Non-invasive brain stimulation techniques for chronic pain

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

This is an updated version of the original Cochrane review published in 2010, Issue 9. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS) and reduced impedance non-invasive cortical electrostimulation (RINCE).

Objectives

To evaluate the efficacy of non-invasive brain stimulation techniques in chronic pain.

Search methods

We searched CENTRAL (2013, Issue 6), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS and clinical trials registers. The original search for the review was run in November 2009 and searched all databases from their inception. To identify studies for inclusion in this update we searched from 2009 to July 2013.

Selection criteria

Randomised and quasi-randomised studies of rTMS, CES, tDCS or RINCE if they employed a sham stimulation control group, recruited patients over the age of 18 with pain of three months duration or more and measured pain as a primary outcome.

Data collection and analysis

Two authors independently extracted and verified data. Where possible we entered data into meta-analyses. We excluded studies judged as being at high risk of bias from the analysis. We used the GRADE system to summarise the quality of evidence for core comparisons.

Main results

We included an additional 23 trials (involving 773 participants randomised) in this update, making a total of 56 trials in the review (involving 1710 participants randomised). This update included a total of 30 rTMS studies, 11 CES, 14 tDCS and one study of RINCE(the original review included 19 rTMS, eight CES and six tDCS studies). We judged only three studies as being at low risk of bias across all criteria.

Meta-analysis of studies of rTMS (involving 528 participants) demonstrated significant heterogeneity. Pre-specified subgroup analyses suggest that low-frequency stimulation is ineffective (low-quality evidence) and that rTMS applied to the dorsolateral prefrontal cortex is ineffective (very low-quality evidence). We found a short-term effect on pain of active high-frequency stimulation of the motor cortex in single-dose studies (low-quality evidence, standardised mean difference (SMD) 0.39 (95% confidence interval (CI) -0.27 to -0.51 P < 0.01)). This equates to a 12% (95% CI 8% to 15%) reduction in pain, which does not exceed the pre-established criteria for a minimal clinically important difference (≥ 15%). Evidence for multiple-dose studies was heterogenous but did not demonstrate a significant effect (very low-quality evidence).

For CES (six studies, 270 participants) no statistically significant difference was found between active stimulation and sham (low-quality evidence).

Analysis of tDCS studies (11 studies, 193 people) demonstrated significant heterogeneity and did not find a significant difference between active and sham stimulation (very low-quality evidence). Pre-specified subgroup analysis of tDCS applied to the motor cortex (n = 183) did not demonstrate a statistically significant effect and this lack of effect was consistent for subgroups of single or multiple-dose studies.

One small study (n = 91) at unclear risk of bias suggested a positive effect of RINCE over sham stimulation on pain (very low-quality evidence).

Non-invasive brain stimulation appears to be frequently associated with minor and transient side effects, though there were two reported incidences of seizure related to active rTMS in the included studies.

Authors' conclusions

Single doses of high-frequency rTMS of the motor cortex may have small short-term effects on chronic pain. It is likely that multiple sources of bias may exaggerate this observed effect. The effects do not meet the predetermined threshold of minimal clinical significance and multiple-dose studies do not consistently demonstrate effectiveness. The available evidence suggests that low-frequency rTMS, rTMS applied to the pre-frontal cortex, CES and tDCS are not effective in the treatment of chronic pain. While the broad conclusions for rTMS and CES have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation and the conclusion regarding the effectiveness of tDCS has changed. We recommend that previous readers should re-read this update. There is a need for larger, rigorously designed studies, particularly of longer courses of stimulation. It is likely that future evidence may substantially impact upon the presented results.

Résumé scientifique

Techniques de stimulation non invasive du cerveau pour la douleur chronique

Contexte

Ceci est une version mise à jour de la revue Cochrane originale publiée en 2010, numéro 9. Les techniques de stimulation cérébrale non invasive visent à induire une stimulation électrique du cerveau pour tenter de réduire la douleur chronique par modification directe de l'activité cérébrale. Elles comprennent la stimulation magnétique transcrânienne répétitive (SMTr), la stimulation par électrothérapie crânienne (SEC), la stimulation transcrânienne à courant continu (STCC) et l'électrostimulation corticale non invasive d'impédance réduite (ESCNIIR).

