Non-invasive brain stimulation techniques for chronic pain

Sham credibility issues for non-invasive brain stimulation studies

An issue regarding the credibility of sham conditions specifically for rTMS studies is whether the sham condition that is employed controls for the auditory (clicking sounds of various frequencies) and sensory stimulation that occurs during active stimulation (Lisanby 2001; Loo 2000). Various types of sham have been proposed including angling the coil away from the scalp (thus preserving the auditory cues but not the sensation of stimulation), using coils that mimic the auditory cues combined with gentle scalp electrical stimulation to mask the sensation and simple inert coils that reproduce neither the sound nor the sensation of active stimulation. Failure to control for such cues may impact negatively on participant blinding, particularly in cross-over design studies. Lisanby 2001 and Loo 2000 suggest that an ideal sham condition for rTMS should:

• not stimulate the cortex;

• be the same as active stimulation in visual terms and in terms of its position on the scalp; and

• not differ from active stimulation in terms of the acoustic and afferent sensory sensations that it elicits.

Strategies have been developed to try to meet these criteria (Borckardt 2008; Rossi 2007; Sommer 2006). There is evidence that simply angling the coil away from the scalp at an angle of less than 90° may still result in brain stimulation and not be truly inert (Lisanby 2001). This strategy is also easily detected by the recipient of stimulation. In these ways this type of sham might obscure or exaggerate a real clinical effect of active stimulation.

In studies of tDCS the sham condition commonly involves the delivery of a short initial period (30 seconds to one minute) of identical stimulation to the active condition, at which point the stimulation is ceased without the participant's knowledge. There is evidence that this achieves effective blinding of tDCS at stimulation intensities of 1 mA in naive participants (Ambrus 2012; Gandiga 2006), but at a stimulation intensity of 2 mA tDCS both participant and assessor blinding has been shown to be inadequate, since participants can distinguish the active condition more than would be expected by chance and a proportion of those receiving active stimulation develop a temporary but visible redness over the electrode sites (O'Connell 2012). At 1.5 mA there are detectable differences in the experience of tDCS that might compromise blinding (Kessler 2013), though a formal investigation of the adequacy of blinding at this intensity has not been published to date.

Types of studies

We included randomised controlled trials (RCTs) and quasi-randomised trials (e.g. by order of entry or date of birth) that utilised a sham control group. We included parallel and cross-over study designs. We included studies regardless of language.

Types of participants

We included studies involving male or female participants over the age of 18 years with any chronic pain syndrome (with a duration of more than three months). It was not anticipated that any studies were likely to exist in a younger population. Migraine and other headache studies were not included due to the episodic nature of these conditions.

Types of interventions

We included studies investigating the therapeutic use of non-invasive forms of brain stimulation (tDCS, rTMS, CES, RINCE or tRNS). We did not include studies of electroconvulsive therapy (ECT), as its mechanism of action (the artificial induction of an epileptic seizure (Stevens 1996)) differs substantially from the other forms of brain stimulation. We also excluded invasive forms of brain stimulation involving the use of electrodes implanted within the brain, and indirect forms of stimulation, such as caloric vestibular stimulation and occipital nerve stimulation. In order to meet our second objective of considering the influence of varying stimulation parameters, we included studies regardless of the number of stimulation sessions delivered, including single-dose studies.

Types of outcome measures

Electronic searches

For the OVID MEDLINE search, we ran the subject search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6 and detailed in box 6.4c of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (Lefebvre 2011). We have slightly adapted this filter to include the term 'sham' in the title or abstract. The search strategies for this update are presented in Appendix 1 and included a combination of controlled vocabulary (MeSH) and free-text terms. We based all database searches on this strategy but appropriately revised them to suit each database.

Searching other resources

Selection of studies

Two review authors (NOC and BW) independently checked the search results and the reference lists of included eligible studies. Initially two review authors (NOC and BW) read the titles or abstracts (or both) of identified studies. Where it was clear from the study title or abstract that the study was not relevant or did not meet the selection criteria we excluded it. If it was unclear then we assessed the full paper, as well as all studies that appeared to meet the selection criteria. Disagreement was resolved through discussion between the two review authors. Where resolution was not achieved a third review author (LDS) considered the paper(s) in question.

Data extraction and management

Two review authors (NOC and BW) extracted data independently using a standardised form that was piloted by both authors independently on three randomised controlled trials of transcutaneous electrical nerve stimulation prior to the searches. We resolved discrepancies by consensus. The form included the following.

• 'Risk of bias' assessment results

• Country of origin

• Study design

• Study population - condition; pain type; duration of symptoms; age range; gender split; prior management

• Sample size - active and control groups

• Intervention - stimulation site, parameters and dosage (including number and duration of trains of stimuli and number of pulses for rTMS studies)

• Type of sham

• Credibility of sham (for rTMS studies - see below)

• Outcomes - mean postintervention pain scores for the active and sham treatment groups at all follow-up points

• Results - short, intermediate and long-term follow-up

• Adverse effects

• Conflict of interest disclosure

Assessment of risk of bias in included studies

We assessed risk of bias using the Cochrane 'Risk of bias' assessment tool outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (Higgins 2011a).

The criteria assessed for parallel study designs (using low/high/unclear judgements) were: adequate sequence generation; adequate allocation concealment; adequate blinding of assessors; adequate blinding of participants; adequate assessment of incomplete outcome data; whether free of suggestion of selective outcome reporting; and whether free of other bias.

The criteria assessed for cross-over study designs (using low/high/unclear judgements) were: adequate sequence generation; whether data were clearly free from carry-over effects; adequate blinding of assessors; adequate blinding of participants; whether free of the suggestion of selective outcome reporting; and whether free of other bias.

As with the previous update, in compliance with new author guidelines from Cochrane Pain, Palliative and Supportive Care and the recommendations of Moore 2010 we added two criteria, 'study size' and 'study duration', to our 'Risk of bias' assessment using the thresholds for judgement suggested by Moore 2010:

• size (we rated studies with fewer than 50 participants per arm as being at high risk of bias, those with between 50 and 199 participants per arm at unclear risk of bias, and 200 or more participants per arm at low risk of bias);

• duration (we rated studies with follow-up of less than two weeks as being at high risk of bias, two to seven weeks at unclear risk of bias and eight weeks or longer at low risk of bias).

