duration of trains 4 sec; ITI 84 sec; total no. pulses 1600

Condition 2: frequency 1 Hz; coil orientation lateromedial; no. of trains 1; duration of trains 26 min, total no. pulses 1600

Condition 3: sham - same as for condition 2 with coil angled away perpendicular to scalp

Stimulation location: motor cortex contralateral to painful side

Number of treatments: 1 for each condition


OutcomesPrimary: VAS 0 to 10 cm, anchors "no pain" to "unbearable pain"

When taken: immediately post-stimulation then daily for 1 week

Secondary: none


NotesData requested from authors and received


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Participants were consecutively assigned to a randomization scheme generated on the web site Randomization.com (Dallal GE, http://www.randomization.com, 2008). We used the second generator, with random permutations for a 3-group trial. The randomization sequence was concealed until interventions were assigned."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 participants lost to follow-up and not accounted for in the data analysis. Given the small sample size it may influence the results

Selective reporting (reporting bias)Low riskPain outcomes reported for all participants. Change from baseline figures given; point measures requested from study authors and received

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "To ensure the double blind evaluation effects, the physician applying magnetic stimulation was different from the one collecting the clinical data, who in turn was not aware of the modality of rTMS that had been used in each session."

Adequate blinding of participants?Unclear riskComment: sham credibility assessment "sub optimal". Coil angled away from scalp and not in contact in sham condition. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Free from carry-over effects?Low riskComment: a 2-week wash-out period was observed between stimulation conditions and possible carry-over effects were checked and ruled out in the analysis

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh risk< 2 weeks follow-up

André-Obadia 2008

MethodsCross-over randomised controlled trial; 3 conditions


ParticipantsCountry of study: France

Setting: laboratory-based

Condition: neuropathic pain (mixed central, peripheral and facial)

Prior management details: refractory to drug management, candidates for invasive MCS

n = 30

Age: 31 to 72, mean 55 (SD 10.5)

Duration of symptoms: mean 5 years (SD 3.9)

Gender distribution: 23 M, 7 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:

Condition 1: frequency 20 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 20; duration of trains 4 sec; ITI 84 sec; total no. pulses 1600

Condition 2: frequency 20 Hz, coil orientation lateromedial; no. of trains 20; duration of trains 4 sec; ITI 84 sec; total no. pulses 1600

Condition 3: sham - same as for active conditions with coil angled away perpendicular to scalp

Stimulation location: motor cortex contralateral to painful side

Number of treatments: 1 for each condition


OutcomesPrimary: 0 to 10 NRS (anchors "no pain" to "unbearable pain")

When taken: daily for 2 weeks post-stimulation

Secondary: none


NotesData requested from authors


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the order of sessions was randomised (by computerized random-number generation)"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 2 participants apparently lost to follow-up and not obviously accounted for in the analysis. However, this is less than 10% and is unlikely to have strongly influenced the results

Selective reporting (reporting bias)Low riskComment: medial-lateral coil orientation condition data not presented but provided by authors on request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "The physician who applied the procedure received from a research assistant one sealed envelope containing the order of the rTMS sessions for a given patient. The order remained unknown to the physician collecting clinical data."

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled away from scalp and not in contact in sham condition. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Free from carry-over effects?Low riskComment: a 2-week wash-out period was observed between stimulation conditions and possible carry-over effects were checked and ruled out in the analysis

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

André-Obadia 2011

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: France

Setting: laboratory-based

Condition: chronic neuropathic pain (mixed)

Prior management details: resistant to conventional pharmacological treatment

n = 45

Age: 31 to 72 (mean 55)

Duration of symptoms: "chronic"

Gender distribution: 28 M, 17 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 20 Hz; coil orientation not specified, no. of trains 20; duration of trains 4 sec; ITI 84 sec; total no. pulses 1600

Stimulation location: M1 hand area

Number of treatments: 1 per group

Control type: sham coil - same sound and appearance, no control for sensory cues


OutcomesPrimary: pain NRS anchors 0 = no pain, 10 = unbearable pain

When taken: daily for 2 weeks following each stimulation

Secondary: none relevant


NotesAdverse events: not reported

Funding source: charity-funded

Conflict of interest: declaration - no COI


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: method of randomisation not specified but less likely to introduce bias in a cross-over design

Quote: "separated into 2 groups determined by the randomization"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: no mention of drop-out/withdrawal

Selective reporting (reporting bias)Low riskComment: primary outcomes reported for all groups and further data made available upon request to authors

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Unclear riskComment: no mention of blinded assessors

Adequate blinding of participants?Unclear riskComment: the authors state "Because the first step of the procedure (motor hotspot and motor threshold determination)that induced motor contractions was identical in placebo and active sessions and the stimulation differed only when intensities below motor threshold were applied, no patient perceived any difference between the 2 types of rTMS"

However, the sensation on the scalp may differ and no formal evaluation of blinding presented

Free from carry-over effects?Low riskComment: 2-week wash-out period observed

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Antal 2010

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: Germany

Setting: laboratory setting

Condition: mixed chronic pain, neuropathic and non-neuropathic

Prior management details: therapy-resistant

n = 23, 10 in parallel (6 active, 4 sham), 13 crossed over

Age: active only group 28 to 70, sham only group 50 to 70, cross-over group 41 to 70

Duration of symptoms: chronic 1.5 to 25 years (mean 7.4)

Gender distribution: 6 M, 17 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 1 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: anode - left M1 hand area, cathode right supraorbital

Number of treatments: x 5, daily

Control type: sham tDCS


OutcomesPrimary: pain VAS 0 to 10; VAS anchors 0 = no pain, 10 = the worst pain possible

When taken: x 3, daily - averaged for daily pain

Secondary: none relevant


NotesFunding: government funding

Conflicts of interest: none declared


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomization was performed using the order of entrance into the study."

Comment:  may not be truly random from description

Allocation concealment (selection bias)Unclear riskComment: not mentioned though unlikely given the randomisation technique. This is a potentially significant source of bias given that only the parallel results were used in this review due to high levels of attrition after the first phase

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: the high level of drop-out renders the cross-over results at high risk of bias. This is less of an issue where only the parallel results from the first phase are used - first-phase data only used in the analysis

Selective reporting (reporting bias)Low riskComment: while not all outcomes at all time points were included in the study report the authors have provided all requested data

Other biasLow riskComment: no other sources of bias detected

Adequate blinding of assessors?Low riskComment: 1 mA intensity and operator blinded

Quote: "The stimulators were coded using a five letter code, programmed by one of the department members who otherwise did not participate in the study. Therefore neither the investigator not the patient knew the type of the stimulation"

Adequate blinding of participants?Low riskComment: see above

Free from carry-over effects?Low riskComment: patients were excluded if pain had not returned to normal. This, however, represents a threat with regard to attrition bias

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Avery 2013

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: unclear

Condition: chronic widespread pain

Prior management details: not reported

n = 19

Age mean (SD): active 54.86 (7.65), sham 51.09 (10.02)

Duration of symptoms (months mean (SD)): 15.64 (6.93)

Gender distribution: all female


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation not specified; 120% RMT; no. of trains 75; duration of trains 4 sec; ITI 26 sec; total no. pulses 3000

Stimulation location: left DLPFC

Number of treatments: 15 sessions over 4 weeks

Control type: sham coil - controls for visual, auditory and scalp sensory cues


OutcomesPrimary: pain NRS 0 to 10 anchors not reported

When taken: end of treatment period, 1 month following and 3 months following

Secondary: pain interference BPI

Adverse events: multiple minor; no clear difference in incidence between active and sham stimulation


NotesGovernment-funded study, manufacturer loaned stimulator


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "At the completion of the baseline assessment, patients were randomly assigned to either real TMS or sham stimulation using a computerized randomization program that uses an adaptive randomization and stratification strategy."

Allocation concealment (selection bias)Low riskQuote: "Based on the randomization, a "smart card" which determined whether the real TMS or sham coil would be administered was assigned to a particular patient. The card had only a code number that did not reveal the randomization." "The research coordinator blind to the randomization repeated the baseline assessments"

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "To examine differences in changes in outcomes over time between TMS and comparison group subjects, we estimated random coefficient models following the intent-to-treat principle."

"11 were randomized to the sham group and 8 were randomized to the TMS group. However, one subject randomized to the TMS had a baseline BIRS score of 4 which was well below the BIRS score of 8 required for randomization. Because of this incorrect randomization, this subject was excluded from the efficacy analyses, but was included in the analysis of side effects. The clinical characteristics of those correctly randomized are in Table 1. One subject in the TMS dropped out after the 10th session because of lack of response and is included in the analyses."

Comment: of 2 drop-outs from the TMS group, 1 was excluded (reasons given)

Selective reporting (reporting bias)Low riskComment: all outcomes presented in full in study report

Other biasLow riskNo other bias detected

Adequate blinding of assessors?Low riskQuote: "The research coordinator blind to the randomization repeated the baseline assessments of pain, functional status, depression, fatigue, and sleep before the 1st and after the 5th, the 10th, and the 15th TMS sessions as well as 1 week, 1 month, and 3 months after the last TMS treatment except for the SF-36, neuropsychological tests, audiometry and the dolorimetry which were only done at baseline and one week after the 15th TMS session."
Comment: while TMS physicians guessed beyond chance the raters were separate from this process

Adequate blinding of participants?Low riskQuote: "... sham stimulation with the electromagnet blocked within the coil by a piece of metal so the cortex was not stimulated. The coils appeared identical. Electrodes were attached to the left side of the forehead for each subject for each session. Those receiving the sham stimulation received an electrical stimulus to the forehead during the sham stimulation. Those receiving the real TMS received no electrical stimulation to the electrodes. Both groups experienced a sensation in the area of the left forehead. In addition, all subjects were given special earplugs and received an audible noise during the stimulation to mask any possible sound differences between the TMS and sham conditions."

Comment: optimal sham - controls for visual, sensory and auditory cues. Formal testing - blinding appears robust

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: > 8 weeks follow-up

Boggio 2009

MethodsCross-over randomised controlled trial; 3 conditions


ParticipantsCountry of study: Brazil

Setting: laboratory

Condition: neuropathic pain (mixed central, peripheral and facial)

Prior management details: refractory to drug management

n = 8

Age: 40 to 82; mean 63.3 (SD 5.6)

Duration of symptoms: 1 to 20 years; mean 8.3 (SD 5.6)

Gender distribution: 2 M, 6 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 30 minutes

Condition 1: active tDCS/active TENS

Condition 2: active tDCS/sham TENS

Condition 3: sham tDCS/sham TENS

Stimulation location: motor cortex contralateral to painful side

Number of treatments: 1 for each condition

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: VAS 0 to 10 anchors "no pain" to "worst possible pain"

When taken: pre and post each stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "All the patients received the 3 treatments.... in a randomised order (we used a computer generated randomisation list with the order of entrance)."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: 2 participants lost to follow-up. It is unclear how these data were accounted for as there are no missing data apparent in the results tables. However, this may have an impact given the small sample size

Selective reporting (reporting bias)Low riskComment: primary outcome data presented clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskQuote: "All evaluations were carried out by a blinded rater"

Comment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Free from carry-over effects?Low riskComment: a 48-hour wash-out period was observed between stimulation conditions and possible carry-over effects were checked and ruled out in the analysis

Quote: "To analyze whether there was a carryover effect, we initially performed and showed that the baselines for the 3 conditions were not significantly different (P = 0.51). We also included the variable order in our model and this model also showed that order is not a significant term (P = 0.7)."

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Borckardt 2009

MethodsCross-over randomised controlled trial; 2 conditions


ParticipantsCountry of study: USA

Setting: laboratory

Condition: peripheral neuropathic pain

Prior management details: not specified

n = 4

Age: 33 to 58; mean 46 (SD 11)

Duration of symptoms: 5 to 12 years; mean 10.25 (SD 3.5)

Gender distribution: 1 M, 3 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 10 Hz; coil orientation not specified; 100% RMT; no. of trains 40; duration of trains 10 sec; ITI 20 sec; total no. pulses 4000

Stimulation location: L pre-frontal cortex

Number of treatments: 3 over a 5-day period

Control type: neuronetics sham coil (looks and sounds identical)


OutcomesPrimary: average daily pain 0 to 10 Likert scale, anchors "no pain at all" to "worst pain imaginable"

When taken: post-stimulation for each condition (unclear how many days post) and daily for 3 weeks post-stimulation

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The order (real first or sham first) was randomised"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out

Selective reporting (reporting bias)Low riskComment: all results reported clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: not specified

Adequate blinding of participants?Unclear riskQuote: "Two of the four participants (50%) correctly guessed which treatment periods were real and sham, which is equal to chance. All four of the participants initially said that they did not know which was which, and it was not until they were pushed to "make a guess" that they were able to offer an opinion about which sessions were real and which were sham."

Comments: sham credibility assessment - sub-optimal. Sham coil controls for auditory cues and is visually indistinguishable from active stimulation but does not control for sensory characteristics of active stimulation

Free from carry-over effects?Low riskComment: a 3-week wash-out period was observed. Presented average pain values are very similar pre- each condition

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Capel 2003

MethodsPartial cross-over randomised controlled trial. NB: only first-phase results were considered therefore the trial was considered as having a parallel design


ParticipantsCountry of study: UK

Setting: residential educational centre

Condition: post-SCI pain (unclear whether this is neuropathic or otherwise)

Prior management details: unclear

n = 30

Age: unclear

Duration of symptoms: unclear

Gender distribution: unclear


InterventionsStimulation type: CES

Stimulation parameters: frequency 10 Hz; pulse width 2 msec; intensity 1 2μA; duration 53 min

Stimulation location: ear clip electrodes

Number of treatments: x 2, daily for 4 days

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: 0 to 10 VAS "level of pain", anchors not specified

When taken: daily during the treatment period

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: method equivalent to picking out of a hat

Quote: "Subjects would be randomly assigned into two groups according to their choice of treatment device... The devices were numbered for identification, but neither the administrators nor the recipients of the treatment could distinguish between the devices."

Allocation concealment (selection bias)Low riskComment: this is achieved through the method of randomisation

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 3 subjects withdrew (not voluntarily) and while the data are not clearly accounted for in the data analysis this constitutes 10% of the overall cohort and is unlikely to have strongly influenced the results

Quote: "Three of the 30 subjects included were withdrawn from the study after commencement, one of whom developed an upper respiratory infection, and two others were withdrawn from the study because their medication (either H2 antagonist anti-ulcer or steroidal inhalant) were interacting with the TCET treatment."

Selective reporting (reporting bias)High riskComment: pain score values are not provided for any time point

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "neither the administrators nor the recipients of the treatment could distinguish between the devices."

Adequate blinding of participants?Low riskQuote: "neither the administrators nor the recipients of the treatment could distinguish between the devices."