Objectifs

Évaluer l'efficacité des techniques de stimulation cérébrale non invasive dans la douleur chronique.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (2013, numéro 6), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS et les registres d'essais cliniques. La recherche originale pour cette revue a été effectuée en novembre 2009 et comprenait la recherche de toutes les bases de données depuis leur création. Afin d'identifier d'autres études à inclure dans cette mise à jour, nous avons effectué des recherches de 2009 à juillet 2013.

Critères de sélection

Études randomisées et quasi randomisées sur la SMTr, la SEC, la STCC ou l'ESCNIIR, si elles utilisaient un groupe témoin de stimulation simulée, avaient recruté des patients âgés de plus de 18 ans avec des douleurs depuis trois mois ou plus et mesuraient la douleur en critère de jugement principal.

Recueil et analyse des données

Deux auteurs ont indépendamment extrait et vérifié les données. Lorsque cela était possible, nous avons saisi les données dans des méta-analyses. Nous avons exclu de l'analyse les études considérées comme étant à risque élevé de biais. Nous avons utilisé le système GRADE pour résumer la qualité des preuves pour les principales comparaisons.

Résultats principaux

Nous avons inclus 23 essais (portant sur 773 participants randomisés) dans cette mise à jour, donnant un total de 56 essais dans la revue (impliquant 1 710 participants randomisés). Cette mise à jour incluait un total de 30 études sur la SMTr, 11 sur la SEC, 14 sur la STCC et une sur l'ESCNIIR (la revue d'origine incluait 19 études sur la SMTr, huit sur la SEC et six sur la STCC). Nous avons jugé que seules trois études étaient à faible risque de biais pour tous les critères de jugement.

La méta-analyse des études sur la SMTr (impliquant 528 participants) a mis en évidence une hétérogénéité significative. Les analyses en sous-groupes pré-spécifiés suggèrent que la stimulation à basse fréquence est inefficace (preuves de faible qualité), tout comme la SMTr appliquée sur le cortex pré-frontal dorsolatéral (preuves de très faible qualité). Nous avons trouvé un effet à court terme sur la douleur de la stimulation active à haute fréquence du cortex moteur dans les études à dose unique (preuves de faible qualité, différence moyenne standardisée (DMS) de 0,39 (intervalle de confiance (IC) à 95 % de -0,27 à -0,51, P < 0,01)). Cela équivaut à une réduction de la douleur de 12 % (IC à 95 % de 8 % à 15 %), qui ne dépasse pas les critères pré-établis pour une différence minimale cliniquement importante (≥ 15 %). Les preuves pour les études à doses multiples étaient hétérogènes, mais n'ont pas mis en évidence d'effet significatif (preuves de très faible qualité).

Pour la SEC (six études, 270 participants), aucune différence statistiquement significative n'était observée entre la stimulation active et simulée (preuves de faible qualité).

L'analyse des études sur la STCC (11 études, 193 patients) a démontré une hétérogénéité significative et n'a pas trouvé de différence significative entre la stimulation active et simulée (preuves de très faible qualité). L'analyse en sous-groupes pré-spécifiés sur la STCC appliquée sur le cortex moteur (n = 183) n'a pas démontré d'effet statistiquement significatif et ce manque d'effet était constant dans les sous-groupes d'études de doses uniques ou multiples.

Une petite étude (n = 91) à risque de biais incertain a suggéré un effet positif de l'ESCNIIR par rapport à la stimulation simulée sur la douleur (preuves de très faible qualité).

La stimulation cérébrale non invasive semble être fréquemment associée à des effets secondaires mineurs et transitoires, bien que deux occurrences de crises épileptiques liées à un traitement par la SMTr active aient été rapportées dans les études incluses.

Conclusions des auteurs

Des doses uniques de la SMTr à haute fréquence du cortex moteur peuvent avoir des effets à court terme de petite taille sur la douleur chronique. Il est probable que les multiples sources de biais aient pu exagérer cet effet observé. Les effets n'atteignaient pas le seuil prédéterminé de signification clinique minimale et les études de doses multiples ne démontraient pas systématiquement d'efficacité. Les preuves disponibles suggèrent que la SMTr à basse fréquence, la SMTr appliquée sur le cortex pré-frontal, la SEC et la STCC ne sont pas efficaces dans le traitement de la douleur chronique. Bien que les conclusions générales pour la SMTr et la SEC n'aient pas changé sensiblement, l'ajout de ces nouvelles preuves et l'application du système GRADE ont modifié notre interprétation en partie et les conclusions concernant l'efficacité de la STCC ont évolué. Nous recommandons donc aux lecteurs précédents de relire cette mise à jour. Il est nécessaire de réaliser des études à plus grande échelle et rigoureusement planifiées, en particulier sur des traitements par stimulation de plus longue durée. Il est probable que les données futures puissent sensiblement impacter les résultats présentés.