Two review authors (NOC and BW) independently checked risk of bias. Disagreement between review authors was resolved through discussion between the two review authors. Where resolution was not achieved a third review author (LDS) considered the paper(s) in question.

Measures of treatment effect

We used standardised mean difference (SMD) to express the size of treatment effect on pain intensity measured with a VAS or NRS. In order to aid interpretation of the pooled effect size we back-transformed the SMD to a 0 to 10 pain intensity rating scale on the basis of the mean standard deviation from trials using a 0 to 10 point VAS. We considered the likely clinical importance of the pooled effect size using the criteria proposed in the IMMPACT consensus statement (Dworkin 2008). Specifically, we judged a decrease in pain of less than 15% as no important change, of 15% or more as a minimally important change, of 30% or more as a moderately important change and of 50% or more as a substantially important change.

Unit of analysis issues

We entered cross-over trials into a meta-analysis where it was clear that these data were free of carry-over effects. We combined the results of cross-over studies with parallel studies using the generic inverse-variance method as suggested in the Cochrane Handbook for Systematic Reviews of Interventions, section 16.4.6.2 (Higgins 2011b). We imputed the post-treatment between-condition correlation coefficient from an included cross-over study that presented individual participant data and used this to calculate the standard error of the standardised mean difference (SE (SMD)). Where data from the same cross-over trials were entered more than once into the same meta-analysis we corrected the number of participants by dividing by the number of times data from that trial were entered in the meta-analysis. We calculated the SMD (SE) for parallel studies in Review Manager 5 (RevMan 5) (RevMan 2014). For each study we entered the SMD (SE) into the meta-analysis using the generic inverse-variance method.

Dealing with missing data

Where insufficient data were presented in the study report to enter a study into the meta-analysis, we contacted the study authors to request access to the missing data.

Assessment of heterogeneity

We conducted separate meta-analysis for each type of brain stimulation. We assessed heterogeneity using the Chi² test to investigate its statistical significance and the I² statistic (Higgins 2003) to estimate the amount. We planned to investigate the influence of altered chronic pain condition or stimulation parameters through pre-planned subgroup analyses (see Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

We planned to consider the possible influence of publication/small study biases on review findings. The influence of small study biases were, in part, addressed by the risk of bias criterion 'study size'. We planned to use funnel plots to visually explore the likelihood of reporting biases when at least 10 studies were included in a meta-analysis and included studies differed in size. For continuous outcomes, we planned to use Egger's test to detect possible small study bias and, for dichotomised outcomes, we planned to test for the possible influence of publication bias on each outcome by estimating the number of participants in studies with zero effect required to change the number needed to treat for an additional beneficial outcome (NNTB) to an unacceptably high level (defined as a NNTB of 10).

Data synthesis

We performed pooling of results where adequate data supported this using RevMan 5 software (RevMan 2014), with a random-effects model. Where an analysis included parallel and cross-over trials we used the generic inverse variance method (see Unit of analysis issues). We conducted separate meta-analyses for different forms of stimulation intervention (i.e. rTMS, tDCS, CES, RINCE and tRNS) and for short-term (0 to < 1 week postintervention), mid-term (≥ 1 to 6 weeks postintervention) and long-term (≥ 6 weeks postintervention) outcomes where adequate data were identified.

Where more than one data point was available for short-term outcomes, we used the first poststimulation measure, and where multiple treatments were given we took the first outcome at the end of the treatment period. For medium-term outcomes where more than one data point was available, we used the measure that fell closest to the mid-point of this time period. We excluded studies from the meta-analysis that we rated at high risk of bias on any criteria, excluding the criteria 'study size' and 'study duration'.

Two review authors (NOC, BW) independently rated the quality of the outcomes. We used the GRADE system to rank the quality of the evidence, and the guidelines provided in Chapter 12.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The GRADE system uses the following criteria for assigning grade of evidence.

• High: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.

• Low: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

• Very low: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Schünemann 2011).

• High: randomised trials; or double-upgraded observational studies

• Moderate: downgraded randomised trials; or upgraded observational studies

• Low: double-downgraded randomised trials; or observational studies

• Very low: triple-downgraded randomised trials; or downgraded observational studies; or case series/case reports

Factors that may decrease the quality level of a body of evidence are:

• limitations in the design and implementation of available studies suggesting high likelihood of bias;

• indirectness of evidence (indirect population, intervention, control, outcomes);

• unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

• imprecision of results (wide confidence intervals);

• high probability of publication bias.

To ensure consistency of GRADE judgements we applied the following criteria to each domain equally for all key comparisons of the primary outcome.

• Limitations of studies: downgrade once if less than 75% of included studies are at low risk of bias across all key 'Risk of bias' criteria.

• Inconsistency: downgrade once if heterogeneity is significant (p<0.05) and the I² value is more than 40%.

• Indirectness: downgrade once if more than 50% of the participants were outside the target group.

• Imprecision: downgrade once if there were fewer than 400 participants for continuous data and fewer than 300 events for dichotomous data (Guyatt 2011).

• Publication bias: downgrade where there is direct evidence of publication bias.

We considered single studies to be both inconsistent and imprecise, unless more than 400 participants were randomised.

Subgroup analysis and investigation of heterogeneity

Where heterogeneity (P < 0.1) was present we explored subgroup analyses. Pre-planned comparisons included site of stimulation, frequency of rTMS stimulation (low ≤ 1 Hz, high ≥ 5 Hz), multiple-dose versus single-dose studies and the type of painful condition (central neuropathic versus peripheral neuropathic versus non-neuropathic pain versus facial pain) for each stimulation type. Central neuropathic pain included pain due to identifiable pathology of the central nervous system (e.g. stroke, spinal cord injury), peripheral neuropathic pain included injury to the nerve root or peripheral nerves, facial pain included trigeminal neuralgia and other idiopathic chronic facial pains, and non-neuropathic pain included all chronic pain conditions without a clear neuropathic cause (e.g. chronic low back pain, fibromyalgia, complex regional pain syndrome type I).

Sensitivity analysis

When sufficient data were available, we conducted sensitivity analyses on the following study factors: risk of bias, sham credibility (for rTMS studies) and cross-over versus parallel-group designs.

Results of the search

For a full description of our screening process, see the study flow diagram (Figure 1). For a summary of the search results for this update see Appendix 2 and Appendix 3. See Appendix 4; Appendix 5; Appendix 6; Appendix 7 and Appendix 8 for full details of the search results and strategies from earlier versions of this review.