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Carretero 2009

MethodsParallel randomised clinical trial


ParticipantsCountry of study: Spain

Setting: outpatient clinic

Condition: fibromyalgia (with major depression)

Prior management details: unclear

n = 26

Age: active group 47.5 (SD 5.7), sham group 54.9 (SD 4.9)

Duration of symptoms: unclear "chronic"

Gender distribution: 2 M, 24 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 1 Hz; coil orientation not specified; 110% RMT; no. of trains 20; duration of trains 60 sec; ITI 45 sec; no. of pulses 1200

Stimulation location: R dorsolateral prefrontal cortex

Number of treatments: up to 20 on consecutive working days

Control type: coil angled 45º from the scalp


OutcomesPrimary: Likert pain scale 0 to 10, anchors "no pain" to "extreme pain"

When taken: 2 weeks, 4 weeks and 8 weeks from commencement of study

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 participant in each group did not complete the study. Unlikely to have strongly influenced the findings

Selective reporting (reporting bias)Low riskComment: outcomes presented clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: patients and raters (but not the treating physician) were blind to the procedure

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled 45º away from scalp. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Cork 2004

MethodsCross-over randomised controlled trial (to be considered as parallel - first treatment phase only as 2nd unblinded)


ParticipantsCountry of study: USA

Setting: pain clinic

Condition: fibromyalgia

Prior management details: unclear

n = 74

Age: 22 to 75; mean 53

Duration of symptoms: 1 to 21 years; mean 7.3

Gender distribution: 4 M, 70 F


InterventionsStimulation type: CES

Stimulation parameters: frequency 0.5 Hz; pulse width unclear; intensity 100 μA; waveform shape modified square wave biphasic 50% duty cycle; duration 60 min

Stimulation location: ear clip electrodes

Number of treatments: ? daily for 3 weeks

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: 0 to 5 numerical pain intensity scale, anchors "no pain" to "worst pain imaginable"

When taken: immediately following the 3-week treatment period

Secondary: Oswestry Disability Index

When taken: immediately following the 3-week treatment period


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: drop-out rate not reported

Selective reporting (reporting bias)High riskComment: pain score numerical values are not provided clearly with measures of variance for any time point

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "All staff, the physicians, and the patient were blind to the treatment conditions."

Adequate blinding of participants?Low riskQuote: "All staff, the physicians, and the patient were blind to the treatment conditions."

Study SizeHigh riskComment: < 50 participants per treatment arm (considered as a parallel trial - 1st phase only)

Study durationHigh riskComment: < 2 weeks follow-up

Defrin 2007

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Israel

Setting: outpatient department

Condition: post-SCI central neuropathic pain

Prior management details: refractory to drug, physical therapy and complementary therapy management

n = 12

Age: 44 to 60; mean 54 (SD 6)

Duration of symptoms: > 12 months

Gender distribution: 7 M, 4 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 5 Hz; coil orientation not specified; 115% RMT; no. of trains 500; duration of trains 10 sec; ITI 30 sec; total no. pulses 500 reported, likely to have been 25,000 judging by these parameters

Stimulation location: motor cortex - midline

Number of treatments: x 10, x 1 daily on consecutive days

Control type: sham coil - visually the same and makes similar background noise


OutcomesPrimary: 15 cm 0 to 10 VAS pain intensity, anchors "no pain sensation" to "most intense pain sensation"

When taken: pre and post each stimulation session

Secondary: McGill pain questionnaire

When taken: 2- and 6-week follow-up period


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Quote: "Patients were randomised into 2 groups that received either real or sham rTMS"

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only one participant withdrew for "logistic reasons". Unlikely to have strongly influenced the findings

Selective reporting (reporting bias)Low riskComment: while group means/SD are not presented in the study report, the study authors have provided the requested data

Other biasUnclear riskComment: baseline differences observed in pain intensity levels (higher in active group)

Adequate blinding of assessors?Low riskQuote: "The patients as well as the person conducting the outcome measurements were blind to the type of treatment received."

Adequate blinding of participants?Unclear riskQuote: "Two coils were used; real and sham, both of which were identical in shape and produced a similar background noise."

Comment: sham credibility assessment - sub-optimal. Sham coil controls for auditory cues and is visually indistinguishable from active stimulation, but does not control for sensory characteristics of active stimulation over the scalp. Given that stimulation was delivered at 110% RMT active stimulation, but not sham, it is likely to have elicited muscle twitches in peripheral muscles

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Fenton 2009

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: USA

Setting: unclear

Condition: chronic pelvic pain

Prior management details: refractory to treatment

n = 7

Age: mean 38

Duration of symptoms: mean 80 months

Gender distribution: all F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 1 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: M1 dominant hemisphere

Number of treatments: 2

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: VAS overall pain, pelvic pain, back pain, migraine pain, bladder pain, bowel pain, abdomen pain and pain with intercourse Anchors not specified

When taken: daily during stimulation and then for 2 weeks post each condition

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out reported

Selective reporting (reporting bias)Low riskComment: variance measures not presented for group means post-stimulation but data provided by author on request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "All other personnel in the study, including the investigators, study coordinators, participants, and their families, and all primary medical caregivers, were blinded."

Adequate blinding of participants?Low riskQuote: "All other personnel in the study, including the investigators, study coordinators, participants, and their families, and all primary medical caregivers, were blinded."

Free from carry-over effects?Unclear riskComments: pre-stimulation data are not presented and no formal investigation for carry-over effects is discussed

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: < 2 weeks follow-up

Fregni 2005

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: USA

Setting: laboratory

Condition: chronic pancreatitis pain

Prior management details: not specified

n = 5

Age: 44 (SD 11)

Duration of symptoms: not specified, "chronic"

Gender distribution: not specified


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 1 Hz; coil orientation not specified; 90% RMT; no. of trains not specified; duration of trains not specified; ITI not specified; total no. pulses 1600

Stimulation location: left and right secondary somatosensory area (SII)

Number of treatments: 1 for each condition

Control type: sham, "specially designed sham coil". No further details


OutcomesPrimary: pain VAS, anchors not specified

When taken: after each stimulation session

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The order of stimulation was randomised and counterbalanced across patients using a Latin square design."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out reported

Selective reporting (reporting bias)High riskComment: pain score numerical values are not provided clearly with measures of variance for any time point for the sham condition

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "Patients were blinded to treatment condition, and a blinded rater evaluated analgesic use, patient's responses in a Visual Analogue Scale (VAS) of pain.... immediately after each session of rTMS."

Adequate blinding of participants?Unclear riskComment: sham credibility assessment "unclear". Type of sham coil not specified

Free from carry-over effects?Low riskQuote: "Importantly, baseline pain scores were not significantly different across the six conditions of stimulation... speaking against carryover effect."

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Fregni 2006a

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Brazil

Setting: laboratory

Condition: post-SCI central neuropathic pain

Prior management details: refractory to drug management

n = 17

Age: mean 35.7 (SD 13.3)

Duration of symptoms: chronic > 3/12

Gender distribution: 14 M, 3 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: motor cortex (contralateral to most painful side or dominant hand)

Number of treatments: 5, x 1 daily on consecutive days

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS 0 to 10 cm, anchors "no pain" to "worst pain possible"

When taken: before and after each stimulation and at 16-day follow-up

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed using the order of entrance in the study and a previous randomisation list generated by a computer using random blocks of six (for each six patients, two were randomised to sham and four to active tDCS) in order to minimize the risk of unbalanced group sizes."

Allocation concealment (selection bias)Low riskComment: the use of a pre-generated randomisation list should ensure this

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "... we analyzed the primary and secondary endpoints using the intention-to-treat method including patients who received at least one dose of the randomised treatment and had at least one post-baseline efficacy evaluation. We used the last evaluation carried out to the session before the missed session, assuming no further improvement after the dropout, for this calculation."

Selective reporting (reporting bias)Unclear riskComment: pain score numerical values are not provided clearly in the study report with measures of variance for any time point. On request data were available for the primary outcome at one follow-up point but not for other follow-up points

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Fregni 2006b

MethodsParallel randomised controlled trial; 3 conditions


ParticipantsCountry of study: Brazil

Setting: laboratory

Condition: fibromyalgia

Prior management details: unclear

n = 32

Age: 53.4 (SD 8.9)

Duration of symptoms: condition 1: 8.4 (SD 9.3) years; condition 2: 10.0 (SD 7.8) years; condition 3: 8.1 (SD 7.5) years

Gender distribution: 0 M, 32 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: condition 1: dorsolateral prefrontal cortex; condition 2: motor cortex; condition 3: sham motor cortex. All conditions contralateral to most painful side or dominant hand

Number of treatments: 5, x 1 daily on consecutive days

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS 0 to 10 cm, anchors not specified

When taken: at the end of the stimulation period and at 21-day follow-up

Secondary: quality of life: Fibromyalgia Impact Questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed using the order of entry into the study and a previous computer-generated randomisation list, using random blocks of 6 patients (for each 6 patients, 2 were randomised to each group) in order to minimize the risk of unbalanced group sizes."

Allocation concealment (selection bias)Low riskComment: the use of a pre-generated randomisation list should have adequately ensured this

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "One patient (in the M1 group) withdrew, and the few missing data were considered to be missing at random. We analyzed data using the intent-to-treat method and the conservative last observation carried forward approach."

Selective reporting (reporting bias)Unclear riskComment: pain score numerical values are not provided clearly with measures of variance for most time points in the study report. On request data were available for the primary outcome at 1 follow-up point but not for other follow-up points

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Fregni 2011

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: laboratory

Condition: chronic visceral pain (chronic pancreatitis)

Prior management details: most on continuous opioid therapy, most had received surgery for their pain

n = 17, 9 in active group, 8 in sham group

Age mean (SD): active group 41.11 (11.27), sham group 46.71 (13.03)

Duration of symptoms: > 2 years

Gender distribution: 14 F, 3 M


InterventionsStimulation type: rTMS

Stimulation parameters:frequency 1 Hz; coil orientation not specified, no. of trains 1; duration of trains not specified; intensity 70% maximum stimulator output, total no. pulses 1600

Stimulation location: SII

Number of treatments: 10, x 1 daily (weekdays only)

Control type: sham rTMS coil


OutcomesPrimary: pain VAS; 0 = no pain, 10 = most intense pain imaginable

When taken: daily pain logs for 3 weeks pre-intervention, daily post-stimulation during intervention period and at 3-week follow-up

Secondary: none relevant


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomised (using a computer generated list with blocks of 4)"

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: drop-out/withdrawal not reported

Selective reporting (reporting bias)High riskComment: reporting of pain scores is incomplete across all time points

Other biasUnclear riskComment: baseline values not presented by group for key outcome variables

Adequate blinding of assessors?Low riskQuote: "The pain evaluation was carried out by a blinded assessor"

Adequate blinding of participants?Low riskQuote "The sham and real TMS coils looked identical and were matched for weight and acoustic artefact. This sham coil induces a similar tapping sensation and generates the same clicking noise as the real TMS coil, but without induction of a significant magnetic field and secondary current."

Comment: sham appears optimal

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Gabis 2003

MethodsParallel randomised controlled trial


ParticipantsCountry of study: USA

Setting: pain clinic

Condition: chronic back and neck pain

Prior management details: unclear

n = 20

Age: 20 to 77

Duration of symptoms: 0.5 to 40 years

Gender distribution: 9 M, 11 F


InterventionsStimulation type: CES

Stimulation parameters: frequency 77 Hz; pulse width 3.3 msec; intensity ≤ 4 mA; waveform shape biphasic asymmetric; duration 30 min

Stimulation location: 3 electrodes, 1 attached to either mastoid process and 1 to the forehead

Number of treatments: 8, x 1 daily on consecutive days

Control type: "active placebo" units visually indistinguishable. Delivered 50 Hz frequency, intensity ≤ 0.75 mA. Note: may not be inert


OutcomesPrimary: pain VAS, anchors not specified

When taken: pre and post each stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The paramedic administered treatments based on a computer-elicited randomisation list."

Allocation concealment (selection bias)Low riskQuote: "The paramedic administered treatments based on a computer-elicited randomisation list. At enrolment in the study, the investigator assigned the next random number in that patient’s category. The investigator did not have access to the randomisation list until after the study was completed."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all participants completed the study

Selective reporting (reporting bias)Low riskComment: while pain score numerical values are not provided clearly with measures of variance for most time points in the study report the study authors have provided the requested data

Other biasUnclear riskComment: an active placebo that delivers current may not be inert and may bias against between group differences (0.75 mA exceeds the intensity of the active arms of other CES trials)

Adequate blinding of assessors?Low riskQuote: "The active placebo device was indistinguishable to the patient and medical team."

Adequate blinding of participants?Low riskQuote: "The active placebo device was indistinguishable to the patient and medical team from the real TCES device - it was designed to give the patient the feeling of being treated, inducing an individual sensation of skin numbness or muscle contraction"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Gabis 2009

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Israel

Setting: pain clinic

Condition: chronic back and neck pain

Prior management details: unclear

n = 75 (excluding headache participants)

Age: mean 53.9, range 22 to 82

Duration of symptoms: 0.5 to 40 years

Gender distribution: 35 M, 40 F


InterventionsStimulation type: CES

Stimulation parameters: frequency 77 Hz; pulse width 3.3 msec; intensity ≤ 4 mA; waveform shape biphasic asymmetric; duration 30 min

Stimulation location: 3 electrodes, 1 attached to either mastoid process and 1 to the forehead

Number of treatments: 8, x 1 daily on consecutive days

Control type: "active placebo" units visually indistinguishable. Delivered 50 Hz frequency, intensity ≤ 0.75 mA. Note: may not be inert


OutcomesPrimary: pain VAS, anchors not specified

When taken: pre and post each stimulation; 3 weeks and 3 months following treatment

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The paramedic administered treatments based on a computer-elicited randomisation list"

Allocation concealment (selection bias)Low riskQuote: "The paramedic administered treatments based on a computer-elicited randomisation list. At enrolment, the investigator assigned the next random number in that patient’s category. The investigator did not have access to the randomisation list until study completion."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is indicated, comparing the results with the number enrolled

Selective reporting (reporting bias)Low riskComment: results for primary outcomes are reported clearly and in full

Other biasUnclear riskComment: an active placebo that delivers current may not be inert and may bias against between group differences (0.75 mA exceeds the intensity of the active arms of other CES trials)

Adequate blinding of assessors?Low riskQuote: "The investigator did not have access to the randomisation list until study completion"

Adequate blinding of participants?Low riskQuote: "The placebo device was indistinguishable from the active device"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: > 8 weeks follow-up

Hargrove 2012

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: "professional clinical setting"

Condition: fibromyalgia

Prior management details: no recent remission of symptoms

n = 91

Age: active group 48 to 54.7, sham group 51 to 57

Duration of symptoms: active group mean 17.12 years, sham group mean 17.5 years

Gender distribution: reported for completers only 71 F, 6 M


InterventionsStimulation type: RINCE (reduced impedance non-invasive cortical electrostimulation)

Stimulation parameters: current density 0.3 mA/cm2, stimulation duration 11 minutes, frequency 10 kHz carrier signal delivered at 40Hz

Stimulation location: parietal region (international 10/20 site PZ), ground leads fixed to earlobes

Number of treatments: x 2 weekly for 11 weeks

Control type: non-activated identical stimulation unit


OutcomesPrimary: FIQ pain VAS; 0 = no pain, 10 = unbearable pain

When taken: end of treatment period

Secondary: total FIQ score


NotesLead author declares an intellectual property interest in the technology and is a shareholder in a company seeking to develop the technology for commercialisation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: per protocol analysis used, drop-out rate 6/45 (13%) in active group and 8/46 (17%) in sham group

Selective reporting (reporting bias)Low riskComment: data reported on all outcomes and supplementary data made available by the study author

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Low riskQuote: "The investigators were blinded to the settings, and no element of hardware or software gave any indication as to which setting had been assigned to the subject."