アブストラクト

慢性痛に対する非侵襲性脳刺激法

背景

本レビューは、2010年に発表されたコクラン・レビュー第9版の更新版である。非侵襲性脳刺激法の目的は、脳に電気刺激を与えて脳活動を直接変化させ、慢性痛を軽減することである。本法には、反復経頭蓋磁気刺激法(rTMS)、頭蓋電気刺激療法(CES)、経頭蓋直流電気刺激(tDCS)、低インピーダンス非侵襲性大脳皮質電気刺激(RINCE)などがある。

目的

慢性痛に対する非侵襲性脳刺激法の有効性を評価すること。

検索戦略

CENTRAL(2013年第6版)、MEDLINE、EMBASE、CINAHL、PsycINFO、LILACSおよび臨床試験登録データベースを検索した。本レビューの初回検索は2009年11月に実施し、いずれのデータベースも最初からすべて検索した。本更新版の対象とする研究を同定するための検索期間は、2009年から2013年7月までとした。

選択基準

rTMS、CES、tDCSまたはRINCEに関するランダム化試験および準ランダム化試験で、疑似刺激対照群を設定しており、慢性痛が3カ月以上持続している18歳超の患者を募集しており、疼痛を主要アウトカムとしていること。

データ収集と分析

2名の著者が独立してデータを抽出し、妥当性を検証した。可能な場合は、データをメタアナリシスに組み入れた。解析の結果、バイアスのリスクが高いと判断した研究は除外した。主要な比較に用いるエビデンスの質の要約にはGRADEシステムを用いた。

主な結果

本更新では、23件(ランダム化された参加者773例)のその後追加された試験を含め、総計56件(ランダム化された参加者1710例)の試験を本レビューの対象とした。本更新版では、rTMS研究30件、CES研究11件、tDCS 研究14件およびRINCE研究1件を対象とした(前版のレビュー対象はrTMS研究19件、CES研究8件およびtDCS研究6件)。3件の研究のみを、すべての基準についてバイアスのリスクが低いと判断した。

rTMS研究のメタアナリシス(参加者528例)では、著しい異質性が示された。既定のサブグループ解析では低周波刺激の効果は認められず(質の低いエビデンス)、前頭前野背外側部にrTMSを施行した場合の効果は認められなかった(きわめて質の低いエビデンス)。運動皮質への能動型高周波刺激単回施行試験では、疼痛に対する短期効果が認められた(質の低いエビデンス、標準化平均差(SMD)0.39、95%信頼区間(CI)-0.27〜-0.51、P < 0.01)。これは12%(95%CI 8%〜15%)の疼痛軽減に相当し、既定の臨床的に有意な最小変化量の基準範囲内(15%以上)であった。複数回施行試験のエビデンスには異質性が認められ、有意な効果は示されなかった(きわめて質の低いエビデンス)。

CES(6件、参加者270例)については、能動的刺激と疑似刺激の間に統計学的有意性は認められなかった(きわめて質の低いエビデンス)。

tDCS研究(11件、193例)の解析では、顕著な異質性が示され、能動的刺激と疑似刺激の間に有意差は認められなかった(きわめて質の低いエビデンス)。運動皮質に施行したtDCSに関する既定のサブグループ解析(n = 183)では統計学的有意性は認められず、単回施行試験および複数回施行試験のサブグループの両方で効果が認められなかった。