This 2017 update is based on a September 2016 search and a further search update in October 2017. For this update, the searches of the databases (see Electronic searches) retrieved 1256 records. Handsearching reference lists of included articles identified one additional RCT that met the inclusion criteria. Our searches of the trials registers identified 305 records. We therefore had a total of 1561 records. Once duplicates had been removed from the main searches and nonrelevant records were removed from the trials registry search results we had a total of 884 records. We excluded 759 records based on titles and abstracts leaving 76 full-text papers, 14 conference reports and 35 trials register records. We obtained the full text of the remaining 76 records. We excluded 12 studies from 15 records, see Characteristics of excluded studies). Fourteen records were conference abstract reports relating to 12 RCTs. Of these we added nine records to Studies awaiting classification and classified three as Ongoing studies. Of the remaining 52 records (47 RCTs), nine RCTs had been included in previous versions of this update.

We included 38 new studies in this review. Of these, 12 studies (355 participants) investigated only rTMS (Boyer 2014; Dall'Agnol 2014; de Oliveira 2014; Jetté 2013; Malavera 2013; Medeiros 2016; Nardone 2017; Nurmikko 2016; Tekin 2014; Umezaki 2016; Yagci 2014; Yilmaz 2014), 22 studies (772 participants) investigated tDCS (Ahn 2017; Ayache 2016; Bae 2014; Brietzke 2016; Chang 2017; Donnell 2015; Fagerlund 2015; Hagenacker 2014; Harvey 2017; Hazime 2017; Jales Junior 2015; Khedr 2017; Kim 2013; Lagueux 2017; Luedtke 2015; Mendonca 2016; Ngernyam 2015; Oliveira 2015; Sakrajai 2014; Souto 2014; Thibaut 2017; Volz 2016) one study (36 participants) investigated tDCS and rTMS (Attal 2016), two studies (16 participants) investigated tRNS (Curatolo 2017; Palm 2016) and one study investigated RINCE (Deering 2017, 46 participants). Overall this updated review included 94 studies (2983 participants), with 42 trials of rTMS (1101 participants), 36 trials of tDCS (1073 participants), 11 studies of CES (572 participants), one study (36 participants) of both rTMS and tDCS, two studies of RINCE (137 participants) and two studies of tRNS (36 participants). We identified 13 conference abstract reports of 11 studies that were not related to full published studies (Ansari 2013; Fricová 2013; Deering 2017; Hwang 2015; Mattoo 2017; Moreno-Duarte 2013a; Muniswamy 2016; Mylius 2013; Parhizgar 2011; Tanwar 2016; Williams 2014). We contacted the authors of these abstracts to try to ascertain whether they were unique studies or duplicates and to acquire full study reports. Of these, two authors confirmed that the studies were ongoing or had been submitted for publication (Ansari 2013; Muniswamy 2016) and they were subsequently included in Ongoing studies. The authors of one abstract (Deering 2017) shared a full unpublished study report and the study was included in this review. Where we were unable to obtain this information we placed these records in Studies awaiting classification. One report previously placed in Studies awaiting classification was identified as a full paper and included in this review (Yagci 2014).

We identified 35 new ongoing studies in total (see Characteristics of ongoing studies). We contacted the authors by email for any relevant data but no data were available for inclusion. Three studies, classified as ongoing after previous searches, had been published and were included in the review (Boyer 2014 NCT00697398; Luedtke 2015 ISRCTN89874874, Thibaut 2017 NCT01599767), one was terminated without results (NCT01608321). The remaining studies identified as ongoing in the last update of this review remain unpublished to our knowledge (NCT00815932; NCT00947622; NCT01112774; NCT01220323; NCT01402960; NCT01404052; NCT01575002; NCT01746355; NCT01747070).

Included studies

See Characteristics of included studies.

Excluded studies

See Characteristics of excluded studies.

In previous versions of this review we excluded 20 studies after consideration of the full study report. Of these, two were not studies of brain stimulation (Carraro 2010; Frentzel 1989), two did not assess self-reported pain as an outcome (Belci 2004; Johnson 2006), seven were not restricted to participants with chronic pain or clearly in a chronic pain population (Avery 2007; Choi 2012a; Choi 2012b; Evtiukhin 1998; Katz 1991; Longobardi 1989; Pujol 1998), two were single case studies (Silva 2007; Zaghi 2009), one study presented duplicate data from a study already accepted for inclusion (Roizenblatt 2007, duplicate data from Fregni 2006b), one did not employ a sham control (Evtiukhin 1998), one was not a randomised controlled trial (O'Connell 2013), one reported uncontrolled long-term follow-up data from an included study (Hargrove 2012b), one employed an intervention that was not designed to alter cortical activity directly through electrical stimulation (Nelson 2010), and one included some participants who did not meet our criterion of chronic pain (Bolognini 2013). A final study was screened by a Russian translator and excluded on the basis that it did not employ a sham control for tDCS (Sichinava 2012).

In this update we excluded a further 14 reports of 12 studies. Three of these studies did not randomly allocate participants to groups (Cummiford 2016; Lindholm 2015; Yoon 2014). Six were not clearly in a chronic population (Bolognini 2015; Choi 2014; Khedr 2005; Ma 2015; Morin 2017; Schabrun 2014), two were not studies of electrical brain stimulation (Maestu 2013; Smania 2005), one did not employ a sham control (Seada 2013).

Sequence generation

For the criterion 'adequate sequence generation' we awarded cross-over trials a judgement of 'low risk of bias' where the study report mentioned that the order of treatment conditions was randomised. Since this criterion has a greater potential to introduce bias in parallel designs we only awarded a judgement of 'low risk of bias' where the method of randomisation was specified and adequate.

We judged 28 trials as having an unclear risk of bias (Antal 2010; Bae 2014; Carretero 2009; Chang 2017; Cork 2004; Curatolo 2017; Deering 2017; Defrin 2007; Hagenacker 2014; Hargrove 2012a; Jales Junior 2015; Jetté 2013; Katsnelson 2004; Lagueux 2017; Lee 2012; Mendonca 2011; Mendonca 2016; Nardone 2017; Palm 2016; Picarelli 2010; Riberto 2011; Rintala 2010; Sakrajai 2014; Tan 2006; Taylor 2013; Thibaut 2017; Tzabazis 2013; Yagci 2014), as they did not specify the method of randomisation used or the description was not clear. We judged two studies as having a high risk of bias for this criterion (Ahmed 2011; Khedr 2005), as the reports suggested that participants were allocated depending on the day of the week on which they were recruited, which we did not judge as being genuinely random. We judged the remaining 64 studies as having a low risk of bias for this domain.