Adequate blinding of participants?Low riskQuote: "The combined involvement of low driving potentials and high carrier frequencies creates a signal that is subthreshold for perceptibility.....Subjects could not feel the signal regardless of group, and therefore could not tell if they were receiving treatment or not"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Hirayama 2006

MethodsCross-over randomised controlled trial; 5 conditions


ParticipantsCountry of study: Japan

Setting: laboratory

Condition: intractable deafferentation pain (mixed central, peripheral and facial)

Prior management details: intractable

n = 20

Age: 28 to 72 years

Duration of symptoms: 1.5 to 24.3 years, mean 6.4 (SD 6)

Gender distribution: 13 M, 7 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 5 Hz; coil orientation not specified; 90% RMT; no. of trains 10; duration of trains 10 sec; ITI 50 sec; total no. pulses 500

Stimulation location: condition 1: motor cortex; condition 2: primary sensory cortex; condition 3: pre-motor area; condition 4: supplementary motor area; condition 5: sham

Number of treatments: 1 for each condition

Control type: coil angled 45º from scalp with synchronised electrical scalp stimulations to mask sensation


OutcomesPrimary: pain intensity VAS, anchors not specified

When taken: 0, 30, 60, 90, 180 minutes post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "All targets were stimulated in random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "All 20 patients underwent all planned sessions of navigation- guided rTMS"

Selective reporting (reporting bias)Low riskComment: pain score numerical values are not provided clearly with measures of variance for any time point but data provided upon request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors not reported

Adequate blinding of participants?Unclear riskQuote: "The patients were unable to distinguish sham stimulation from actual rTMS, because the synchronized electrical stimulation applied to the forehead made the forehead spasm, as was the case with actual TMS"

Comment: sham credibility assessment - sub-optimal. Sensory and auditory aspects are controlled for but angulation of coil away from the scalp may be visually distinguishable

Free from carry-over effects?Low riskComment: authors provided requested data. Appears free of carry-over effects

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Hosomi 2013

MethodsCross-over RCT


ParticipantsCountry of study: Japan

Setting: multicentre, laboratory-based

Condition: mixed neuropathic pain

Prior management details: pain persisted despite "adequate treatments"

n = 70 of which 64 analysed

Age mean (SD): 60.7 (10.6)

Duration of symptoms: 58.2 (10.6)

Gender distribution: 40 M, 24 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 5 Hz; coil orientation para-sagittal, no. of trains 10; duration of trains 10 sec; ITI 50 sec, intensity 90% RMT, total no. pulses per session 500

Stimulation location: M1 corresponding to painful region

Number of treatments: 10, x 1 daily (consecutive working days)

Control type: sham coil


OutcomesCurrent daily pain 0 to 100 VAS (anchors not reported), SF McGill

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Before the patient enrolment, the independent data center developed a randomization program to assign each patient to one of 2 treatment groups (1:1). A real rTMS period was followed by a sham period in group A, and a real rTMS period came after a sham period in group B. We used Pocock and Simon’s minimization method to stratify treatment groups according to institution, age (< 60 or P60 years), sex, and underlying disease (a cerebral lesion or not), and the Mersenne twister for random number generation."

Allocation concealment (selection bias)Low riskQuote: "After confirmation of patient eligibility, the data center received a registration form from an assessor who collected questionnaires and assessed adverse events, and then sent an assignment notice to an investigator who conducted the rTMS intervention. Patients were identified by sequential numbers that were assigned by the data center. Patients and assessors were blind to group assignment until the study was completed. The data center was responsible for assigning patients to a treatment group, data management, central monitoring, and statistical analyses."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: drop-out low (total 6 from recruited 70 participants)

Quote: "Seventy patients were enrolled and randomly assigned to 2 groups. Of these patients, one patient never

came to the hospital after the registration, and a suicidal wish became apparent before the start of the intervention in another patient. Sixty-eight patients received the interventions and 64 patients were included in the intention-to-treat analysis after excluding 4 patients without any data collection."

Selective reporting (reporting bias)Low riskComment: while full numerical means and SDs are not reported for all time points all data were made available upon request to the study authors

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Low riskQuote: "Patients and assessors were blind to group assignment until the study was completed."

Adequate blinding of participants?Low riskQuote: "Realistic sham stimulation [32] was implemented in this study. Ten trains of electrical stimuli at 2 times the intensity of the sensory threshold (one train, 50 stimuli at 5 Hz; inter train interval, 50 s) were delivered with a conventional electrical stimulator through the electrodes fixed on the head. The cortical effect of the cutaneous electrical stimulation was considered to be negligible at this intensity because of the high electrical resistance of the skull and brief duration of the stimulation [32]. A figure-8 coil, which did not connect to a magnetic stimulator, was placed on the head in the same manner as a real rTMS session. Another coil, which discharged simultaneously with the electrical stimuli, was placed near the unconnected coil to produce the same sound as real rTMS, but not to stimulate the brain."

Comment: sham controls for sensory auditory and visual cues

Free from carry-over effects?Low riskQuote: "To evaluate carry-over effects, Grizzle’s test for carry-over effect was applied to the values at day 0 for each period ... Grizzle's test showed no carry-over effects in VAS and SF-MPQ"

Study SizeUnclear riskComment: > 50 but < 200 participants per treatment condition

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Irlbacher 2006

MethodsCross-over randomised controlled trial; 3 conditions


ParticipantsCountry of study: Germany

Setting: laboratory

Condition: phantom limb pain (PLP) and central neuropathic pain (CNP)

Prior management details: unclear

n = 27

Age: (median) PLP 46.6, CNP 51.1

Duration of symptoms: mean PLP 15.2 (SD 14.8), CNP 3.9 (SD 4.1)

Gender distribution: 16 M, 11 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:

Condition 1: frequency 1 Hz; coil orientation not specified; 95% RMT; no. of trains not specified; duration of trains not specified; ITI not specified; total no. pulses 500

Condition 2: frequency 5 Hz; coil orientation not specified; 95% RMT; no. of trains not specified; duration of trains not specified; ITI not specified; total no. pulses 500

Condition 3: sham frequency 2 Hz; coil orientation not specified; no. of trains not specified; duration of trains not specified; ITI not specified; total no. pulses 500

Stimulation location: motor cortex, contralateral to painful side

Number of treatments: x 1 for each condition

Control type: sham coil; mimics sight and sound of active treatment


OutcomesPrimary: 0 to 100 mm VAS pain intensity, anchors "no pain" and "most intense pain imaginable"

When taken: pre- and post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: 13 of 27 participants did not complete all treatment conditions and this drop-out is not clearly accounted for in the analysis

Selective reporting (reporting bias)Low riskComment: primary outcome data presented clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is not reported

Adequate blinding of participants?Unclear riskSham credibility assessment - sub-optimal. Sham coil controls for auditory cues and is visually indistinguishable from active stimulation but does not control for sensory characteristics of active stimulation

Free from carry-over effects?Low riskQuote: "The VAS values before the stimulation showed no significant differences in the various types of treatment"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Jensen 2013

MethodsCross-over RCT


ParticipantsCountry of study: USA

Setting: laboratory

Condition: post-spinal cord injury pain (neuropathic and non-neuropathic)

Prior management details: not reported

n = 31 randomised

Age: 22 to 77

Duration of symptoms (months): > 6 months

Gender distribution: 22 M, 8 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: M1 contralateral to painful side or on left where pain bilateral

Number of treatments: 1

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: 0 to 10 NRS; 0 = no pain, 10 = most intense pain sensation imaginable. An average of current, least, worst and average pain scores

When taken: post-stimulation

Secondary: none relevant


NotesAdverse events not reported

Government-funded


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote "The remaining 31 individuals were randomly assigned to receive the five procedure conditions in one of five orders, using a Latin square design."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: of 31 randomised there are data from 28 following active tDCS and 27 following sham

Selective reporting (reporting bias)Low riskComment: outcomes adequately reported

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Free from carry-over effects?Low riskComment: baseline pain levels pre active and sham tDCS session appear equivalent

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Kang 2009

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: South Korea

Setting: university hospital outpatient setting

Condition: post-SCI central neuropathic pain

Prior management details: resistant to drug, physical or complementary therapies

n = 11

Age: 33 to 75, mean 54.8

Duration of symptoms: chronic

Gender distribution: 6 M, 5 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation angled 45º posterolaterally; 80% RMT; no. of trains 20; duration of trains 5 sec; ITI 55 sec; total no. pulses 1000

Stimulation location: R motor cortex, hand area

Number of treatments: 5, x 1 daily

Control type: coil elevated and angled away from the scalp


OutcomesPrimary: NRS average pain over last 24 hours, anchors "no pain sensation" to "most intense pain sensation imaginable"

When taken: immediately after the 3rd and 5th treatments and 1, 3, 5 and 7 weeks after the end of the stimulation period

Secondary: BPI - pain interference (surrogate measure of disability)

When taken: as for the NRS


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The real and sham rTMS stimulations were separated by 12 weeks and performed in a random order according to the prepared allocation code."

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no participants withdrew after receiving the first treatment condition

Selective reporting (reporting bias)Low riskComment: results for primary outcomes are reported clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "... a different researcher collected the clinical data; the latter researcher was not aware of the type of rTMS (real or sham)"

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled away from scalp and not in contact in sham condition. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Free from carry-over effects?Low riskComment: a 12-week wash-out period was observed. The pre-stimulation baseline scores closely match

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Katsnelson 2004

MethodsParallel randomised controlled trial; 3 conditions


ParticipantsCountry of study: Russia

Setting: unclear

Condition: hip and knee osteoarthritis

Prior management details: unclear

n = 64

Age: unclear

Duration of symptoms: unclear

Gender distribution: unclear


InterventionsStimulation type: CES

Stimulation parameters: frequency not specified; pulse width not specified; intensity 11 to 15 mA; waveform shape: condition 1 symmetric, condition 2 asymmetric; duration 40 min

Stimulation location: appears to be 1 electrode attached to either mastoid process and 1 to the forehead

Number of treatments: 5, x 1 daily for 5 consecutive

Control type: sham unit - visually indistinguishable from active units


OutcomesPrimary: 0 to 10 NRS, anchors "no pain" to "very painful"

When taken: unclear. Likely to be pre and post each stimulation session and then daily for 1 week after

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "If subjects passed all criteria they were randomly assigned to one of the two active treatments or the sham treatment."

Comment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: not specified

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: drop-out level not specified

Selective reporting (reporting bias)High riskComment: it is unclear in the report which time points are reported for primary outcomes

Other biasHigh riskComment: the reporting of baseline group characteristics is insufficient

Adequate blinding of assessors?Low riskQuote: "The physicians, like all other participants in the study, were unaware of which treatment each subject received."

Adequate blinding of participants?Low riskQuote: "The physicians, like all other participants in the study, were unaware of which treatment each subject received."

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Khedr 2005

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Egypt

Setting: university hospital neurology department

Condition: neuropathic pain, mixed central (post-stroke) and facial (trigeminal neuralgia) pain

Prior management details: refractory to drug management

n = 48

Age: post-stroke 52.3 (SD 10.3), trigeminal neuralgia 51.5 (SD 10.7)

Duration of symptoms: post-stroke 39 months (SD 31), trigeminal neuralgia 18 months (SD 17)

Gender distribution: 8 M, 16 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 20 Hz; coil orientation not specified; 80% RMT; no. of trains 10; duration of trains 10 sec; ITI 50 sec; total no. pulses 2000

Stimulation location: motor cortex contralateral to the side of worst pain

Number of treatments: 5, x 1 on consecutive days

Control type: coil elevated and angled away from scalp


OutcomesPrimary: pain VAS, anchors not specified

When taken: post 1st, 4th and 5th stimulation session and 15 days after the last session

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuote: "Patients were randomly assigned to one of the two groups, depending on the day of the week on which they were recruited."

Comment: not truly random

Allocation concealment (selection bias)High riskComment: the method of sequence generation makes concealment of allocation unlikely

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is apparent from the data presented

Selective reporting (reporting bias)Low riskComment: while pain score numerical values are not provided clearly with measures of variance for all time points in the study report, the study authors have provided the requested data

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "The second author evaluated these measures blindly—that is, without knowing the type of rTMS"

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled away from scalp and not in contact in sham condition. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Lee 2012

MethodsParallel RCT


ParticipantsCountry of study: Korea

Setting: outpatient clinic

Condition: fibromyalgia

Prior management details: none reported

n = 22

Age mean (SD): low-frequency group 45.6 (9.6), high-frequency group 53 (4.2), sham group 51.3 (6.2)

Duration of symptoms (months mean (SD)): low-frequency group: 47.2 (20.1), high-frequency group 57.1 (6.4), sham group 44.7 (10.3)

Gender distribution: all female


InterventionsStimulation type: rTMS

Stimulation parameters:

Low-frequency group: frequency 1 Hz; coil orientation not specified, no. of trains 2; duration of trains 800 sec; ITI 60 sec; total no. pulses 1600

High-frequency group: frequency 10 Hz; coil orientation not specified, no. of trains 25; duration of trains 8 sec; ITI 10 sec; total no. pulses 2000

Stimulation location: right DLPFC (low-frequency), left M1 (high-frequency)

Number of treatments: 10, x 1 daily (weekdays only) for 2 weeks

Control type: sham - coil orientated away from scalp


OutcomesPrimary: 0 to 100 mm pain VAS; 0 = none, 100 = an extreme amount of pain

When taken: post-treatment and at 1 month follow-up

Secondary: Fibromyalgia Impact Questionnaire


NotesComment: no information on adverse events given relating to those participants who did not complete all sessions


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: no intention-to-treat analysis described -  appears to be per protocol. 3/8 in low-frequency group, 2/5 in high-frequency group and 2/5 in sham group

Selective reporting (reporting bias)Low riskComment: point measures presented in full for all outcomes

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors not specified

Adequate blinding of participants?Unclear riskComment: sham credibility assessment - sub-optimal. Coil angled away from scalp. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Lefaucheur 2001a

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: France

Setting: laboratory

Condition: intractable neuropathic pain (mixed central and facial)

Prior management details: refractory to drug management

n = 14

Age: 34 to 80, mean 57.2

Duration of symptoms: not specified "chronic"

Gender distribution: 6 M, 8 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 10 Hz; coil orientation not specified; 80% RMT; no. of trains 20; duration of trains 5 sec; ITI 55 sec; total no. pulses 1000

Stimulation location: motor cortex, contralateral to painful side

Number of treatments: x 1 for each condition

Control type: sham coil used (? inert)


OutcomesPrimary: 0 to 10 VAS, anchors not specified

When taken: daily for 12 days post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Two different sessions of rTMS separated by 3 weeks at least were randomly performed in each patient."