バイアスのリスクが不明な 1件の小規模研究(n = 91)では、RINCEが疑似刺激と比較して疼痛に有効であることが示唆された(きわめて質の低いエビデンス)。

非侵襲性脳刺激法では、軽度で一過性の副作用が高頻度で認められるようであるが、対象試験で報告された能動型rTMSと関連のある副作用は発作2例のみであった。

著者の結論

運動皮質に対する高周波rTMSの単回施行は、慢性痛に対し、わずかではあるが短期効果を示す可能性がある。複数のバイアスが原因で、観察された効果を過大評価している可能性がある。この効果は、既定の臨床的に有意な最小変化量の閾値を満たしておらず、複数回施行試験では一貫した有効性が認められなかった。入手可能なエビデンスから、低周波rTMS、前頭前野に施行したrTMS、CESおよびtDCSは慢性痛の治療に効果が認められないことが示唆される。rTMSおよびCESの広義の結論に大きな変更はないが、新たなエビデンスの追加およびGRADEシステムの適用によって一部の解釈を修正し、tDCSの有効性に関する結論を変更した。前版の読者は本更新版を再読することを推奨する。主に長期間の刺激に関する綿密にデザインされた、より大規模な試験が必要である。今後得られるエビデンスが現在の結果に大きな影響を与える可能性がある。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.6]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Stimulating the brain without surgery in the management of chronic pain

Various devices are available that can electrically stimulate the brain without the need for surgery or any invasive treatment in order to manage chronic pain. There are four main treatment types: repetitive transcranial magnetic stimulation (rTMS) in which the brain is stimulated by a coil applied to the scalp, cranial electrotherapy stimulation (CES) in which electrodes are clipped to the ears or applied to the scalp, transcranial direct current stimulation (tDCS) and reduced impedance non-invasive cortical electrostimulation (RINCE) in which electrodes are applied to the scalp. These have been used to try to reduce pain by aiming to alter the activity of the brain, but the efficacy of these treatments is uncertain.

This review update included 56 studies: 30 of rTMS, 11 of CES, 14 of tDCS and one of RINCE. We judged only three studies as having a low risk of bias. Low or very low-quality evidence suggests that low-frequency rTMS and rTMS applied to pre-frontal areas of the brain are not effective but that a single dose of high-frequency stimulation of the motor cortex area of the brain provides short-term pain relief. This effect appears to be small and may be exaggerated by a number of sources of bias. Studies that gave a course of multiple treatments of rTMS produced conflicting results with no overall effect seen when we pooled the results of these studies. Most studies of rTMS are small and there is substantial variation between studies in terms of the treatment methods used. Low-quality evidence does not suggest that CES or tDCS are effective treatments for chronic pain. A single small study of RINCE provided very low-quality evidence of a short-term effect on pain. For all forms of stimulation the evidence is not conclusive and uncertainty remains.

The reporting of side effects varied across the studies. Of the studies that clearly reported side effects, short-lived and minor side effects such as headache, nausea and skin irritation were usually reported both after real and sham stimulation. There were two reports of seizure following real rTMS.

While the broad conclusions for rTMS and CES have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation. Previous readers should re-read this update.

More studies of rigorous design and adequate size are required to evaluate accurately all forms of non-invasive brain stimulation for the treatment of chronic pain.

Résumé simplifié

Stimulation du cerveau sans chirurgie dans la prise en charge de la douleur chronique

Divers dispositifs sont disponibles qui permettent de stimuler électroniquement le cerveau sans la nécessité d'une intervention chirurgicale ou de tout traitement invasif pour gérer la douleur chronique. Il existe quatre types de traitement principaux : la stimulation magnétique transcrânienne répétitive (SMTr) dans laquelle le cerveau est stimulé par une bobine appliquée sur le cuir chevelu, la stimulation par électrothérapie crânienne (SEC) dans laquelle des électrodes sont attachées aux oreilles ou appliqués sur le cuir chevelu, la stimulation transcrânienne à courant continu (STCC) et l'électrostimulation corticale non invasive d'impédance réduite (ESCNIIR) dans laquelle des électrodes sont appliquées sur le cuir chevelu. Ces traitements ont été utilisés pour tenter de réduire la douleur par la modification de l'activité du cerveau, mais leur efficacité est incertaine.

Cette revue mise à jour incluait 56 études : 30 sur la SMTr, 11 sur la SEC, 14 sur la STCC et une sur l'ESCNIIR. Nous avons jugé trois études seulement comme présentant un faible risque de biais. Des preuves de qualité faible ou très faible suggèrent que la SMTr à basse fréquence et la SMTr appliquée sur les zones pré-frontales du cerveau ne sont pas efficaces, mais qu'une dose unique de stimulation à haute fréquence de la région du cortex moteur du cerveau apporte un soulagement de la douleur à court terme. Cet effet semble être de petite taille et a pu être exagéré par un certain nombre de sources de biais. Les études dans le cadre desquelles plusieurs traitements par la SMTr étaient administrés ont produit des résultats contradictoires, et aucun effet global n'a été observé lorsque nous avons regroupé les résultats de ces études. La plupart des études sur la SMTr sont de petite taille et la variation entre les études est significative en termes de méthodes de traitement utilisées. Des preuves de faible qualité ne suggèrent pas que la SEC ou la STCC soient des traitements efficaces contre la douleur chronique. Une seule étude de petite taille sur l'ESCNIIR a fourni des preuves de très faible qualité d'un effet à court terme sur la douleur. Pour toutes les formes de stimulation, les preuves ne sont pas concluantes et l'incertitude subsiste.