Allocation concealment

We only considered allocation concealment for parallel designs or cross-over trials from which only data from the first cross-over phase of the study was included (i.e. we considered them as parallel-group studies). Thirty-four studies did not clearly report concealment of allocation and we judged them as unclear (Antal 2010; Avery 2013; Bae 2014; Carretero 2009; Cork 2004; Curatolo 2017; de Oliveira 2014; Deering 2017; Defrin 2007; Donnell 2015; Fagerlund 2015; Fregni 2011; Hargrove 2012a; Harvey 2017; Jales Junior 2015; Katsnelson 2004; Kim 2013; Lee 2012; Mendonca 2011; Nardone 2017; Passard 2007; Picarelli 2010; Riberto 2011; Rintala 2010; Sakrajai 2014; Soler 2010; Tan 2006; Taylor 2013; Tekin 2014; Thibaut 2017; Tzabazis 2013; Umezaki 2016; Volz 2016; Yilmaz 2014), and we judged two studies as having a high risk of bias for this criterion since the method of randomisation employed would not have supported concealment of allocation (Ahmed 2011; Khedr 2005). We judged 28 studies as having a low risk of bias for this domain.

Blinding

Incomplete outcome data

We assessed 19 studies as having an unclear risk of bias for this criterion (Ahmed 2011; André-Obadia 2006; André-Obadia 2011; Bae 2014; Brietzke 2016; Boggio 2009; Chang 2017; Cork 2004; Fagerlund 2015; Fregni 2011; Hargrove 2012a; Jales Junior 2015; Katsnelson 2004; Lefaucheur 2006; Lichtbroun 2001; Mendonca 2016; Tzabazis 2013; Volz 2016; Yagci 2014). Of these, Ahmed 2011; Bae 2014; Cork 2004; Fregni 2011; Jales Junior 2015; Katsnelson 2004; Lefaucheur 2006; Lichtbroun 2001; Tzabazis 2013 and Volz 2016 did not report the level of dropout from their studies. Tzabazis 2013 reported recruiting 16 participants in the full study report (Tzabazis 2013), but an earlier abstract report of the same study reported the recruitment of 45 participants. In the study of André-Obadia 2006, two participants (17% of the study cohort) did not complete the study and this was not clearly accounted for in the data analysis. This was also the case for Boggio 2009, where two participants (25% of the cohort) failed to complete the study. Brietzke 2016 and Mendonca 2016 reported dropout of more than10% and used the last observation carried forward (LOCF) approach for imputation. Chang 2017 and Yagci 2014 reported dropout of more than 10% and conducted an available case analysis. Fagerlund 2015 had a high noncompletion rate for some outcomes and did not clearly report how many participants were analysed for each outcome.

We assessed fifteen studies as having a high risk of bias for this criterion (Antal 2010; Boyer 2014; Deering 2017; Hagenacker 2014; Harvey 2017; Irlbacher 2006; Kim 2013; Lee 2012; Nurmikko 2016; Palm 2016; Rintala 2010; Souto 2014; Tan 2000; Thibaut 2017; Umezaki 2016). In the Antal 2010 study, of 23 participants recruited only 12 completed the full cross over. Boyer 2014 reported dropout of more than 20% and, while an intention-to-treat approach was reported the details of this and any imputation of missing data were not reported. Deering 2017 excluded eight out of 15 participants randomised to the sham condition on the basis that "an unexpected signal source was discovered in EEG traces". Harvey 2017 reported a 25% dropout rate in the active stimulation arm only and those participants appear to have been excluded from the analysis. In the study by Irlbacher 2006, only 13 of the initial 27 participants completed all of the treatment conditions. Kim 2013 reported a 15% dropout rate and excluded those participants from the analysis. Nurmikko 2016 reported a 33% dropout rate with a per-protocol analysis. Palm 2016 reported 13% dropout and excluded those participants from the analysis. Souto 2014 reported 20% dropout and used the LOCF method to impute missing data. In the studies of Hagenacker 2014; Lee 2012 and Rintala 2010, attrition exceeded 30% of the randomised cohort. In the study by Tan 2000, 17 participants did not complete the study (61% of the cohort) and this was not clearly accounted for in the analysis. Thibaut 2017 reported a 57% dropout rate. Umezaki 2016 reported dropout of more than 20% and conducted a per-protocol analysis.

Selective reporting

We assessed studies as having a high risk of bias for this criterion where the study report did not produce adequate data to assess the effect size for all groups/conditions at all follow-up time points, and these data were not made available upon request. We assessed 18 studies as having a high risk of bias for this criterion (Attal 2016; Capel 2003; Cork 2004; Curatolo 2017; Dall'Agnol 2014; Deering 2017; Donnell 2015; Fregni 2005; Fregni 2011; Katsnelson 2004; Kim 2013; Lichtbroun 2001; Mendonca 2011; Onesti 2013; Portilla 2013; Tzabazis 2013; Umezaki 2016; Valle 2009). We judged three studies as being at unclear risk of bias (Fregni 2006a; Fregni 2006b; Medeiros 2016). In the reports of Fregni 2006a and Fregni 2006b data were not presented in a format that could be easily interpreted. On request data were available from these two studies for the primary outcome at baseline and short-term follow-up but not for other follow-up points. Medeiros 2016 reported pain VAS scores but not the results of pain diaries that were described in the methods. We assessed the remaining 73 studies as having a low risk of bias for this criterion. For this update, we first made requests for data (by email where possible). If any data are made available in time for future updates then we will revise judgements on this criterion accordingly.

Other potential sources of bias

Overall, we judged 13 studies at unclear risk of bias and one study at high risk of bias on this criterion. Five studies (Deering 2017; Fregni 2011; Jales Junior 2015; Katsnelson 2004; Tzabazis 2013) were judged at unclear risk of bias as they did not adequately report baseline values for the groups to allow assessment of baseline comparability. One of those studies (Deering 2017) was rated as unclear on the criteria as no formal baseline comparisons were presented and around half of those randomised to the sham group were excluded from the baseline score. We judged four studies (Ahn 2017; Defrin 2007; Riberto 2011; Tan 2011) at unclear risk of bias as baseline differences were apparent for pain-related measures. We rated Harvey 2017 at high risk of bias on the basis of a greater than 3-point difference between the active and sham groups in baseline pain levels on a 0 to 10 scale.