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is apparent from the data presented

Selective reporting (reporting bias)Low riskComment: pain score numerical values are not provided clearly with measures of variance for any time point in the report but were provided by authors on request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is not reported

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. This study uses the same sham coil as that used in Lefaucheur 2004, which in that paper is stated as not meeting the criteria for an ideal sham

Free from carry-over effects?Low riskComment: 3/52 wash-out period makes carry-over effects unlikely

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Lefaucheur 2001b

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: France

Setting: laboratory

Condition: neuropathic pain (mixed central and peripheral)

Prior management details: refractory to drug management

n = 18

Age: 28 to 75, mean 54.7

Duration of symptoms: not specified "chronic"

Gender distribution: 11 M, 7 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:

Condition 1: frequency 10 Hz; coil orientation posteroanterior; 80% RMT; no. of trains 20; duration of trains 5 sec; ITI 55 sec; total no. pulses 1000

Condition 2: frequency 0.5 Hz; coil orientation posteroanterior; no. of trains 1; duration of trains 20 minutes; total no. pulses 600

Condition 3: sham - same as for condition 1 with sham coil

Stimulation location: motor cortex contralateral to painful side

Number of treatments: x 1 for each condition


OutcomesPrimary: 0 to 10 VAS pain, anchors not specified

When taken: 5 to 10 minutes post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "To study the influence of the frequency of stimulation, three different sessions of rTMS separated by three weeks at least were randomly performed in each patient"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is apparent from the data presented

Selective reporting (reporting bias)Low riskComment: results for primary outcomes are reported clearly and in full

Other biasUnclear riskComment: the results of some of the planned data analysis (ANOVA of group differences after each condition) are not reported. However, adequate data are available for inclusion in the meta-analysis

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is not reported

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. This study uses the same sham coil as that used in Lefaucheur 2004, which in that paper is stated as not meeting the criteria for an ideal sham

Free from carry-over effects?Low riskComment: 3-week wash-out observed and no clear imbalance in pre-stimulation pain scores between conditions

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Lefaucheur 2004

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: France

Setting: laboratory

Condition: neuropathic pain (mixed central, peripheral and facial)

Prior management details: refractory to drug management

n = 60

Age: 27 to 79, mean 54.6

Duration of symptoms: not specified "chronic"

Gender distribution: 28 M, 32 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:frequency 10 Hz; coil orientation posteroanterior; 80% RMT; no. of trains 20; duration of trains 5 sec; ITI 55 sec; total no. pulses 1000

Stimulation location: motor cortex contralateral to painful side

Number of treatments: x 1 for each condition

Control type: sham coil


OutcomesPrimary: 0 to 10 VAS pain, anchors not specified

When taken: 5 minutes post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "one of the following two protocols was applied in a random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is apparent from the data presented

Selective reporting (reporting bias)Low riskComment: results for primary outcomes are reported clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is not reported

Adequate blinding of participants?Unclear riskQuote: "ideal sham...which should be performed by means of a coil similar to the real one in shape, weight, and location on the scalp, producing a similar sound and similar scalp skin sensation, but generating no electrical field within the cortex. Such a sham coil has not yet been designed, and at present, the sham coil used in this study is to our knowledge the more valid for clinical trials."

Comments: sham credibility assessment - sub-optimal

Free from carry-over effects?Low riskComment: 3-week wash-out observed and no clear imbalance in pre-stimulation pain scores between conditions

Study SizeUnclear riskComment: > 50 but < 200 participants per treatment condition

Study durationHigh riskComment: < 2 weeks follow-up

Lefaucheur 2006

MethodsCross-over randomised controlled trial, 3 conditions


ParticipantsCountry of study: France

Setting: laboratory

Condition: unilateral chronic neuropathic pain (mixed central and peripheral)

Prior management details: refractory to drug management

n = 22

Age: 28 to 75, mean 56.5 (SD 2.9)

Duration of symptoms: 2 to 18 years, mean 5.4 (SD 4.1)

Gender distribution: 12 M, 10 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:

Condition 1: frequency 10 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 20; duration of trains 6 sec; ITI 54 sec; total no. pulses 1200

Condition 2: frequency 1 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 1; duration of trains 20 minutes; total no. pulses 1200

Condition 3: sham coil

Stimulation location: motor cortex contralateral to painful side

Number of treatments: x 1 for each condition


OutcomesPrimary: 0 to 10 VAS pain, anchors not specified

When taken: pre and post-stimulation

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Three sessions of motor cortex rTMS, separated by at least 3 weeks, were performed in random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: level of drop-out not reported and unclear from the data presented

Selective reporting (reporting bias)Low riskComment: pain score numerical values are not provided clearly with measures of variance for any time point in the study report but were provided by the authors on request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is only reported for measures of cortical excitability

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. This study uses the same sham as Lefaucheur 2004, which in that paper is stated as not meeting the criteria for an ideal sham

Free from carry-over effects?Low riskQuote: "Post hoc tests did not reveal any differences between the three pre-rTMS assessments regarding excitability values or pain levels"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Lefaucheur 2008

MethodsCross-over randomised controlled trial, 3 conditions


ParticipantsCountry of study: France

Setting: laboratory

Condition: neuropathic pain (mixed central, peripheral and facial)

Prior management details: refractory to drug management for at least 1 year

n = 46

Age: 27 to 79, mean 54.2

Duration of symptoms: chronic > 1 year

Gender distribution: 23 M, 23 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters:

Condition 1: frequency 10 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 20; duration of trains 6 sec; ITI 54 sec; total no. pulses 1200

Condition 2: frequency 1 Hz; coil orientation posteroanterior; 90% RMT; no. of trains 1; duration of trains 20 minutes; total no. pulses 1200

Condition 3: sham coil

Stimulation location: motor cortex contralateral to painful side

Number of treatments: x 1 for each condition


OutcomesPrimary: 0 to 10 VAS, anchors not specified

When taken: pre- and post-stimulation

Secondary: none


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Three different sessions of rTMS..... were performed in a random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 2 participants dropped out but this is < 5% of the cohort. Unlikely to have strongly influenced the findings

Selective reporting (reporting bias)Low riskComment: results for all outcomes are reported clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "In all cases, the examiner was blinded to the type of rTMS administered."

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. This study uses the same sham coil as that used in Lefaucheur 2004, which in that paper is stated as not meeting the criteria for an ideal sham

Free from carry-over effects?Low riskComment: 3-week wash-out observed and no clear imbalance in pre-stimulation pain scores between conditions

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Lichtbroun 2001

MethodsParallel randomised controlled study


ParticipantsCountry of study: USA

Setting: outpatient fibromyalgia clinic

Condition: fibromyalgia

Prior management details: unclear

n = 60

Age: 23 to 82, mean 50

Duration of symptoms: 1 to 40 years, mean 11

Gender distribution: 2 M, 58 F


InterventionsStimulation type: CES

Stimulation parameters: frequency 0.5 Hz; 50% duty cycle; intensity 100 μA; waveform shape biphasic square wave; duration 60 min

Stimulation location: ear clip electrodes

Number of treatments: 30, x 1 daily for consecutive days

Control type: sham unit - indistinguishable from active unit


OutcomesPrimary: 10-point self rating pain scale, anchors not specified

When taken: post-stimulation (not precisely defined)

Secondary: quality of life - 0 to 10 VAS scale (data not reported)


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the subjects were randomly assigned into three separate groups by an office secretary who drew their names, which were on separate sealed slips of paper in a container"

Allocation concealment (selection bias)Low riskComment: probably, given the quote above

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out levels are not specified in the report. Intention-to-treat analysis not discussed in the report

Selective reporting (reporting bias)High riskComment: pain score numerical values are not provided clearly with measures of variance for any time points in the study report

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "All subjects, staff, the examining physician and the psychometrician remained blind to the treatment conditions"

Adequate blinding of participants?Low riskComment: see previous quote

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Mendonca 2011

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Brazil/USA

Setting: laboratory

Condition: fibromyalgia

Prior management details: not reported

n = 30 (6 per group)

Age, mean (SD): 43.2 (9.8)

Duration of symptoms: not reported

Gender distribution: 28 F, 2 M


InterventionsStimulation type: tDCS

Stimulation parameters: simulation intensity 2 mA, 20 minutes duration

Stimulation location: Group 1 cathodal M1; Group 2 cathodal supraorbital; Group 3 anodal M1; Group 4 anodal supraorbital; Group 5 sham

Number of treatments: 1 session

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS; 0 = no pain, 10 = worst possible pain

When taken: immediately post-stimulation

Secondary: none relevant


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-outs occurred

Selective reporting (reporting bias)High riskNo numerical data are provided for any post-treatment clinical outcome. Data not provided upon request to authors

Other biasLow riskNo other bias detected

Adequate blinding of assessors?Unclear riskComment: 2 mA intensity used - empirical evidence that assessor blinding may be sub-optimal at this intensity

Adequate blinding of participants?Unclear riskComment: 2 mA intensity used - empirical evidence that participant blinding may be sub-optimal at this intensity

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Mhalla 2011

MethodsParallel RCT


ParticipantsCountry of study: France

Setting: laboratory

Condition: fibromyalgia

Prior management details: not reported but concomitant treatments allowed

n = 40

Age, mean (SD): active group 51.8 (11.6), sham group 49.6 (10)

Duration of symptoms (mean (SD) years): active group 13 (12.9), sham group 14.1 (11.9)

Gender distribution: all female


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation posteroanterior, no. of trains 15; duration of trains 10 sec; ITI 50 sec, intensity 80% RMT, total no. pulses 1500

Stimulation location: left M1

Number of treatments: 14, x 1 daily for 5 days, x 1 weekly for 3 weeks, x 1 fortnightly for 6 weeks, x 1 monthly for 3 months

Control type: sham coil, does not control for sensory cues


OutcomesPrimary: pain NRS; 0 = no pain, 10 = maximal pain imaginable

When taken: day 5, 3 weeks, 9 weeks, 21 weeks, 25 weeks

Secondary: BPI interference scale, Fibromyalgia Impact Questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned to 2 groups...with equal numbers in each group. A study nurse prepared the concealed allocation schedule by computer randomisation of these 2 treatment groups to a consecutive number series; the nurse had no further participation in the trial. Patients were assigned in turn to the next consecutive number."

Allocation concealment (selection bias)Low riskComment: see quote above

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 25% drop-out at long-term follow-up but intention-to-treat analysis used with BOCF imputation

Selective reporting (reporting bias)Low riskComment: no numeric point measures provided for the primary outcome but provided upon request to the authors

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Low riskQuote: "Both patients and investigators were blind to treatment group. Cortical excitability measurements and transcranial stimulation were performed by an independent investigator not involved in the selection or clinical assessment of the patients."

Adequate blinding of participants?Unclear riskComment: sham credibility assessment - sham coil controls for sound and appearance but not the skin sensation of stimulation

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: > 8 weeks follow-up

Mori 2010

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Italy

Setting: laboratory

Condition: neuropathic pain secondary to multiple sclerosis

Prior management details: refractory to drug management and medication discontinued over previous month

n = 19

Age: 23 to 69, mean 44.8 (SD 27.5)

Duration of symptoms: 1 to 10 years, mean 2.79 (SD 2.64)

Gender distribution: 8 M, 11 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: motor cortex, contralateral to painful side

Number of treatments: 5, x 1 daily on consecutive days

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: 0 to 100 mm VAS pain, anchors "no pain" to "worst possible pain"

When taken: end of treatment period and x 1 weekly over 3-week follow-up

Secondary: quality of life, multiple sclerosis quality of life-54 scale (MSQoL-54)

When taken: as for primary outcome


NotesAdverse events: none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed using the order of entrance in the study and a previous randomization list generated by a computer."

Allocation concealment (selection bias)Low riskComment: likely given that the randomisation list was generated pre-study

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-outs observed

Quote: "... none of the patients enrolled discontinued the study."

Selective reporting (reporting bias)Low riskComment: between-group means are not presented clearly to allow meta-analysis but data provided on request

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Onesti 2013

MethodsRandomised cross-over trial


ParticipantsCountry of study: Italy

Setting: laboratory

n = 25

Condition: neuropathic pain from diabetic neuropathy

Prior management details: resistant to standard therapies for at least 1 year

Age mean (SD): 70.6 (8.5)

Duration of symptoms (months mean (SD)): not reported

Gender distribution: 9 F 14 M


InterventionsStimulation type: rTMS using H-coil

Stimulation parameters: frequency 20 Hz; coil orientation H coil, no. of trains 30; duration of trains 2.5 sec; ITI 30 sec, intensity 100% RMT, total no. pulses 1500

Stimulation location: M1 lower limb (deep in central sulcus)

Number of treatments: 5 per condition on consecutive days

Control type: sham coil, controls for scalp sensory, auditory and visual cues


OutcomesPrimary: pain VAS 0 to 100, no pain to worst possible pain

When taken: immediately post-stimulation, 3 weeks post-stimulation

Secondary: none relevant


NotesCOI: 2 authors have links to the manufacturer of the H-coil


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "After enrolment, patients were randomly assigned in a 1:1 ratio to two counterbalanced arms by receiving a sequential number from a computer-generated random list."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 2 patients lost to follow-up

Selective reporting (reporting bias)High riskComment: data are not presented by stimulation condition - rather they are grouped by the order in which interventions were delivered. No SDs presented. Data requested

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Unclear riskComment: while study is described as "double blind" there is no specific mention of blinding assessors

Adequate blinding of participants?Low riskQuote: "Sham stimulation was delivered with a sham coil placed in the helmet encasing the active rTMS coil. The sham coil produced a similar acoustic artefact and scalp sensation as the active coil and could also mimic the facial muscle activation induced by the active coil. It induced only a negligible electric field inside the brain because its non-tangential orientation on the scalp and components cancelling the electric field ensured that it rapidly reduced the field as a function of distance"

Comment: controls for visual auditory and sensory aspects of stimulation

Free from carry-over effects?Low riskComment: 5-week wash-out period observed with no difference at T3

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Passard 2007

MethodsParallel randomised controlled trial


ParticipantsCountry of study: France

Setting: laboratory

Condition: fibromyalgia

Prior management details: unclear

n = 30

Age: active group: 52.6 (SD 7.8), sham group 55.3 (SD 8.9)

Duration of symptoms: active group: 8.1 (SD 7.9), sham group: 10.8 (SD 8.6)

Gender distribution: 1 M, 29 F


InterventionsStimulation type: rTMS, figure of 8 coil

Stimulation parameters: frequency 10 Hz; coil orientation posteroanterior; 80% RMT; no. of trains 25; duration of trains 8 sec; ITI 52 sec; total no. pulses 2000

Stimulation location: motor cortex contralateral to painful side

Number of treatments: 10, x 1 daily for 10 working days

Control type: sham rTMS coil. Mimics sight and sound of active treatment


OutcomesPrimary: 0 to 10 NRS of average pain intensity over last 24 hours, anchors "no pain" to "maximal pain imaginable"

When taken: daily during treatment period and at 15, 30 and 60 days post-treatment follow-up

Secondary: Fibromyalgia Impact Questionnaire

When taken: as for primary outcome


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "patients who met all inclusion criteria were randomly assigned, according to a computer-generated list, to two groups"

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: equal drop-out in each group and appropriately managed in the data analysis

Quote: "All randomized patients with a baseline and at least one post-baseline visit with efficacy data were included in the efficacy analyses (intent to treat analysis)."

"All the patients received the full course of treatment and were assessed on D15 and D30. Four patients (two in each treatment group) withdrew from the trial between days 30 and 60."

Selective reporting (reporting bias)Low riskComment: while pain score numerical values are not provided clearly with measures of variance for all time points in the study report, the study authors have provided the requested data

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "... investigators were blind to treatment group."

Adequate blinding of participants?Unclear riskQuote: "Sham stimulation was carried out with the 'Magstim placebo coil system', which physically resembles the active coil and makes similar sounds."