La notification des effets secondaires variait selon les études. Dans les études ayant rapporté clairement les effets secondaires, des effets secondaires mineurs de courte durée tels que des maux de tête, des nausées et une irritation cutanée étaient généralement rapportés après la stimulation réelle et simulée. Deux occurrences de crises d'épilepsie ont été rapportées après la SMTr réelle.

Bien que les conclusions générales pour la SMTr et la SEC n'aient pas changé sensiblement, l'ajout de ces nouvelles preuves et l'application du système GRADE ont modifié notre interprétation en partie. Nous conseillons donc aux lecteurs précédents de relire cette mise à jour.

D'autres études de conception rigoureuse et de taille appropriée sont nécessaires pour évaluer précisément toutes les formes de stimulation non invasive du cerveau pour le traitement de la douleur chronique.

Notes de traduction

Traduit par: French Cochrane Centre 22nd July, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Laički sažetak

Stimulacija mozga bez kirurškog zahvata za liječenje kronične boli

Danas postoje različiti uređaji koji omogućuju električnu stimulaciju mozga bez potrebe za kirurškim zahvatom ili bilo kakvom drugom invazivnom terapijom, a koji se pokušavaju primijeniti za liječenje kronične boli. Postoje četiri glavne vrste tih terapija: ponavljanja transkranijalna magnetska stimulacija (engl. repetitive transcranial magnetic stimulation, rTMS) kod koje se mozak stimulira pomoću zavojnice primijenjene na kožu glave; kranijalna elektroterapijska stimulacija (engl. cranial electrotherapy stimulation, CES) kod koje se elektrode zakače na uši ili stavljaju na kožu glave; transkranijalna direktna stimulacija strujom (engl. transcranial direct current stimulation, tDCS) i neinvazinva kortikalna elektrostimulacija smanjene impedancije (engl. reduced impedance non-invasive cortical electrostimulation, RINCE) kod koje se elektrode primjenjuju na kožu glave. Ti se uređaji pokušavaju koristiti za ublažavanje boli, pri čemu im je cilj mijenjanje aktivnosti mozga, ali djelotvornost tih terapija nije sigurna.

Ovo je obnovljena verzija Cochrane sustavnog pregleda koji sad uključuje 56 studija: 30 o rTMS, 11 o CES, 14o tDCS i jednu o metodi RINCE. Procijenjeno je da su samo 3 studije imale nizak rizik od pristranosti (odnosno, samo su 3 studije bile visoko-kvalitetne). Pronađeni su dokazi niske ili vrlo niske kvalitete koji pokazuju da nisko-frekventna rTMS i rTMS, ako se primijene na prefrontalna područja mozga, nisu djelotvorna za kroničnu bol, ali jedna doza visoko-frekventne stimulacije motornog područja moždane kore omogućuje kratkoročno ublažavanje boli. Čini se da je taj učinak malen i možda je pretjeran zbog niza metodoloških manjkavosti studija. Studije koje su davale niz terapija korištenjem rTMS uređaja dale su suprotstavljene rezultate i kad se ti rezultati zajedno analiziraju ne pokazuju da je takva terapija djelotvorna. Većina studija u kojima je korišten rTMS bile su malene (uključile malen broj ispitanika) i te su se studije međusobno znatno razlikovale po metodama terapije koje su korištene. Dokazi niske kvalitete pokazuju da CES ili TDCS nisu djelotvorne terapije za kroničnu bol. Jedna mala studija o RINCE metodi dala je dokaze vrlo niske kvalitete koji pokazuju da ta terapija može kratkoročno djelovati na bol. Za sve oblike stimulacije, dokazi o njihovu djelovanju na kroničnu bol nisu dosljedni te je i dalje otvoreno pitanje o njihovoj djelotvornosti.