One study of CES also applied electrical stimulation to the painful body area as part of the treatment, which may have affected the final outcomes (Tan 2000). Two studies of CES used an "active placebo condition" that delivered a level of cortical stimulation that was greater than that used in the active arm of other CES studies (Gabis 2003; Gabis 2009). It is possible that delivering cortical stimulation in the sham group might mask differences between the sham and active condition. Also such a large difference in current intensity compared with other studies of CES might be a source of heterogeneity. We judged these three studies as 'unclear' on this criterion. We rated one study (Lefaucheur 2001b) at unclear risk of bias as the outcome of a planned statistical analysis was not reported. We judged 80 studies at low risk of bias for this criterion.

Primary outcome: pain intensity

Transcranial direct current stimulation (tDCS): short-term (0 to < 1 week postintervention)

Adequate data were available from 27 studies (Ahn 2017; Antal 2010; Ayache 2016; Bae 2014; Boggio 2009; Brietzke 2016; Chang 2017; Fagerlund 2015; Fenton 2009; Fregni 2006a; Fregni 2006b; Hazime 2017; Jales Junior 2015; Jensen 2013; Khedr 2017; Lagueux 2017; Luedtke 2015; Mendonca 2016; Mori 2010; Ngernyam 2015; Oliveira 2015; Riberto 2011; Sakrajai 2014; Soler 2010; Villamar 2013; Volz 2016; Wrigley 2014) for this analysis (n = 747). We were unable to include data from Donnell 2015; Mendonca 2011; and Valle 2009 (combined n = 95) as the necessary data were not reported in the study report or available upon request to the study authors. We analysed data using the generic inverse variance method. We imputed the correlation coefficient (0.635) used to calculate the SE (SMD) for cross-over studies from data extracted from Boggio 2009 (see Unit of analysis issues). One study compared two distinct active stimulation conditions to one sham condition (Fregni 2006b). We considered that combining the treatment conditions would be inappropriate, as each involved stimulation of different locations and combination would hinder subgroup analysis. Instead we included both comparisons separately with the number of participants in the sham control group divided by the number of comparisons. We excluded data from Harvey 2017 as there was a baseline imbalance greater than 3 out of 10 in pain scores. We only included first-stage data from the study of Antal 2010 (n = 12) due to the unsustainable level of attrition following this stage.

The overall meta-analysis demonstrated an effect of active stimulation (SMD -0.43, 95% CI -0.63 to -0.22, P < 0.001) (Analysis 3.1), but heterogeneity was high (I² = 60%, P < 0.001). We back-transformed the SMD to a mean difference using the mean standard deviation of the post-treatment sham group scores of the studies included in this analysis (1.91). We then used this to estimate the real percentage change on a 0 to 10 pain intensity scale of active stimulation compared with the mean post-stimulation score from the sham groups of the included studies (4.77). This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome, which meets our threshold for a clinically important difference, though the lower confidence interval is substantially below that threshold. Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency due to heterogeneity and once for evidence of possible publication bias (see Summary of findings 3).

Subgrouping studies by multiple or single dose decreased heterogeneity in the single-dose subgroup (I² = 0%, P = 0.70) but did not reduce heterogeneity in the multiple-dose subgroup (I² = 64%, P < 0.001). Inclusion of studies at high risk of bias (Analysis 3.4; Antal 2010; Hagenacker 2014; Kim 2013; Souto 2014; Thibaut 2017) slightly increased the effect size (SMD -0.48, 95% CI -0.67 to -0.29, P < 0.001, I² = 60%, P < 0.001). Analysis restricted to comparisons of active motor cortex stimulation (single- and multiple-dose studies) (n = 655, Analysis 3.5) did not reduce heterogeneity substantially (I² = 58%, P < 0.001) and demonstrated an effect (SMD -0.47, 95% CI -0.67 to -0.28, P < 0.001).

There were insufficient data to support the planned subgroup analysis by the type of painful condition as planned. However, a modified subgroup analysis by neuropathic or non-neuropathic pain conditions (Analysis 3.8) demonstrated no subgroup difference (P = 0.41) though heterogeneity was reduced in the neuropathic pain group (I² = 40%, P = 0.10).

Responder data were only available from a small number of studies, all that were considered at high risk of bias. As such we did not conduct a formal meta-analysis but the data can be seen in Analysis 3.9; Analysis 3.10; Analysis 3.12 and Analysis 3.13.

To assess whether the imputation of standard errors for cross-over studies was robust we repeated the analyses with the imputed correlation coefficient reduced and increased by a value of 0.1 (Analysis 3.2; Analysis 3.3; Analysis 3.6; Analysis 3.7). This had no meaningful impact upon the results.

Small study effects

We investigated small study effects using Egger's test. Funnel plot asymmetry was apparent and Egger's test indicated small study effects for the overall comparisons (Figure 4, P = 0.019) and the subgroups of motor cortex stimulation studies (Figure 5, P = 0.002).

Secondary outcome: disability

Secondary outcome: quality of life

Secondary outcome: adverse events

Repetitive transcranial magnetic stimulation (rTMS) for chronic pain

Meta-analysis of all rTMS studies in chronic pain demonstrated substantial heterogeneity. Predetermined subgroup analysis suggests a short-term effect of single-dose, high-frequency rTMS applied to the motor cortex on chronic pain. This effect is small and does not conclusively exceed the threshold of minimal clinical importance. The evidence from multiple-dose studies of rTMS demonstrates conflicting results with substantial heterogeneity both overall and when the analysis is confined to high-frequency motor cortex studies. Low-frequency rTMS does not appear to be effective. rTMS applied to the prefrontal cortex does not appear to be effective. That the majority of studies in this analysis are at unclear risk of bias, particularly for participant blinding, suggests that the observed effect sizes might be exaggerated. While there is substantial unexplained heterogeneity the available evidence does not strongly suggest an effect of rTMS in the medium term. The limited evidence at long-term follow-up consistently suggests no effect of rTMS. The evidence for all comparisons or rTMS is considered to be of low to very low quality.