Comment: sham credibility assessment - sub-optimal. Sham coil controls for auditory cues and is visually indistinguishable from active stimulation but does not control for sensory characteristics of active stimulation over the scalp

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: ≥ 8 weeks follow-up

Picarelli 2010

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Brazil

Setting: laboratory

Condition: CRPS type I

Prior management details: refractory to best medical treatment

n = 23

Age mean (SD): active group 43.5 (12.1), sham group 40.6 (9.9)

Duration of symptoms (months mean (SD)): active group 82.33 (34.5), sham group 79.27 (32.1)

Gender distribution: 14 F, 9 M


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10Hz; coil orientation posteroanterior, no. of trains 25; duration of trains 10 sec; ITI 60 sec, intensity 100% RMT, total no. pulses 2500

Stimulation location: M1 contralateral to painful limb

Number of treatments: 10, x 1 daily on consecutive weekdays

Control type: sham coil - does not control for sensory cues


OutcomesPrimary: pain VAS; 0 = "no pain", 10 = "most severe pain"

When taken: after first and last session then 1 and 3 months post-treatment

Secondary: quality of life SF-36, not reported


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: while states "randomized" the method of randomisation is not reported

Allocation concealment (selection bias)Unclear riskAllocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 participant dropped out at follow-up

Selective reporting (reporting bias)Low riskComment: data presented for primary outcome. While this is not adequate for meta-analysis is does not really constitute selectivity. No response received to request for full data access

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Unclear riskComment: study described as "double-blinded" but assessor blinding not specifically reported

Adequate blinding of participants?Unclear riskComment: sham sub-optimal as it does not control for scalp sensation. Study reported that number who guessed the condition correctly was similar but no formal data or analysis is reported

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: ≥ 8 weeks follow-up

Pleger 2004

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: Germany

Setting: laboratory

Condition: complex regional pain syndrome type I

Prior management details: drug management ceased for 48 hours prior to study

n = 10

Age: 29 to 72, mean 51

Duration of symptoms: 24 to 72 months, mean 35

Gender distribution: 3 M, 7 F


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation unspecified; 110% RMT; no. of trains 10; duration of trains 1.2 sec; ITI 10 sec; total no. pulses 120

Stimulation location: motor cortex hand area

Number of treatments: 1 for each condition

Control type: coil angled 45º away from scalp


OutcomesPrimary: 0 to 10 VAS current pain intensity, anchors "no pain" to "most extreme pain"

When taken: 30 sec, 15, 45 and 90 min post-stimulation

Secondary: none

When taken: 30 seconds, 15, 45 and 90 minutes post-stimulation


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Using a computerized random generator, five patients were first assigned to the placebo group (sham rTMS), while the others were treated using verum rTMS"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out is apparent from the data presented

Selective reporting (reporting bias)Low riskComment: while sham group results not presented in the study report, the study authors have provided the requested data

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors not reported

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled 45º away from scalp. Does not control for sensory characteristics of active stimulation and is visually distinguishable

Free from carry-over effects?Low riskQuote: "The initial pain intensities (VAS) were similar prior to verum and sham rTMS (Student’s paired t-test, P = 0.47). The level of intensity was also independent of whether the patients were first subjected to sham or verum rTMS (P > 0.05)."

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Portilla 2013

MethodsRandomised cross-over study


ParticipantsCountry of study: USA

Setting: laboratory

Condition: post-burn neuropathic pain

Prior management details: varied

n = 3

Age range: 34 to 52

Duration of symptoms: > 6 months

Gender distribution: 2 F 1 M


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, duration 20 minutes

Stimulation location: M1 contralateral to most painful side

Number of treatments: 1 per condition

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS; 0 = "no pain", 10 = "worst pain ever felt"

When taken: before and after stimulation

Secondary: none relevant


NotesDepartmentally funded


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "subjects were randomized to either active tDCS or sham stimulation."

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all 3 patients completed study

Selective reporting (reporting bias)High riskComment: no numeric data provided for pain outcomes

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Free from carry-over effects?Unclear riskComment: 1-week wash-out observed but no data reported for pain outcome so unable to assess this issue

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Riberto 2011

MethodsParallel RCT


ParticipantsCountry of study: Brazil

Setting: rehabilitation clinic

Condition: fibromyalgia

Prior management details: none reported

n = 23

Age mean (SD): active group 58.3 (12.1), sham group 52.4 (11.5)

Duration of symptoms, months (mean (SD)): active group 9.9 (11.8), sham group 6.4 (10.3)

Gender distribution: all female


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, duration 20 minutes

Stimulation location: M1 (contralateral to most painful side or dominant hand)

Number of treatments: 10, x 1 weekly for 10 weeks

Control type: sham tDCS (switched off after 30 seconds stimulation)

Both groups received 4 months rehabilitation programme


OutcomesPrimary: pain VAS; 0 = "no pain", 10 = "worst pain"

When taken: immediately at end of 4-month rehabilitation programme

Secondary: quality of life SF36, Fibromyalgia Impact Questionnaire


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: states simple randomisation method but method not described

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-outs

Selective reporting (reporting bias)Low riskComment: while numeric data on the primary outcome not reported in study report the authors have made it available upon request

Other biasUnclear riskComment: there are group imbalances at baseline on the duration of pain, education, age and economic activity

Adequate blinding of assessors?Unclear riskComment: 2 mA intensity used - empirical evidence that assessor blinding may be sub-optimal at this intensity

Adequate blinding of participants?Unclear riskComment: 2 mA used, which may threaten assessor blinding, though formal analysis of blinding appears acceptable

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Rintala 2010

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: outpatient clinic, patients take device home

Condition: pain related to Parkinson's disease

Prior management details: not reported

n = 19 (reduced to 13 through drop-out)

Age mean (SD): active group 74.7 (7.8), sham group 74.4 (8.3)

Duration of symptoms: > 6 months

Gender distribution: 15 M, 4 F


InterventionsStimulation type: CES

Stimulation parameters: frequency not specified; pulse width not specified; intensity 100 μA; waveform shape not specified; duration 40 minutes per session

Stimulation location: earlobe clips

Number of treatments: 42, x 1 daily for 42 days

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: pain VAS 0 to 10, anchors not reported

When taken: at the end of the treatment period

Secondary: none


NotesComments: equipment provided by CES manufacturer as an "unrestricted gift"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: states randomised but method of randomisation not reported

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: > 30% drop-out

Selective reporting (reporting bias)Low riskComment: mean (SD) pain scores reported for both groups pre- and post-stimulation

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Low riskComment: participants and the study co-ordinator were blinded to group assignment and the code sheet indicating which devices were active and which were sham was kept by another person who was not in contact with the participants

Adequate blinding of participants?Low riskComment: see above comment

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Rollnik 2002

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: Germany

Setting: pain clinic

Condition: chronic pain (mixed musculoskeletal and neuropathic)

Prior management details: "intractable"

n = 12

Age: 33 to 67, mean 51.3 (SD 12.6)

Duration of symptoms: mean 2.7 (SD 2.4)

Gender distribution: 6 M, 6 F


InterventionsStimulation type: rTMS, circular coil for arm symptoms, double cone coil for leg symptoms

Stimulation parameters: frequency 20 Hz; coil orientation not specified; 80% RMT; no. of trains 20; duration of trains 2 sec; ITI not specified; total no. pulses 800; treatment duration 20 minutes

Stimulation location: motor cortex (midline)

Number of treatments: x 1 for each condition

Control type: coil angled 45º away from the scalp


OutcomesPrimary: 0 to 100 mm VAS pain intensity, anchors "no pain" to "unbearable pain"

When taken: 0, 5, 10 and 20 minutes post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "sham and active stimulation were given in a random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 participant withdrew due to "headaches". Unlikely to have strongly influenced the findings

Selective reporting (reporting bias)Low riskComment: while pain score numerical values are not provided clearly with measures of variance for all time points in the study report, the study authors have provided the requested data

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors is not reported

Adequate blinding of participants?Unclear riskComments: sham credibility assessment - sub-optimal. Coil angled 45º away from scalp. Does not control for sensory characteristics of active stimulation over the scalp and is visually distinguishable. Given that stimulation was delivered at 110% RMT active stimulation, but not sham, is likely to have elicited muscle twitches in peripheral muscles

Free from carry-over effects?Low riskComment: not clearly demonstrated in the study report but clear from unpublished data provided by the study authors (baseline mean group pain scores: active stimulation 65.1 (SD 16), sham stimulation 66.9 (SD 17.4))

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Saitoh 2007

MethodsCross-over randomised controlled trial, 4 conditions


ParticipantsCountry of study: Japan

Setting: laboratory

Condition: neuropathic pain (mixed central and peripheral)

Prior management details: intractable

n = 13

Age: 29 to 76, mean 59.4

Duration of symptoms: 2 to 35 years, mean 10.2 (SD 9.7)

Gender distribution: 7 M, 6 F


InterventionsStimulation type: rTMS figure of 8 coil

Stimulation parameters:

Condition 1: frequency 10 Hz; coil orientation not specified; 90% RMT; no. of trains 5; duration of trains 10 sec; ITI 50 sec; total no. pulses 500

Condition 2: frequency 5 Hz; coil orientation not specified; 90% RMT; no. of trains 10; duration of trains 10 sec; ITI 50 sec; total no. pulses 500

Condition 3: frequency 1 Hz; coil orientation not specified; 90% RMT; no. of trains 1; duration of trains 500 sec; total no. pulses 500

Condition 4: sham, coil angled 45º from scalp with synchronised electrical scalp stimulations to mask sensation

Stimulation location: motor cortex over the representation of the painful area

Number of treatments: 1 for each condition


OutcomesPrimary: VAS pain, anchors not specified

When taken: 0, 15, 30, 60, 90 and 180 minutes post-stimulation

Secondary: none


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "rTMS was applied to all the patients at frequencies of 1, 5, and 10 Hz and as a sham procedure in random order"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "All 13 patients participated in all planned sessions of navigation-guided rTMS"

Comment: no drop-outs observed

Selective reporting (reporting bias)Low riskComment: while pain score numerical values are not provided clearly with measures of variance for all time points in the study report, the study authors have provided the requested data

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: blinding of assessors not reported

Adequate blinding of participants?Unclear riskComment: sham credibility assessment - sub-optimal. Sensory and auditory aspects are controlled for but angulation of coil away from the scalp may be visually distinguishable

Free from carry-over effects?Low riskComment: not clearly demonstrated in the study report but paired t-tests on unpublished baseline data provided by the study authors suggest that carry-over was not a significant issue

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Short 2011

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: laboratory

Condition: fibromyalgia

Prior management details: naive to TMS

n = 20

Age mean (SD): active group 54.2 (8.28) sham group 51.67 (18.19)

Duration of symptoms, years mean (SD): active group 12.1 (7.75), sham group 10.10 (12.81)

Gender distribution: 84% female


InterventionsStimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation para-sagittal, no. of trains 80; duration of trains 5 sec; ITI 10 sec, intensity 120% RMT, total no. pulses per session 4000

Stimulation location: left DLPFC

Number of treatments: 10, x 1 daily (working days) for 2 weeks

Control type: sham coil


OutcomesPrimary: pain VAS; 0 = "no pain", 10 = "worst pain"

When taken: after 1 and 2 weeks of treatment, then 1 week and 2 weeks post-treatment

Secondary: Fibromyalgia Impact Questionnaire, Brief Pain Inventory function scale


NotesAdverse events: no data provided.

COI: 1 researcher has received research grants from the device manufacturer and holds patents for TMS technology


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomly assigned (random generator software developed by JJB in the Brain Stimulation Laboratory)

Allocation concealment (selection bias)Low riskQuote: "A co investigator not directly involved in ratings or treatment released treatment condition to the TMS operator"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no loss to follow-up

Selective reporting (reporting bias)Low riskComment: full reporting of primary outcomes

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Low riskQuote: "A masked continuous rater assessed patients at baseline, at the end of each treatment week, and at the 2 follow-up weeks. Importantly the continuous rater did not administer the TMS, minimizing the chances of unmasking due to events during the TMS treatment session."

Adequate blinding of participants?Low riskQuote: "A specially designed sham TMS coil is used for all sham conditions that produces auditory signals identical to active coils but shielded so that actual stimulation does not occur. However, subjects do experience sensory stimulation that is difficult to distinguish from real rTMS"

Comment: sensory, auditory and visual cues controlled for

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Soler 2010

MethodsParallel randomised controlled trial


ParticipantsCountry of study: Spain

Setting: laboratory

Condition: post-spinal cord injury neuropathic pain

Prior management details: stable pharmacological treatment for at least 2 weeks prior to start of treatment. Unresponsive to medication

n = 39

Age mean (SD): 45 (15.5)

Duration of symptoms: not reported

Gender distribution: 30 M, 9 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, duration 20 minutes

Stimulation location: M1 (contralateral to most painful side or dominant hand)

Number of treatments: 10, x 1 daily (working days) for 2 weeks

Control type: 4 groups, tDCS + visual illusion, sham tDCS + visual illusion, tDCS + control illusion, sham tDCS + control illusion


OutcomesPrimary: pain VAS; 0 = no pain, 10 = unbearable pain; mean over previous 24 hours

When taken: end of treatment period, 12 and 24 days post-treatment

Secondary: BPI pain interference scale


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "We used a computer generated list as randomisation strategy."

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 3 drop-outs, 1 in each group

Selective reporting (reporting bias)Low riskComment: all main outcomes reported

Other biasLow riskComment: no other biases detected

Adequate blinding of assessors?Unclear riskComment: 2 mA intensity used - empirical evidence that assessor blinding may be sub-optimal at this intensity

Adequate blinding of participants?Unclear riskComment: 2 mA may threaten blinding but assessment of blinding seemed OK

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Tan 2000

MethodsCross-over randomised controlled trial


ParticipantsCountry of study: USA

Setting: tertiary care teaching hospital

Condition: neuromuscular pain (excluding fibromyalgia)

Prior management details: unclear

n = 28

Age: 45 to 65, mean 55.6

Duration of symptoms: 4 to 45 years, mean 15

Gender distribution: 25 M, 3 F


InterventionsStimulation type: CES

Stimulation parameters: frequency 0.5 Hz; pulse width not specified; intensity 10 to 600 μA; waveform shape not specified

Stimulation location: ear clip electrodes

Number of treatments: 12, frequency of treatment not specified

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: VAS 0 to 5 pain intensity

When taken: pre and post each treatment

Secondary: life interference scale, sickness impact profile - Roland Scale

When taken: not specified


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "each subject was randomly assigned to receive either the active or the sham treatment first"

Comment: method of randomisation not specified but less critical in cross-over design

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: only 17 participants completed the study and this drop-out (over 50%) is not clearly accounted for in the analysis

Selective reporting (reporting bias)Low riskComment: primary outcome data presented clearly

Other biasUnclear riskComment: participants also received local stimulation to the painful area that may have elicited a therapeutic effect

Adequate blinding of assessors?Unclear riskComment: blinding of assessors not reported

Adequate blinding of participants?Low riskQuote: "sham treatment was made possible by having the treatment delivered via a black box"

Comment: sham and active stimulators visually indistinguishable

Free from carry-over effects?Low riskQuote: "Note that there were no significant differences in pain ratings pre-post changes between the active and sham groups"

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Tan 2006

MethodsParallel randomised controlled trial


ParticipantsCountry of study: USA

Setting: medical centre

Condition: post-SCI pain (not clearly neuropathic)

Prior management details: unclear

n = 40

Age: 38 to 82

Duration of symptoms: chronic > 6 months

Gender distribution: all male


InterventionsStimulation type: CES

Stimulation parameters: frequency not specified; pulse width not specified; intensity 100 to 500 μA; waveform shape not specified; duration 1 hour per session

Stimulation location: ear clip electrodes

Number of treatments: 21, x 1 daily for consecutive days

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: Brief Pain Inventory (0 to 10 NRS), anchors "no pain" to "pain as bad as you can imagine"

When taken: post-treatment period

Secondary: pain interference sub-scale of BPI

When taken: as for primary outcome


NotesAdverse events: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The participants were then randomly assigned to either the active or sham CES treatment groups"

Comment: method of randomisation not specified

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not specified

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 2 (5%) patients withdrew from the study. Unlikely to have strongly influenced the findings

Selective reporting (reporting bias)Low riskComment: primary outcomes presented clearly and in full

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Low riskQuote: "The investigators,research assistant (RA), and participants were blinded to treatment type until the end of the initial phase."