Opisivanje nuspojava razlikovalo se u pojedinačnim studijama. U studijama koje su nuspojave jasno opisale, te su nuspojave bile kratkoročne i sporedne, kao što su glavobolja, mučnina i nadražaj kože, ali takve su nuspojave ispitanici opisali i prilikom stvarne i lažne stimulacije. Nakon stvarne primjene rTMS terapije opisana su dva slučaja razvoja epileptičkih napadaja.

Iako se općeniti zaključak o rTMS i CES terapijama nije značajno promijenio, uključivanje novih dokaza u ovu obnovljenu verziju Cochrane sustavnog pregleda i primjena novog načina procjene kvalitete dokaza po GRADE sustavu dovela je do promjene u tumačenju dijela rezultata. Stoga se u ovom obnovljenom sustavnom pregledu mogu naći nove informacije.

Potrebno je više studija, visoko-kvalitetne metodologije i s primjerenim brojem ispitanika kako bi se propisno procijenili svi oblici neinvazivnih stimulacija mozga za liječenje kronične boli.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
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平易な要約

手術を実施せずに慢性的な痛みを管理するための脳への刺激

手術や侵襲的な治療を行わずに脳に電気的刺激を与えて慢性的な痛みを治療するさまざまな機器が存在する。治療法は主に4種類あり、頭皮にコイルを装着して脳を刺激する反復経頭蓋磁気刺激法(rTMS)、電極で耳を挟むか電極を頭皮に装着する頭蓋電気刺激療法(CES)、経頭蓋直流電気刺激(tDCS)および電極を頭皮に装着する低インピーダンス非侵襲性大脳皮質電気刺激(RINCE)である。これらの治療法は、脳の活動を変化させて痛みを軽減するために使用されてきたが、その有効性については明らかになっていない。

このレビュー更新版では、56件の研究を対象とした。 内訳は、rTMSが30件、CESが11件、tDCSが14件、RINCEが1件であった。バイアスのリスクが低いと判断したのは3件の研究のみであった。質の低いエビデンスまたはきわめて質の低いエビデンスにより、低周波rTMSおよび脳の前頭前野に実施するrTMSには効果が認められないが、脳の運動皮質へ高周波刺激を1回与えると、短期間痛みを軽減することが示唆されている。この効果は小さいと考えられるが、複数のバイアスによって過大評価されている可能性がある。rTMSの複数回施行試験結果をプール(統合)した場合、総合的な効果は認められず、結果には矛盾が認められた。rTMSに関する研究の多くは小規模で、採用された治療法は研究によって大きく異なっていた。質の低いエビデンスでは、慢性的な痛みに対するCESまたはtDCSの有効性は示唆されなかった。RINCEの小規模単一試験では、痛みに対する短期効果に関するきわめて質の低いエビデンスが得られた。いずれの刺激法についても決定的なエビデンスは得られておらず、不確実性が残る。

副作用の報告内容は研究ごとに異なっていた。副作用を明確に報告している研究では、概して実際の刺激後および疑似刺激後共に、頭痛、吐き気および皮膚刺激などの短期間の軽微な副作用が確認された。実際にrTMSを実施した後の発作が2件報告された。

rTMSおよびCESの広義の結論に大きな変化はないが、新たなエビデンスの追加およびGRADEシステムの適用によって一部の解釈が修正された。前版を読んだ人はこの更新版を再読すべきである。

慢性的な痛みに対する種々の非侵襲性脳刺激法の効果を正確に評価するためには、綿密にデザインされた適切な規模の試験がさらに必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.6]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. For full details of the GRADE judgements for each comparison see Appendix 6.

Repetitive transcranial magnetic stimulation (rTMS) compared with sham for chronic pain

Intervention: active rTMS

Comparison: sham rTMS

Outcomes: pain (VAS or NRS)
Comparison No 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

Background

This is an updated version of the original Cochrane review published in 2010, Issue 9, on non-invasive brain stimulation techniques for chronic pain (O'Connell 2010).