Cranial electrotherapy stimulation (CES) for chronic pain

The evidence from trials where it is possible to extract data is not clearly suggestive of a beneficial effect of CES on chronic pain. While there are substantial differences within the trials in terms of the populations studied and the stimulation parameters used, there is no measurable heterogeneity and no trial shows a clear benefit of active CES over sham stimulation. The evidence for all comparisons or CES is considered to be of low to very low quality.

Transcranial direct current stimulation (tDCS) for chronic pain

Meta-analysis of all tDCS studies in chronic pain demonstrated heterogeneity but did demonstrate an effect versus sham interventions. Predetermined subgroup analyses did not reduce heterogeneity. This effect may be exaggerated by study biases and small study effects. The evidence available at the medium term also demonstrates an effect but with substantial heterogeneity. Evidence from long follow-up does not suggest an effect of tDCS. We consider the evidence for all comparisons for tDCS to be of low to very low quality.

Reduced impedance non-invasive cortical electrostimulation (RINCE) stimulation for chronic pain

We analysed one small trial suggesting a positive effect of RINCE over sham for chronic pain. This trial is at unclear risk of bias due to possible attrition bias. As such, further high-quality research is needed to confirm this exploratory finding.

Transcranial random noise stimulation (tRNS) for chronic pain

We identified two small studies of tRNS, both at high risk of bias. We are unable to draw any conclusions about the effectiveness or lack of effectiveness of tRNS for chronic pain.

Secondary outcome measures

The available evidence does not suggest an effect of rTMS or tDCS on disability levels at any follow-up point. There is insufficient evidence from which to draw conclusions regarding CES for disability.

Limited, low-quality to very low-quality evidence suggests that rTMS and tDCS may have positive effects on quality of life. Given the limited amount of data available to inform these analyses, the risks of bias in the evidence base and the small effects observed in pain for both rTMS and tDCS we would recommend that this finding should be interpreted with caution. Limited evidence suggest that RINCE has no effect on quality of life.

rTMS, CES, tDCS, RINCE, tRNS and sham stimulation are associated with transient adverse effects such as headache, scalp irritation and dizziness, but reporting of adverse effects was inconsistent and did not allow for a detailed analysis. There were two incidences of seizure following active rTMS, which occurred in separate studies. For all forms of stimulation, adverse events reporting is inconsistent across studies.

CENTRAL (years 2009 to 2013 searched)

#1           MeSH descriptor: [Pain] explode all trees

#2           (chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint" or "temperomandib* joint" or "tempromandib* joint" or central or (post next stroke) or complex or regional or "spinal cord") near/4 pain*:ti,ab,kw  (Word variations have been searched)

#3           (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* near/2 neuralg*) or (herp* near/2 neuralg*) or (diabet* near/2 neuropath*) or (reflex near/4 dystroph*) or (sudeck* near/2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back near/4 surg*) or (failed back near/4 syndrome*)):ti,ab,kw  (Word variations have been searched)

#4           #1 or #2 or #3

#5           MeSH descriptor: [Transcranial Magnetic Stimulation] this term only

#6           MeSH descriptor: [Electronarcosis] explode all trees

#7           (brain* or cortex or cortical or transcranial* or cranial or magneti*) near/4 stimulat*:ti,ab,kw  (Word variations have been searched)

#8           (transcrani* or crani* or brain*) near/4 (electrostim* or electro-stim* or electrotherap* or electro-therap*):ti,ab,kw  (Word variations have been searched)

#9           (non-invasive or non*invasive) near/4 stimulat*:ti,ab,kw  (Word variations have been searched)

#10         "theta burst stimulat*" or iTBS or cTBS:ti,ab,kw  (Word variations have been searched)

#11         "transcranial magnetic stimulation" or rTMS or "transcranial direct current stimulat*" or tDCS or "cranial electrostimulation" or "cranial electrotherap*":ti,ab,kw  (Word variations have been searched)

#12         (electrosleep* or electronarco*):ti,ab,kw  (Word variations have been searched)

#13         #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12

#14         #4 and #13 from 2009 to 2013

MEDLINE and MEDLINE IN PROCESS (OVID)  

1     exp Pain/ (283010)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).tw. (74023)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).tw. (28679)

4     or/1-3 (325946)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (6328)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).tw. (25872)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).tw. (147)

8     ((non-invasive or non*invasive) adj4 stimulat*).tw. (822)

9     (theta burst stimulat* or iTBS or cTBS).tw. (575)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).tw. (7423)

11     (electrosleep or electronarco*).tw. (357)

12     or/5-11 (28316)

13     randomized controlled trial.pt. (337806)

14     controlled clinical trial.pt. (84996)

15     randomized.ab. (241501)

16     placebo.ab. (134421)

17     drug therapy.fs. (1571905)

18     randomly.ab. (173459)

19     trial.ab. (248492)

20     groups.ab. (1134392)

21     13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 (2928552)

22     exp animals/ not humans.sh. (3751730)

23     21 not 22 (2487755)

24     4 and 12 and 23 (295)

25     (200911* or 200912* or 2010* or 2011* or 2012* or 2013*).ed. (2428299)

26     24 and 25 (112)

Embase (OVID)

1     exp Pain/ (729490)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).tw. (112128)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).tw. (41462)

4     or/1-3 (759765)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (11875)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).tw. (35587)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).tw. (194)

8     ((non-invasive or non*invasive) adj4 stimulat*).tw. (1314)

9     (theta burst stimulat* or iTBS or cTBS).tw. (770)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).tw. (10413)

11     (electrosleep or electronarco*).tw. (375)

12     or/5-11 (39959)

13     4 and 12 (3078)

14     random$.tw. (793677)

15     factorial$.tw. (20700)

16     crossover$.tw. (46383)

17     cross over$.tw. (21096)

18     cross-over$.tw. (21096)

19     placebo$.tw. (189884)

20     (doubl$ adj blind$).tw. (140353)

21     (singl$ adj blind$).tw. (13272)

22     assign$.tw. (220119)

23     allocat$.tw. (74677)

24     volunteer$.tw. (170305)

25     Crossover Procedure/ (36109)

26     double-blind procedure.tw. (224)

27     Randomized Controlled Trial/ (338884)

28     Single Blind Procedure/ (16955)

29     or/14-28 (1300700)