Adequate blinding of participants?Low riskComment: see quote above

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Tan 2011

MethodsParallel randomised controlled trial


ParticipantsCountry of study: USA

Setting: 4 veterans affairs medical centres and 1 private rehabilitation clinic

Condition: post-spinal cord injury neuropathic pain

Prior management details: not reported

n = 105

Age mean (SD): active group 52.1 (10.5), sham group 52.5 (11.7)

Gender distribution: 90 M, 15 F


InterventionsStimulation type: CES

Stimulation parameters: frequency not specified; pulse width not specified; intensity 100 μA; waveform shape not specified; duration 1 hour per session

Stimulation location: earlobe clips

Number of treatments: 21, x 1 daily

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: Brief Pain Inventory pain intensity VAS 0 to 100, anchors not reported

When taken: at end of treatment period

Secondary: quality of life SF-12 physical and mental component sub-scales


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The equipment was set up for a double-blind study by the manufacturer such that the participants could not differentiate active from sham CES devices. Research staff members who interacted with the participants (e.g. recruited and trained participants, administered questionnaires, followed up by telephone) did not know which devices were sham and which were active. Randomization was achieved by selecting a device from a box initially containing equal numbers of active and sham devices."

Comment: whilst unconventional it appears to avoid a systematic bias

Allocation concealment (selection bias)Low riskComment: see quote/comment above

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: available case analysis with small loss to follow-up

Selective reporting (reporting bias)Low riskComment: key outcomes fully reported

Other biasUnclear riskComment: baseline between-group imbalances on BPI pain interference, SF-36 pain sub-scale and coping strategies

Adequate blinding of assessors?Low riskComment: stimulation sub-sensory and units indistinguishable

Adequate blinding of participants?Low riskComment: Stimulation sub sensory and units indistinguishable

Study SizeUnclear riskComment: > 50 but < 200 participants per treatment condition

Study durationHigh riskComment: < 2 weeks follow-up

Taylor 2013

MethodsParallel RCT


ParticipantsCountry of study: USA

Setting: community rheumatology practices

Condition: fibromyalgia

Prior management details: not reported but continued stable medication usage

n = 57 (46 after drop-out)

Age mean (SD): active group 51(10.6) sham group 51.5 (10.9), usual care group 48.6 (9.8)

Duration of symptoms: not reported

Gender distribution: 43 F, 3 M (data reported on completers)


InterventionsStimulation type: CES

Stimulation parameters: frequency 0.5 Hz; pulse width not specified; intensity 100 μA; waveform shape square wave biphasic, duration 1 hour per session

Stimulation location: earlobe clip electrodes

Number of treatments: x 1 daily for 8 weeks

Control type: sham CES unit indistinguishable from active unit


OutcomesPrimary: pain VAS, anchors not reported

When taken: at the end of each week of treatment period

Secondary: Fibromyalgia Impact Questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: described as randomised but method of randomisation not reported

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: of 57, 11 did not complete -  unclear if ITT analysis employed. However, only 2 to 4 per group and balanced -  mostly due to assessment burden

Selective reporting (reporting bias)Low riskComment: while no numeric data were provided on primary outcomes in the study report, these data were provided upon request to the authors

Other biasLow riskComment: no other source of bias detected

Adequate blinding of assessors?Low riskComment: participants self rated at home

Adequate blinding of participants?Low riskComment: identical devices given to sham and active group with sub-sensory stimulation parameters

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Tzabazis 2013

MethodsUnclear, likely parallel RCT (for 1 Hz only), 10 Hz data open-label therefore excluded from this review


ParticipantsCountry of study: USA

Setting: not reported, likely laboratory

Condition: fibromyalgia

Prior management details: "moderate to severe despite current and stable treatment regime"

n = unclear, abstract report (Schneider 2012) states 45, but full paper states 16

Age mean (SD): 53.2 (8.9)

Duration of symptoms, years mean (SD): not reported

Gender distribution: 14 female, 2 male


InterventionsStimulation type: rTMS 4-coil configuration

Stimulation parameters: frequency 1 Hz; no of trains not reported; duration of trains not reported; ITI not reported, intensity 110% RMT, total no. pulses per session 1800, stimulation duration 30 min

Stimulation location: targeted to the anterior cingulate cortex

Number of treatments: 20, x 1 daily (working days) for 4 weeks

Control type: sham coil


OutcomesPrimary: Brief Pain Inventory average pain last 24 hours NRS, anchors not reported

When taken: end of treatment, 4 weeks post-treatment

Secondary: Fibromyalgia Impact Questionnaire


NotesCOI: 3 authors have acted as paid consultants to the manufacturer of the stimulation device, of which 2 hold stock in the company and 1 founded the company, is its chief medical officer and has intellectual property rights


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: no description of the sequence generation process used

Allocation concealment (selection bias)Unclear riskComment: no description of allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: no mention of the degree of drop-out or how it was managed. However, 45 participants with fibromyalgia reported in the abstract of the same study (Schneider 2012), but only 16 reported in the full paper

Selective reporting (reporting bias)High riskComment: no presentation of numeric pain data with measures of variance

Other biasUnclear riskComment: baseline and demographic data not presented for clinical group

Adequate blinding of assessors?Unclear riskComment: no description or mention of blinding assessors for clinical part of study

Adequate blinding of participants?Unclear riskComment: no description of blinding of participants for clinical part of study. Sham coil controls for auditory cues and is visually indistinguishable from active stimulation but does not control for sensory characteristics of active stimulation over the scalp

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

Valle 2009

MethodsParallel randomised controlled trial, 3 conditions


ParticipantsCountry of study: Brazil

Setting: laboratory

Condition: fibromyalgia

Prior management details: refractory to medical intervention

n = 41

Age: mean 54.8 (SD 9.6) years

Duration of symptoms: condition 1: 7.54 (SD 3.93) years; condition 2: 8.39 (SD 2.06) years; condition 3: 8.69 (SD 3.61) years

Gender distribution: 0 M; 41 F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, 35 cm2 electrodes, duration 20 minutes

Stimulation location: condition 1: left dorsolateral prefrontal cortex; condition 2: left motor cortex, condition 3; sham left motor cortex

Number of treatments: 10, x 1 daily on consecutive working days

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS 0 to 10 cm, anchors not specified

When taken: immediately post-treatment, averaged over 3 days post-treatment, 30 and 60 days post-treatment

Secondary: quality of life; Fibromyalgia Impact Questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed using the order of entrance in the study and a previous randomisation list generated by a computer"

Allocation concealment (selection bias)Low riskComment: the use of a pre-generated randomisation list should have adequately ensured this

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no drop-out occurred

Selective reporting (reporting bias)High riskComment: pain score numerical values are not provided clearly with measures of variance for any post-treatment time point in the study report

Other biasLow riskComment: no significant other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationLow riskComment: ≥ 8 weeks follow-up

Villamar 2013

MethodsRandomised cross-over trial


ParticipantsCountry of study: USA

Setting: laboratory

Condition: fibromyalgia

Prior management details: pain refractory to common analgesics and muscle relaxants

n = 18 randomised of which 17 allocated

Age mean (SD): 50.3 (8.5)

Duration of symptoms (years) mean (SD): 10.7 (6.8)

Gender distribution: 15 F, 3 M


InterventionsStimulation type: HD-tDCS

Stimulation parameters: intensity 2 mA, duration 20 minutes, anodal/cathodal/sham 4 x 1-ring configuration

Stimulation location: left motor cortex

Number of treatments: x 1 per condition

Control type: sham tDCS


OutcomesPrimary: pain visual numerical scale; 0 = complete absence of pain, 10 = worst pain imaginable

When taken: baseline, immediately post-stimulation, 30 minutes post-stimulation

Secondary: adapted quality if life scale for persons with chronic illness (7 points: 1 = terrible, 7 = delighted)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the order of stimulation was counterbalanced and randomly assigned for each individual"

Comment: method of randomisation not specified but less likely to introduce bias in a cross-over design

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 loss to follow-up and multiple imputation used

Selective reporting (reporting bias)Low riskComment: primary outcomes reported in full

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Free from carry-over effects?Low riskComment: 7 day wash-out periods observed. Data similar at baseline

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationHigh riskComment: < 2 weeks follow-up

Wrigley 2014

MethodsCross-over RCT


ParticipantsCountry of study: Australia

Setting:laboratory

Condition: chronic neuropathic pain post SCI

Prior management details; none

n = 10

Age mean (SD): 56.1 (14.9)

Duration of symptoms: 15.8 (11.3) years

Gender distribution: 8M 2F


InterventionsStimulation type: tDCS

Stimulation parameters: intensity 2 mA, duration 20 minutes

Stimulation location: M1 (contralateral to most painful side or dominant hand)

Number of treatments: 5, x 1 daily 5 days

Control type: sham tDCS (switched off after 30 seconds stimulation)


OutcomesPrimary: pain VAS; 0 = "no pain", 10 = "worst possible pain"

When taken: at end of treatment, 4 weeks post-treatment

Secondary: none relevant


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: method of randomisation not specified but less important for cross-over design

Quote: "A randomized crossover design was used so that all subjects participated in an active treatment (transcranial direct current stimulation) and sham treatment period. Both the subject and the response assessor were blinded to the randomization sequence."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no loss to follow-up

Selective reporting (reporting bias)Low riskComment: primary outcomes reported in full

Other biasLow riskComment: no other bias detected

Adequate blinding of assessors?Unclear riskComment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity (see Assessment of risk of bias in included studies)

Free from carry-over effects?Low riskComment: 4-week wash-out period observed and data appear free of carry-over effects

Study SizeHigh riskComment: < 50 participants per treatment arm

Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks follow-up

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Avery 2007The duration of painful symptoms is unclear. May not be exclusively chronic pain

Belci 2004Pain is not measured as an outcome

Bolognini 2013Inclusion of acute and chronic pain patients

Carraro 2010Not a study of electrical brain stimulation

Choi 2012bStudy of acute pain

Choi 2012aStudy of acute pain

Evtiukhin 1998A study of postoperative pain. No sham control employed

Frentzel 1989Not a study of brain stimulation

Hargrove 2012aUncontrolled long-term follow-up data from Hargrove 2012

Johnson 2006Self reported pain is not measured

Katz 1991Study not confined to chronic pain

Longobardi 1989Not clearly studying chronic pain

Nelson 2010Intervention not designed to alter cortical activity directly by electrical stimulation - a neuro feedback intervention

O'Connell 2013Not a RCT or quasi-RCT - no randomisation specifically to treatment group or order

Pujol 1998Participants are a mixture of acute and chronic pain patients

Sichinava 2012No sham control employed for tDCS

Silva 2007A single case report

Zaghi 2009Single case report

 
Characteristics of studies awaiting assessment [ordered by study ID]
Acler 2012

MethodsParallel RCT

ParticipantsPost-polio patients, n = 32

InterventionstDCS, bi-anodal, bilateral motor cortex, 1.5 mA, 20 minutes, daily for 5 days

OutcomesPain, quality of life

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Albu 2011

MethodsSham controlled study, unclear whether randomised

ParticipantsPost-spinal cord injury chronic neuropathic pain, n = 30

InterventionstDCS motor cortex, 2 mA, 10 sessions

OutcomesPain intensity

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Ansari 2013

MethodsParallel RCT

ParticipantsFibromyalgia, n = 118

InterventionsrTMS right DLPFC, low-frequency, 20 sessions

OutcomesUnclear whether self reported pain scores were collected

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Fricova 2009

MethodsSham controlled trial, unclear whether randomised

ParticipantsChronic neurogenic orofacial pain, n = 26

InterventionsrTMS motor cortex, frequency unclear, appears to be a single session of stimulation per condition

OutcomesPain VAS

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Fricova 2011

MethodsSham controlled trial, unclear whether randomised, likely to be a cross-over design

ParticipantsChronic neurogenic orofacial pain, n = 26

InterventionsrTMS motor cortex, frequency unclear, appears to be a single session of stimulation per condition

OutcomesPain VAS

NotesPublished as conference abstract only. Published as conference abstract only. Likely to be a duplicate report of Fricova 2009. Attempts to contact authors currently unsuccessful

Klirova 2010

MethodsParallel RCT

ParticipantsNeuropathic orofacial pain, n = 29

InterventionsrTMS, motor cortex, 10 Hz, 5 treatment sessions

OutcomesPain VAS

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Klirova 2011

MethodsParallel RCT

ParticipantsNeuropathic orofacial pain, medication resistant, n = 29

InterventionsrTMS, motor cortex, 10 Hz, 5 treatment sessions

OutcomesPain VAS

NotesPublished as conference abstract only. Likely to be a duplicate report of Klirova 2010. Attempts to contact authors currently unsuccessful

Knotkova 2011

MethodsParallel RCT

ParticipantsComplex regional pain syndrome type I, n = 25

InterventionstDCS, motor cortex, 2 mA, 20 minutes per session, daily for 5 days

OutcomesPain, quality of life, physical activity

NotesCurrently published as conference abstract only. Correspondence with authors - data unavailable as currently being re-analysed

Pellaprat 2012

MethodsCross-over RCT

ParticipantsParkinson's disease with related pain, n = 19

InterventionsrTMS 20 Hz motor cortex, ? whether single session

OutcomesPain VAS

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

Shklar 1997

MethodsUnable to retrieve study report

Participants

Interventions

Outcomes

Notes

Vatashsky 1997

MethodsUnable to retrieve study report

Participants

Interventions

Outcomes

Notes

Yaĝci 2013

MethodsParallel RCT

ParticipantsFibromyalgia, n = 25

InterventionsrTMS motor cortex, 1 Hz, 90% RMT, 10 sessions daily

OutcomesPain VAS, FIQ

NotesPublished as conference abstract only. Attempts to contact authors currently unsuccessful

 
Characteristics of ongoing studies [ordered by study ID]
ISRCTN89874874

Trial name or titleEffectiveness of anodal transcranial direct current stimulation (tDCS) in patients with chronic low back pain: a randomised controlled trial

MethodsParallel RCT

ParticipantsChronic low back pain, n = 135

InterventionstDCS 2 mA, 20 minutes, daily for 5 consecutive days

OutcomesPain VAS, disability (Oswestry Disability Index), patient perceived satisfactory improvement, quality of life (SF-36)

Starting date20 February 2011

Contact informationKerstin Luedtke, Matinistr. 52, Hamburg, Germany, 20246

NotesCorrespondence with authors - trial currently ongoing

NCT00697398

Trial name or titleRepetitive Trans-Cranial Magnetic Stimulation of the Motor Cortex in Fibromylagia: A Study Evaluating the Clinical Efficiency and the Metabolic Correlate in 18FDG-PET

MethodsParallel RCT

ParticipantsFibromyalgia

InterventionsrTMS motor cortex, parameters not specified

OutcomesAnalgesic efficiency at 36-month follow-up, quality of life

Starting dateOctober 2008

Contact informationDr Eric Guedj, eric.guedj@ap-hm.fr

NotesCorrespondence with authors: Study complete and currently under peer review for publication

NCT00815932

Trial name or titleThe Effect of Transcranial Direct Current Stimulation (t-DCS) On the P300 Component of Event-Related Potentials in Patients With Chronic Neuropathic Pain Due To CRPS or Diabetic Neuropathy

MethodsCross-over RCT

ParticipantsChronic neuropathic pain due to CRPS or diabetic neuropathy

InterventionstDCS or sham, 2 mA, 20 minutes, x 1 session, location not specified

OutcomesPain intensity

Starting dateFebruary 2009

Contact informationDr Pesach Schvartzman, spesah@bgu.ac.il

NotesContact in 2010 - study ongoing, recent attempts to contact for update unsuccessful

NCT00947622

Trial name or titleOccipital Transcranial Direct Current Stimulation in Fibromyalgia

MethodsCross-over RCT

ParticipantsFibromyalgia

InterventionstDCS or sham, parameters not specified

OutcomesPain VAS and FIQ

Starting dateJuly 2009

Contact informationDr Mark Plazier, mark.plazier@uza.be

NotesAttempts to contact authors currently unsuccessful

NCT01112774

Trial name or titleApplication of transcranial direct current stimulation in patients with chronic pain after spinal cord injury

MethodsParallel RCT

ParticipantsChronic pain after spinal cord injury, proposed n = 60

InterventionstDCS 2 mA, 10 sessions

OutcomesPain VAS, quality of life

Starting dateApril 2010

Contact informationDr Felipe Fregni, ffregni@neuromodulationlab.org, Kayleen Weaver, kmweaver@partners.org

NotesContact with author - study at "to be analysed and reported" stage

NCT01220323

Trial name or titleTranscranial direct current stimulation for chronic pain relief

MethodsCross-over RCT

ParticipantsChronic pain patients, proposed n = 100

InterventionstDCS, motor cortex, 2 mA, daily for 5 days

OutcomesPain relief

Starting dateNovember 2010

Contact informationDr Silvio Brill, Tel Aviv Sourasky Medical Centre

NotesCorrespondence with authors: study ongoing

NCT01402960

Trial name or titleExploration of parameters of transcranial direct current stimulation in chronic pain

MethodsParallel RCT

ParticipantsChronic pain following traumatic spinal cord injury, n = 60

InterventionstDCS or sham, 2 mA, motor cortex, 20 minutes, x 1 daily for 5 days

OutcomesPain

Starting dateApril 2010

Contact informationDr Felipe Fregni, ffregni@partners.org; Kayleen Weaver, kmweaver@partners.org

NotesContact with author - study at "to be analysed and reported" stage

NCT01404052

Trial name or titleEffects of transcranial direct current stimulation and transcranial ultrasound on osteoarthritis pain of the knee

MethodsParallel RCT

ParticipantsChronic knee osteoarthritis pain, n = 30

InterventionstDCS or sham, 20 minutes, 2 mA, motor cortex, 5 sessions

OutcomesPain

Starting dateJanuary 2011

Contact informationDr Felipe Fregni, ffregni@partners.org; Kayleen Weaver, kmweaver@partners.org

NotesContact with author - study at "to be analysed and reported" stage

NCT01575002

Trial name or titleEffects of transcranial direct current stimulation in chronic corneal pain

MethodsCross-over RCT

ParticipantsChronic corneal pain

InterventionstDCS, active or sham, 1 session of each, parameters not reported

OutcomesPain VAS

Starting dateJanuary 2012

Contact informationDr Felipe Fregni, ffregni@partners.org; Kayleen Weaver, kmweaver@partners.org

NotesContact with author - study at "to be analysed and reported" stage

NCT01599767

Trial name or titleSpaulding-Harvard model system: Effects of transcranial direct current stimulation on chronic pain in spinal cord injury

MethodsParallel RCT

ParticipantsModerate to severe sub-lesional pain post-spinal cord injury

InterventionsAnodal tDCS 15 sessions x 1 daily, parameters not reported

OutcomesPain

Starting dateDecember 2011

Contact informationDr Felipe Fregni, ffregni@partners.org; Kayleen Weaver, kmweaver@partners.org

NotesContact with author - study at "to be analysed and reported" stage

NCT01608321

Trial name or titlerTMS for the treatment of chronic pain in GW1 veterans

MethodsParallel RCT

ParticipantsChronic pain related to Gulf War illness that meets diagnostic criteria for fibromyalgia, n = 206

InterventionsrTMS 20 sessions, stimulation parameters unclear

OutcomesMcGill pain questionnaire

Starting dateAugust 2012

Contact informationDr Ansgar Furst, Dr John Ashford, ansgar.furst@va.gov, wes.ashford@va.gov

NotesCorrespondence with authors: recruiting due to commence Spring 2013

NCT01746355

Trial name or titleAssessment and treatment patients with atypical facial pain through repetitive transcranial magnetic stimulation

MethodsParallel RCT

ParticipantsAtypical facial pain, n = 40

InterventionsrTMS or sham, parameters not reported, 5 sessions

OutcomesPain VAS

Starting dateMarch 2011

Contact informationRicardo Galhardoni

NotesCorrespondence with authors: study near completion.

NCT01747070

Trial name or titleEffect of cranial stimulation and acupuncture on pain, functional capability and cerebral function in osteoarthritis

MethodsParallel RCT

ParticipantsChronic osteoarthritis pain, n = 80

Interventions4 groups, real tDCS + electroacupuncture sham; sham tDCS + electroacupuncture sham, sham tDCS + electroacupuncture, real tDCS + electroacupuncture

tDCS 2 mA motor cortex. All single session.

OutcomesDaily pain intensity, WOMAC

Starting dateJanuary 2012

Contact informationDr Wolnei Caumo, caumo@cpovo.net

NotesCorrespondence with authors: study ongoing

 
Comparison 1. Repetitive transcranial magnetic stimulation (rTMS)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain: short-term follow-up21Std. Mean Difference (Fixed, 95% CI)-0.20 [-0.26, -0.13]

    1.1 Low-frequency ≤ 1 Hz
6Std. Mean Difference (Fixed, 95% CI)0.15 [-0.01, 0.31]

    1.2 High-frequency ≥ 5 Hz
20Std. Mean Difference (Fixed, 95% CI)-0.27 [-0.35, -0.20]

 2 Pain: short-term follow-up, subgroup analysis: multiple-dose vs single-dose studies21Std. Mean Difference (Random, 95% CI)-0.19 [-0.33, -0.06]

    2.1 Single-dose studies
12Std. Mean Difference (Random, 95% CI)-0.23 [-0.37, -0.09]

    2.2 Multiple-dose studies
9Std. Mean Difference (Random, 95% CI)-0.12 [-0.47, 0.23]

 3 Pain: short-term follow-up, subgroup analysis, neuropathic pain participants only14Std. Mean Difference (Fixed, 95% CI)-0.20 [-0.27, -0.12]

    3.1 Low-frequency ≤ 1 Hz
5Std. Mean Difference (Fixed, 95% CI)0.15 [-0.02, 0.32]

    3.2 High-frequency ≥ 5 Hz
14Std. Mean Difference (Fixed, 95% CI)-0.27 [-0.35, -0.19]

 4 Pain: short-term follow-up, subgroup analysis, non-neuropathic pain participants only6Std. Mean Difference (Fixed, 95% CI)-0.19 [-0.44, 0.05]

    4.1 Low-frequency ≤ 1 Hz
1Std. Mean Difference (Fixed, 95% CI)0.16 [-0.29, 0.61]

    4.2 High-frequency ≥ 5 Hz
5Std. Mean Difference (Fixed, 95% CI)-0.34 [-0.63, -0.05]

 5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded17Std. Mean Difference (Random, 95% CI)-0.32 [-0.46, -0.17]

    5.1 Single-dose studies
12Std. Mean Difference (Random, 95% CI)-0.39 [-0.51, -0.27]

    5.2 Multiple-dose studies
5Std. Mean Difference (Random, 95% CI)-0.07 [-0.41, 0.26]

 6 Sensitivity analysis - imputed correlation coefficient increased. Pain: short-term follow-up23Std. Mean Difference (Random, 95% CI)-0.21 [-0.34, -0.08]

    6.1 Low-frequency ≤ 1 Hz
7Std. Mean Difference (Random, 95% CI)0.15 [0.01, 0.29]

    6.2 High-frequency ≥ 5 Hz
22Std. Mean Difference (Random, 95% CI)-0.30 [-0.44, -0.16]

 7 Sensitivity analysis - imputed correlation coefficient decreased. Pain: short-term follow-up22Std. Mean Difference (Random, 95% CI)-0.20 [-0.34, -0.06]

    7.1 Low-frequency ≤ 1 Hz
6Std. Mean Difference (Random, 95% CI)0.17 [-0.03, 0.37]

    7.2 High-frequency ≥ 5 Hz
21Std. Mean Difference (Random, 95% CI)-0.28 [-0.42, -0.13]

 8 Sensitivity analysis - imputed correlation increased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded17Std. Mean Difference (Random, 95% CI)-0.33 [-0.47, -0.20]

    8.1 Single-dose studies
12Std. Mean Difference (Random, 95% CI)-0.41 [-0.53, -0.29]

    8.2 Multiple-dose studies
5Std. Mean Difference (Random, 95% CI)-0.08 [-0.39, 0.23]

 9 Sensitivity analysis - imputed correlation decreased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded17Std. Mean Difference (Random, 95% CI)-0.31 [-0.46, -0.17]

    9.1 Single-dose studies
12Std. Mean Difference (Random, 95% CI)-0.38 [-0.49, -0.27]

    9.2 Multiple-dose studies
5Std. Mean Difference (Random, 95% CI)-0.11 [-0.48, 0.25]

 10 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up25Std. Mean Difference (Fixed, 95% CI)-0.23 [-0.31, -0.16]

    10.1 Low-frequency ≤ 1 Hz
9Std. Mean Difference (Fixed, 95% CI)0.09 [-0.05, 0.24]

    10.2 High-frequency ≥ 5 Hz
23Std. Mean Difference (Fixed, 95% CI)-0.34 [-0.42, -0.26]

 11 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded21Std. Mean Difference (Random, 95% CI)-0.39 [-0.56, -0.23]

    11.1 Single-dose studies
14Std. Mean Difference (Random, 95% CI)-0.36 [-0.48, -0.24]

    11.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.50 [-0.99, -0.01]

 12 Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only4Std. Mean Difference (Random, 95% CI)-0.47 [-1.48, 0.54]

    12.1 Multiple-dose studies
4Std. Mean Difference (Random, 95% CI)-0.47 [-1.48, 0.54]

 13 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only5Std. Mean Difference (Random, 95% CI)-0.48 [-1.32, 0.37]

    13.1 Multiple-dose studies
5Std. Mean Difference (Random, 95% CI)-0.48 [-1.32, 0.37]

 14 Pain: medium-term follow-up7Std. Mean Difference (Random, 95% CI)-0.18 [-0.43, 0.06]

    14.1 Low-frequency ≤ 1 Hz
1Std. Mean Difference (Random, 95% CI)0.36 [-0.41, 1.13]

    14.2 High-frequency ≥ 5 Hz
6Std. Mean Difference (Random, 95% CI)-0.23 [-0.48, 0.03]

 15 Sensitivity analysis - inclusion of high risk of bias studies. Pain: medium-term follow-up10Std. Mean Difference (Random, 95% CI)-0.43 [-0.76, -0.10]

    15.1 Low-frequency ≤ 1 Hz
2Std. Mean Difference (Random, 95% CI)-0.08 [-1.26, 1.10]

    15.2 High-frequency ≥ 5 Hz
9Std. Mean Difference (Random, 95% CI)-0.48 [-0.83, -0.13]

 16 Pain: long-term follow-up3Std. Mean Difference (Random, 95% CI)-0.12 [-0.46, 0.21]

 17 Sensitivity analysis - inclusion of high risk of bias studies. Pain: long-term follow-up4Std. Mean Difference (Random, 95% CI)-0.46 [-1.10, 0.17]

 18 Disability/pain interference: short-term follow-up5Std. Mean Difference (Random, 95% CI)-0.29 [-0.87, 0.29]

 19 Disability/pain interference: medium-term follow-up4Std. Mean Difference (Random, 95% CI)-0.37 [-1.07, 0.33]

 20 Disability/pain interference: long-term follow-up3Std. Mean Difference (Random, 95% CI)-0.23 [-0.62, 0.16]

 21 Quality of life: short-term follow-up (Fibromyalgia Impact Questionnaire)380Mean Difference (IV, Random, 95% CI)-10.38 [-14.89, -5.87]

 22 Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire)380Mean Difference (IV, Fixed, 95% CI)-11.49 [-17.04, -5.95]

 23 Quality of life: long-term follow-up1Std. Mean Difference (Random, 95% CI)Totals not selected

 
Comparison 2. Cranial electrotherapy stimulation (CES)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain: short-term follow-up5270Std. Mean Difference (IV, Random, 95% CI)-0.24 [-0.48, 0.01]

 2 Disability/function/pain interference1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 3 Quality of life1Std. Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 3. Transcranial direct current stimulation (tDCS)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain: short-term follow-up11Std. Mean Difference (Random, 95% CI)-0.18 [-0.46, 0.09]

    1.1 Single-dose studies
3Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]

    1.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.22 [-0.69, 0.25]

 2 Pain: short-term follow-up, subgroup analysis: motor cortex studies only11Std. Mean Difference (Random, 95% CI)-0.23 [-0.48, 0.01]

    2.1 Single-dose studies
3Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]

    2.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.35 [-0.79, 0.09]

 3 Pain: short-term sensitivity analysis: correlation increased11Std. Mean Difference (Random, 95% CI)-0.20 [-0.47, 0.06]

 4 Pain: short-term sensitivity analysis: correlation decreased11Std. Mean Difference (Random, 95% CI)-0.23 [-0.51, 0.06]

 5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation increased11Std. Mean Difference (Random, 95% CI)-0.23 [-0.48, 0.02]

    5.1 Single-dose studies
3Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]

    5.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.35 [-0.79, 0.10]

 6 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation decreased11Std. Mean Difference (Random, 95% CI)-0.24 [-0.48, -0.00]

    6.1 Single-dose studies
3Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]

    6.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.36 [-0.79, 0.07]

 7 Pain: medium-term follow-up5Std. Mean Difference (Random, 95% CI)-0.20 [-0.63, 0.24]

 8 Disability (pain interference): short-term follow-up1Mean Difference (IV, Random, 95% CI)Subtotals only

 9 Quality of life: short-term follow-up242Std. Mean Difference (IV, Random, 95% CI)0.88 [0.24, 1.53]

 10 Quality of life: medium-term follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected

 11 Pain: short-term follow-up, subgroup analysis: motor cortex studies only11Std. Mean Difference (Random, 95% CI)-0.26 [-0.49, -0.03]

    11.1 Single-dose studies
3Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]

    11.2 Multiple-dose studies
8Std. Mean Difference (Random, 95% CI)-0.38 [-0.80, 0.03]

 
Comparison 4. Reduced impedance non-invasive cortical electrostimulation (RINCE)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain: short-term follow-up1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 2 Fibromyalgia Impact Questionnaire total score1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 
Summary of findings for the main comparison.