30     (animal/ or nonhuman/) not human/ (4566449)

31     29 not 30 (1146950)

32     13 and 31 (574)

33     (200911* or 200912* or 2010* or 2011* or 2012* or 2013*).dd. (4384183)

34     32 and 33 (303)

PsycINFO (OVID)

1     exp Pain/ (33859)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).tw. (17914)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).tw. (3654)

4     or/1-3 (39372)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (3412)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).tw. (9508)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).tw. (55)

8     ((non-invasive or non*invasive) adj4 stimulat*).tw. (401)

9     (theta burst stimulat* or iTBS or cTBS).tw. (441)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).tw. (4745)

11     (electrosleep or electronarco*).tw. (6)

12     or/5-11 (9914)

13     4 and 12 (481)

14     clinical trials/ (6486)

15     (randomis* or randomiz*).tw. (39676)

16     (random$ adj3 (allocat$ or assign$)).tw. (22629)

17     ((clinic$ or control$) adj trial$).tw. (33763)

18     ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. (15332)

19     (crossover$ or "cross over$").tw. (5478)

20     random sampling/ (445)

21     Experiment Controls/ (435)

22     Placebo/ (2892)

23     placebo$.tw. (23869)

24     exp program evaluation/ (12521)

25     treatment effectiveness evaluation/ (11860)

26     ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw. (45199)

27     or/14-26 (142131)

28     13 and 27 (95)

29     limit 28 to yr="2009 -Current" (60)

CINAHL (EBSCO)

S26         S25         Limiters - Published Date from: 20091101-20130231

S25         S15 AND S24      

S24         S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23               

S23         (allocat* random*)        

S22         (MH "Quantitative Studies")      

S21         (MH "Placebos")             

S20         placebo*            

S19         (random* allocat*)        

S18         (MH "Random Assignment")     

S17         (Randomi?ed control* trial*)     

S16         (singl* blind* ) or (doubl* blind* ) or (tripl* blind* ) or (trebl* blind* ) or (trebl* mask* ) or (tripl* mask* ) or (doubl* mask* ) or (singl* mask* )         

S15         S4 AND S14        

S14         S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13            

S13         TI ( (electrosleep OR electronarco*) ) OR AB ( (electrosleep OR electronarco*) )               

S12         TI ( ("transcranial magnetic stimulation" OR rTMS OR "transcranial direct current stimulation" OR tDCS OR "cranial electrostimulation" OR "cranial electrotherapy") ) OR AB ( ("transcranial magnetic stimulation" OR rTMS OR "transcranial direct current stimulation" OR tDCS OR "cranial electrostimulation" OR "cranial electrotherapy") )    

S11         TI ( ("theta burst stimulat*" OR iTBS OR cTBS) ) OR AB ( ("theta burst stimulat*" OR iTBS OR cTBS) )          

S10         TI ( (("non-invasive brain" OR "non*invasive brain") AND stimulat*) ) OR AB ( (("non-invasive brain" OR "non*invasive brain") AND stimulat*) )                

S9           TI ( ((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)) ) OR AB ( ((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)) )                

S8           TI ( ((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)) ) OR AB ( ((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)) )                

S7           TI ( ((brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti*) AND stimulat*) ) OR AB ( ((brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti*) AND stimulat*) )     

S6           (MH "Electric Stimulation")         

S5           (MH "Electronarcosis")

S4           S1 OR S2 OR S3

S3           TI ( (sciatica OR back-ache OR back*ache OR lumbago OR fibromyalg* OR "trigemin* neuralg*" OR "herp* neuralg*" OR "diabet* neuropath*" OR "reflex dystroph*" OR "sudeck* atroph*" OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR "failed back surg*" OR "failed back syndrome*") ) OR AB ( (sciatica OR back-ache OR back*ache OR lumbago OR fibromyalg* OR "trigemin* neuralg*" OR "herp* neuralg*" OR "diabet* neuropath*" OR "reflex dystroph*" OR "sudeck* atroph*" OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR "failed back surg*" OR "failed back syndrome*") )  

S2           TI ( ((chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck OR myofasc* OR "temporomandib* joint*" OR "temperomandib* joint*" OR "tempromandib* joint*" OR central OR post*stroke OR complex OR regional OR spinal cord) AND pain*). ) OR AB ( ((chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck OR myofasc* OR "temporomandib* joint*" OR "temperomandib* joint*" OR "tempromandib* joint*" OR central OR post*stroke OR complex OR regional OR spinal cord) AND pain*))      

S1           (MH "Pain+")

LILACS  (7 February 2013)

1.       (chronic$ or back or musculoskel$ or intractabl$ or neuropath$ or phantom limb or fantom limb or neck or myofasc$ or temporomandib$ or temperomandib$ or tempromandib$ or central or (post stroke) or complex or regional or spinal cord sciatica or back-ache or back ache or lumbago or fibromyalg$ or trigemin$ neuralg$ or herp$  neuralg$ or diabet$ neuropath$ or reflex dystroph$ or sudeck$  atrophy$ or causalg$ or whip-lash or whip$lash or polymyalg$ or failed back)  69863

2.       (brain$ or cortex or cortical or transcrani$ or cranial or magneti$ stimulat$ or electrostim$ or electro-stim$ or electrotherapy$ or electro-therap$ or non-invasive or non invasive or stimul$ or theta burst stimulat$ or iTBS or cTBS or transcranial magnetic stimulat$ or rTMS or transcranial direct current stimulat$ or tDCS or cranial electrostimulation or cranial electrotherapy$ or electrosleep$ or electronarco$) 24787

3.       1&2  5559

4.       (randomized controlled trial or controlled clinical trial or placebo or sham or randomly or trial or groups) 31227

5.       3&4  545

6.       REMOVE ANY PRE 2009 (removed 292) 253

1. Cochrane PaPaS Group Specialised Register, saved search: 177 results

“electric* stimulat* therap*” or “brain* stimulat*” or “cort* stimulat*” or “transcranial* stimulat*” or “cranial stimulat*” or “magneti* stimulat*” or “direct current stimulat*” or “electric* stimulat*” or electrostim* or electrotherapy* or electro-therap* or “theta burst stimulat*” or “transcran* magnet* stimulat*” or iTBS or cTBS or rTMS or “transcran* direct current stimulat*” or tDCS or electrosleep or electronarco*