Repetitive transcranial magnetic stimulation (rTMS) compared with sham for chronic pain

Intervention: active rTMS

Comparison: sham rTMS

Outcomes: pain (VAS or NRS)

ComparisonNo of participants
(studies)
Effect size

(SMD, 95% CIs)
Relative effect

(average % improvement (reduction) in pain (95% CIs) in relation to post-treatment score from sham group)*

*statistically significant outcomes with low heterogeneity only
Quality of the evidence
(GRADE)

Pain: short-term follow-up

Subgroup analysis: low-frequency rTMS
81
(6)
Ineffective

0.15 (-0.01 to 0.31) P = 0.07
⊕⊕⊝⊝ low

Pain: short-term follow-up

subgroup analysis: high-frequency rTMS
447

(20)
Effective

-0.27 (-0.35 to -0.20) P < 0.01
⊕⊕⊝⊝ low

Pain: short-term follow-up

Subgroup analysis: motor cortex studies only, low-frequency studies excluded, single-dose studies
233

(12)
Effective

-0.39 (-0.51 to -0.27)

P < 0.01
12% (8% to 15%)⊕⊕⊝⊝ low

Pain: short-term follow-up

Subgroup analysis: motor cortex studies only, low-frequency studies excluded, multiple-dose studies
157

(5)
Ineffective

-0.07 (-0.41 to 0.26)

P = 0.68
⊕⊝⊝⊝ very low

Pain: short-term follow-up
Subgroup analysis: prefrontal cortex studies only
68

(5)
Ineffective

-0.47 (-1.48 to 0.11)

P = 0.36
⊕⊝⊝⊝ very low

Pain: medium-term follow-up

rTMS all studies
184

(8)
Ineffective

-0.18 (-0.43 to 0.06)

P = 0.15
⊕⊝⊝⊝ very low

Pain: long-term follow-up

rTMS all studies
59

(3)
Ineffective

-0.12 (-0.46 to 0.21)

P = 0.47
⊕⊕⊝⊝ low

CES compared with sham for chronic pain

Intervention: active CES

Comparison: sham CES

Outcomes: pain (VAS or NRS)

Pain: short-term follow-up

CES all studies
270

(5)
Ineffective

-0.24 (-0.48 to 0.01)

P = 0.06
⊕⊕⊝⊝ low

tDCS compared with sham for chronic pain

Intervention: active tDCS

Comparison: sham tDCS

Outcomes: pain (VAS or NRS)

Pain: short-term follow-up

tDCS all studies
183

(10)
Ineffective

-0.18 (-0.56 to 0.09)

P = 0.19
⊕⊝⊝⊝ very low

Pain: short-term follow-up
Subgroup analysis: motor cortex studies only (single and multiple-dose studies)
172

(10)
Ineffective

-0.23 (-0.48 to 0.01)

P = 0.06
⊕⊕⊝⊝ low

Pain: short-term follow-up
Subgroup analysis: motor cortex studies only (multiple-dose studies only)
119

(7)
Ineffective

-0.35 (-0.79 to 0.09)

P = 0.12
⊕⊝⊝⊝ very low

Pain: medium-term follow-up

tDCS
77

(4)
Ineffective

-0.20 (-0.63 to 0.24)

P = 0.37
⊕⊕⊝⊝ low

RINCE compared with sham for chronic pain

Intervention: active RINCE

Comparison: sham RINCE

Outcomes: pain (VAS or NRS)

Pain: short-term follow-up

tDCS all studies
91

(1)
Effective

-1.41 (-2.48 to -0.34) P = 0.01
⊕⊝⊝⊝ very low

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

CES: cranial electrotherapy stimulation; CI: confidence interval; NRS: numerical rating scale; RINCE: reduced impedance non-invasive cortical electrostimulation; rTMS: repetitive transcranial magnetic stimulation; tDCS: transcranial direct current stimulation; VAS: visual analogue scale

 For full details of the GRADE judgements for each comparison see Appendix 6.
 
Table 1. rTMS studies - characteristics of stimulation

StudyLocation of stimulationCoil orientationFrequency (Hz)Intensity (% RMT)Number of trainsDuration of trainsInter-train intervals (sec)Number of pulses per sessionTreatment sessions per group

Ahmed 2011M1 stump region45° angle from sagittal line20801010 sec5020005, x 1 daily

André-Obadia 2006M1 contralateral to painful sidePosteroanterior20, 19020 Hz: 20

1Hz: 1
20 Hz: 4 sec

1 Hz: 26 min
20 Hz: 8416001

André-Obadia 2008M1 contralateral to painful sidePosteroanterior

Medial-lateral
2090204 sec8416001

André-Obadia 2011M1 hand area, not clearly reported but likely contralateral to painful sideNot specified2090204 sec8416001

Avery 2013Left DLPFCNot specified1012075426300015

Short 2011Left DLPFCPara-sagittal10120805 sec10 sec400010, x 1 daily (working days) for 2 weeks

Borckardt 2009Left PFCNot specified101004010 sec2040003 over a 5-day period

Carretero 2009Right DLPFCNot specified11102060 sec451200Up to 20 on consecutive working days

Defrin 2007M1 midlineNot specified511550010 sec30? 500*10, x 1 daily

Fregni 2005Left and right SIINot specified190Not specifiedNot specifiedNot specified16001

Fregni 2011Right SIINot specified170% maximum stimulator output intensity (not RMT)1Not specifiedNot specified160010, x 1 daily (week days only)

Hirayama 2006M1, S1, PMA, SMANot specified5901010 sec505001

Hosomi 2013M1 corresponding to painful regionNot specified5901010 sec5050010, x 1 daily (week days only)

Irlbacher 2006M1 contralateral to painful sideNot specified5, 195Not specifiedNot specifiedNot specified5001

Kang 2009Right M145º postero-lateral1080205 sec5510005, x 1 daily

Khedr 2005M1 contralateral to painful sideNot specified20801010 sec5020005, x 1 daily

Lee 2012Right DLPFC (low-frequency)

Left M1 (high-frequency)
Not specified10, 110 Hz: 80

1 Hz: 110
10 Hz:25

1 Hz: 2
10 Hz: 8 sec

1 Hz: 800 sec
10 Hz: 10

1 Hz: 60
10 Hz: 2000

1 Hz: 1600
10, x 1 daily (week days only)

Lefaucheur 2001aM1 contralateral to painful sideNot specified1080205 sec5510001

Lefaucheur 2001bM1 contralateral to painful sidePosteroanterior10, 0.58010 Hz: 20

0.5 Hz: 1
10 Hz: 5 sec

0.5 Hz: 20 min
10 Hz: 5510 Hz: 1000

0.5 Hz: 600
1

Lefaucheur 2004M1 contralateral to painful sidePosteroanterior1080205 sec5510001

Lefaucheur 2006M1 contralateral to painful sidePosteroanterior10, 19010 Hz: 20

1 Hz: 1
10 Hz: 6 sec

1 Hz: 20 min
10 Hz: 5410 Hz: 1200

1 Hz: 1200
1

Lefaucheur 2008M1 contralateral to painful sidePosteroanterior10, 19010 Hz: 20

1 Hz: 1
10 Hz: 6 sec

1 Hz: 20 min
10 Hz: 5410 Hz: 1200

1 Hz: 1200
1

Mhalla 2011Left M1Posteroanterior10801510 sec50150014, 5 x 1 daily (working days), then 3 x 1 weekly, then 3 x 1 fortnightly, then 3 x 1 monthly

Onesti 2013M1 deep central sulcusH-coil20100302.5 sec3015005, x 1 daily on consecutive days

Passard 2007M1 contralateral to painful sidePosteroanterior1080258 sec52200010, x 1 daily (working days)

Picarelli 2010M1 contralateral to painful sidePosteroanterior101002510 sec60250010, x 1 daily (working days)

Pleger 2004M1 hand areaNot specified10110101.2 sec101201

Rollnik 2002M1 midlineNot specified2080202 secNot specified8001

Saitoh 2007M1 over motor representation of painful areaNot specified10, 5, 19010 Hz; 5

5 Hz: 10

1 Hz: 1
10 Hz: 10 sec

5 Hz: 10 sec

1 Hz: 500 sec
10 Hz: 50

5 Hz: 50
5001

Tzabazis 2013Targeted to ACC4-coil configuration1 Hz (10 Hz data excluded as not randomised)110Not reportedNot reportedNot reported180020, x 1 daily (working days)

 ACC: anterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; M1: primary motor cortex; PFC: prefrontal cortex; PMA: pre-motor area; RMT: resting motor threshold; dS1: primary somatosensory cortex; SII: secondary somatosensory cortex; SMA: supplementary motor area
 
Table 2. CES studies - characteristics of stimulation

StudyElectrode placementFrequency (Hz)Pulse width (msec)Waveform shapeIntensityDuration (min)Treatment sessions per group

Capel 2003Ear clip electrodes102Not specified12 μA53x 2 daily for 4 days

Cork 2004Ear clip electrodes0.5Not specifiedModified square wave biphasic100 μA60? daily for 3 weeks

Gabis 2003Mastoid processes and forehead773.3Biphasic asymmetric≤ 4 mA30x 1 daily for 8 days

Gabis 2009Mastoid processes and forehead773.3Biphasic asymmetric≤ 4 mA30x 1 daily for 8 days

Katsnelson 2004Mastoid processes and foreheadNot specifiedNot specified2 conditions: symmetric, asymmetric11 to 15 mA40x 1 daily for 5 days

Lichtbroun 2001Ear clip electrodes0.5Not specifiedBiphasic square wave100 μA60x 1 daily for 30 days

Rintala 2010Ear clip electrodesNot specifiedNot specifiedNot specified100 μA40x 1 daily for 6 weeks

Tan 2000Ear clip electrodes0.5Not specifiedNot specified10 to 600 μA2012 (timing not specified)

Tan 2006Ear clip electrodesNot specifiedNot specifiedNot specified100 to 500 μA60x 1 daily for 21 days

Tan 2011Ear clip electrodesNot specifiedNot specifiedNot specified100 μA60x 1 daily for 21 days

Taylor 2013Ear clip electrodes0.5Not specifiedModified square-wave biphasic100 μA60x 1 daily for 8 weeks

 
Table 3. tDCS studies - characteristics of stimulation

StudyLocation of stimulationElectrode pad sizeIntensity (mA)Anodal or cathodal?Stimulus duration (min)Treatment sessions per group

Antal 2010M1 left hand area35 cm21 mAAnodal205, x 1 daily

Boggio 2009M1 contralateral to painful side35 cm22 mAAnodal301

Fenton 2009M1 dominant hemisphere35 cm21 mAAnodal202

Fregni 2006aM1 contralateral to painful side or dominant hand35 cm22 mAAnodal205, x 1 daily

Fregni 2006bM1 and DLPFC contralateral to painful side or dominant hand35 cm22 mAAnodal205, x 1 daily

Jensen 2013M1 left35cm22 mAAnodal201

Mendonca 2011Group 1: anodal left M1

Group 2: cathodal left M1

Group 3: anodal supraorbital

Group 4: cathodal supraorbital

Group 5: sham
35 cm22 mAAnodal or cathodal201

Mori 2010M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily

Portilla 2013M1 contralateral to painful side35 cm22 mAAnodal20x 1 per condition

Riberto 2011M1 contralateral to painful side or dominant hand35 cm22 mAAnodal2010, x 1 weekly

Soler 2010M1 contralateral to painful side or dominant hand35 cm22 mAAnodal2010, x 1 daily (week days only)

Valle 2009M1 and DLPFC contralateral to painful side or dominant hand35 cm22 mAAnodal205, x 1 daily

Villamar 2013M1 leftHD-tDCS 4 x 1-ring montage2 mAAnodal or cathodal20x 1 per condition

Wrigley 2014M1 contralateral to painful side or dominant hand35 cm22 mAAnodal205, x 1 daily

 DLPFC: dorsolateral prefrontal cortex; M1: primary motor cortex
HD-tDCS: High definition tDCS
 
Table 4. GRADE judgements for core comparisons

ComparisonResultLimitations of studiesInconsistencyIndirectnessImprecisionPublication biasGRADE judgement

rTMS

Pain: short-term

Low-frequency rTMS allIneffective
SMD 0.15 (-0.01 to 0.31)
Down one

< 75% at low risk of bias
None

(I2 = 0%, P = 0.78)
NoneDown one, n = 81No direct evidenceLow

High-frequency TMS allEffective
SMD -0.27 (-0.35 to -0.20)
Down one

< 75% studies at low risk of bias
Down one

(I2 = 64%, P < 0.01)
NoneNone, n = 447No direct evidenceLow

Single-dose, high-frequency rTMS applied to the motor cortex on chronic painEffective
SMD -0.39 (-0.51 to -0.27)
Down one

< 75% studies at low risk of bias
None

(I2 = 31%, P = 0.13)
NoneDown one, n = 233No direct evidenceLow

Multiple-dose, high-frequency rTMS applied to the motor cortex on chronic painIneffective
SMD -0.07 (-0.41 to 0.26)
Down one

< 75% studies at low risk of bias
Down one

(I2 = 71%, P < 0.01)
NoneDown one, n = 157No direct evidenceVery low

rTMS prefrontal cortexIneffective
SMD -0.47 (-1.48 to 0.54)
Down one

< 75% studies at low risk of bias
Down one

(I2 = 82%, P < 0.01)
NoneDown one, n = 68No direct evidenceVery low

Pain: medium-term

rTMS allIneffective
SMD -0.15 (-0.41 to 0.11)
Down one

< 75% studies at low risk of bias
Down one

(I2 = 60%, P = 0.01)
NoneDown one, n = 184No direct evidenceVery low

Pain: long-term

rTMS allIneffective
SMD -0.12, (-0.46 to 0.21)
Down one

< 75% studies at low risk of bias
None

(I2 = 0%, P = 0.95)
NoneDown one, n = 59No direct evidenceLow

CES

Pain: short-term

CES allIneffective
SMD -0.24 (-0.48 to 0.01)
Down one

< 75% studies at low risk of bias
None

(I2 = 0%, P = 0.43)
NoneDown one, n = 270No direct evidenceLow

tDCS

Pain: short-term

tDCS allIneffective
SMD -0.18 (-0.46 to 0.09)
Down one

< 75% studies at low risk of bias
Down one (I2 = 49%, P = 0.02)NoneDown one, n = 183No direct evidenceVery low

tDCS motor cortexIneffective
SMD -0.23 (-0.48 to 0.01)
Down one

< 75% studies at low risk of bias
None

(I2 = 33%, P = 0.13)
NoneDown one, n = 182No direct evidenceLow

tDCS motor cortex multiple-dose studiesIneffective
SMD -0.35 (-0.79 to 0.09)
Down one

< 75% studies at low risk of bias
Down one

(I2 = 51%, P = 0.05)
NoneDown one, n = 129No direct evidenceVery low

Pain: medium-term

tDCS allIneffective
SMD -0.32 (-0.76 to 0.11)
Down one

< 75% studies at low risk of bias
None (I2 = 40%, P = 0.14)NoneDown one n = 87No direct evidenceLow

RINCE

Pain: short-termEffective
SMD -1.41 (-2.48 to -0.34) P = 0.01
Down one -

study at unclear risk of bias
n/a - single study onlyNoneDown two, as only a single study availableNo direct evidence - only a single studyVery low

 CES: cranial electrotherapy stimulation
RINCE: reduced impedance non-invasive cortical electrostimulation
rTMS: repetitive transcranial magnetic stimulation
SMD: standardised mean difference
tDCS: transcranial direct current stimulation
TMS: transcranial magnetic stimulation