2. CENTRAL in The Cochrane Library

3a. MEDLINE

Database: Ovid MEDLINE(R) <1950 to November Week 3 2009>

1     exp Pain/ (252061)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).ab,ti. (61945)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).ab,ti. (25802)

4     1 or 3 or 2 (288507)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (4240)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).ab,ti. (21248)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).ab,ti. (116)

8     ((non-invasive or non*invasive) adj4 stimulat*).ab,ti. (526)

9     (theta burst stimulat* or iTBS or cTBS).ab,ti. (359)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).ab,ti. (5306)

11     (electrosleep or electronarco*).ab,ti. (357)

12     8 or 6 or 11 or 7 or 10 or 9 or 5 (23212)

13     4 and 12 (1069)

14     randomised controlled trial.pt. (291031)

15     controlled clinical trial.pt. (82962)

16     randomized.ab. (196258)

17     (placebo or sham).ab,ti. (164609)

18     drug therapy.fs. (1385685)

19     randomly.ab. (141449)

20     trial.ab. (203139)

21     groups.ab. (961704)

22     or/14-21 (2562312)

23     exp animals/ not humans.sh. (3518581)

24     22 not 23 (2157467)

25     24 and 13 (219)

3b. Database: Ovid MEDLINE(R) In-process & Other non-indexed citations

<25 November 2009>

1     exp Pain/ (6)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).ab,ti. (4772)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).ab,ti. (1251)

4     1 or 3 or 2 (5661)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (0)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).ab,ti. (1057)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).ab,ti. (5)

8     ((non-invasive or non*invasive) adj4 stimulat*).ab,ti. (42)

9     (theta burst stimulat* or iTBS or cTBS).ab,ti. (38)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).ab,ti. (375)

11     (electrosleep or electronarco*).ab,ti. (0)

12     8 or 6 or 11 or 7 or 10 or 9 or 5 (1113)

13     4 and 12 (39)

4. Database: Embase

<1980 to 2009 Week 47>

1     exp Pain/ (394924)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or "temporomandib* joint*" or "temperomandib* joint*" or "tempromandib* joint*" or central or post*stroke or complex or regional or spinal cord) adj4 pain*).ab,ti. (57196)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).ab,ti. (21356)

4     1 or 3 or 2 (410258)

5     Transcranial Magnetic Stimulation/ or Electronarcosis/ (5841)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).ab,ti. (18227)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).ab,ti. (74)

8     ((non-invasive or non*invasive) adj4 stimulat*).ab,ti. (498)

9     (theta burst stimulat* or iTBS or cTBS).ab,ti. (330)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).ab,ti. (5259)

11     (electrosleep or electronarco*).ab,ti. (20)

12     8 or 6 or 11 or 7 or 10 or 9 or 5 (19954)

13     4 and 12 (1331)

14     random*.ti,ab. (415216)

15     factorial*.ti,ab. (8708)

16     (crossover* or cross over* or cross-over*).ti,ab. (40788)

17     placebo*.ti,ab. (114266)

18     (doubl* adj blind*).ti,ab. (87525)

19     (singl* adj blind*).ti,ab. (7775)

20     assign*.ti,ab. (113729)

21     allocat*.ti,ab. (36179)

22     volunteer*.ti,ab. (102464)

23     CROSSOVER PROCEDURE.sh. (21985)

24     DOUBLE-BLIND PROCEDURE.sh. (74829)

25     RANDOMIZED CONTROLLED TRIAL.sh. (176320)

26     SINGLE BLIND PROCEDURE.sh. (8721)

27     or/14-26 (691134)

28     ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/ (3551150)

29     HUMAN/ (6702208)

30     28 and 29 (569432)

31     28 not 30 (2981718)

32     27 not 31 (601828)

33     32 and 13 (234)

5. Database: PsycINFO

<1806 to November Week 4 2009>

1     exp Pain/ (26560)

2     ((chronic* or back or musculoskel* or intractabl* or neuropath* or phantom limb or fantom limb or neck or myofasc* or temp?romandib* joint or central or post*stroke or complex or regional or spinal cord) adj4 pain*).ab,ti. (14094)

3     (sciatica or back-ache or back*ache or lumbago or fibromyalg* or (trigemin* adj2 neuralg*) or (herp* adj2 neuralg*) or (diabet* adj2 neuropath*) or (reflex adj4 dystroph*) or (sudeck* adj2 atroph*) or causalg* or whip-lash or whip*lash or polymyalg* or (failed back adj4 surg*) or (failed back adj4 syndrome*)).ab,ti. (2649)

4     1 or 3 or 2 (30822)

5     Transcranial Magnetic Stimulation/ or Electrosleep treatment/ (1830)

6     ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).ab,ti. (7832)

7     ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).ab,ti. (47)

8     ((non-invasive or non*invasive) adj4 stimulat*).ab,ti. (144)

9     (theta burst stimulat* or iTBS or cTBS).ab,ti. (259)

10     (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).ab,ti. (2652)

11     (electrosleep or electronarco*).ab,ti. (140)

12     8 or 6 or 11 or 7 or 10 or 9 or 5 (8307)

13     4 and 12 (277)

14     (random* or placebo* or sham or trial or groups).ti,ab. (391590)

15     13 and 14 (64)

6. CINAHL

<Search run 11 January 2010>

7. SCOPUS

We did not search this database as it includes all of MEDLINE, all of Embase and some of CINAHL, which have been searched separately.

8. Search strategy for LILACS

http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/

1. Pain$ or dolor$ or intractabl$ or neuropath$ or phantom or fantom or myofasc$ or temp$romandibular or sciatic$ or back-ache or backache or ache or lumbago or fibromyalg$ or neuralg$ or dystroph$ or atroph$ or causalgi$ or whip-lash or whiplash or polymyalg$ [Words] 

2. ((Estimulaci$ or stimulat$) and (cerebra$ or brain$ or cortex or cortical or crania$ or transcranial$ or magneti$)) or electrostim$ or electrotherapy$ or electro-therap$ or “theta burst stimul$” or iTBS or Ctbs or “transcrani$ magnet$ stimulat$” or rTMS or “transcrani$ direct current stimulat$” or tDCS or “cranial electrostimulat$” or “cranial electrotherapy$ or electrosleep or electronarco$ [Words] 

3. ((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]

4. 1 and 2 and 3 (68)