Description of the condition

Chronic pain is a common problem. When defined as pain of greater than three months duration, prevalence studies indicate that up to half the adult population suffer from chronic pain, and 10% to 20% experience clinically significant chronic pain (Smith 2008). In Europe, 19% of adults experience chronic pain of moderate to severe intensity with serious negative implications for their social and working lives and many of these receive inadequate pain management (Breivik 2006). Chronic pain is a heterogenous phenomenon that results from a wide variety of pathologies including chronic somatic tissue injury such as arthritis, peripheral nerve injury and central nervous system injury, as well as a range of chronic pain syndromes such as fibromyalgia. It is likely that different mechanisms of pain production underpin these different causes of chronic pain (Ossipov 2006).

Description of the intervention

Brain stimulation techniques have been used to address a variety of pathological pain conditions including fibromyalgia, chronic post-stroke pain and complex regional pain syndrome (Cruccu 2007; Fregni 2007; Gilula 2007), and clinical studies of both invasive and non-invasive techniques have produced preliminary data showing reductions in pain (Cruccu 2007; Fregni 2007; Lefaucheur 2008b). Various types of brain stimulation, both invasive and non-invasive, are currently in clinical use for the treatment of chronic pain (Cruccu 2007). Non-invasive stimulation techniques require no surgical procedure and are therefore easier and safer to apply than invasive procedures.

Repetitive transcranial magnetic stimulation (rTMS) involves stimulation of the cerebral cortex (the outer layer of the brain) by a stimulating coil applied to the scalp. Electric currents are induced in the neurons (brain cells) directly using rapidly changing magnetic fields (Fregni 2007). Trains of these stimuli are applied to the target region of the cortex to induce alterations in brain activity both locally and in remote brain regions (Leo 2007). A recent meta-analysis suggested that rTMS may be more effective in the treatment of neuropathic pain conditions (pain arising as a result of damage to the nervous system, as in diabetes, traumatic nerve injury, stroke, multiple sclerosis, epilepsy, spinal cord injury and cancer) with a central compared to a peripheral nervous system origin (Leung 2009).

Transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES) involve the safe and painless application of low-intensity (commonly ≤ 2 mA) electrical current to the cerebral cortex of the brain (Fregni 2007; Gilula 2007; Hargrove 2012). tDCS has been developed as a clinical tool for the modulation of brain activity in recent years and uses relatively large electrodes that are applied to the scalp over the targeted brain area to deliver a weak constant current (Lefaucheur 2008a). Recent clinical studies have concluded that tDCS was more effective than sham stimulation at reducing pain in both fibromyalgia and spinal cord injury related pain (Fregni 2006a; Fregni 2006b). CES was initially developed in the USSR as a treatment for anxiety and depression in the 1950s and its use later spread to Europe and the USA where it began to be considered and used as a treatment for pain (Kirsch 2000). The electrical current in CES is commonly pulsed and is applied via clip electrodes that are attached to the patient's earlobes. A Cochrane Review of non-invasive treatments for headaches identified limited evidence that CES is superior to placebo in reducing pain intensity after six to 10 weeks of treatment (Bronfort 2004). Reduced impedance non-invasive cortical electrostimulation (RINCE) similarly applies an electrical current via scalp electrodes but utilises specific stimulation frequencies which are hypothesised to reduce electrical impedance from the tissues of the skin and skull, allowing deeper cortical penetration and modulation of lower-frequency cortical activity (Hargrove 2012).

How the intervention might work

Brain stimulation techniques primarily seek to modulate activity in brain regions by directly altering the level of brain activity. The aim of brain stimulation in the management of pain is to reduce pain by altering activity in the areas of the brain that are involved in pain processing.

Both tDCS and rTMS have been shown to modulate brain activity specific to the site of application and the stimulation parameters. As a general rule, low-frequency rTMS (≤ 1 Hz) results in lowered cortical excitability at the site of stimulation, whereas high-frequency stimulation (≥ 5 Hz) results in raised cortical excitability (Lefaucheur 2008a; Pascual-Leone 1999). Similarly, anodal tDCS, wherein the anode electrode is placed over the cortical target, results in a raised level of excitability at the target, whereas cathodal stimulation decreases local cortical excitability (Nitsche 2008). It is suggested that the observed alterations in cortical excitability (readiness for activity) following rTMS and tDCS that last beyond the time of stimulation are the result of long-term synaptic changes (Lefaucheur 2008a). Modulation of activity in brain networks is also proposed as the mechanism of action of CES and RINCE therapy and it is suggested that the therapeutic effects are primarily achieved by direct action upon the hypothalamus, limbic system and/or the reticular activating system (Gilula 2007).

Imaging studies in humans suggest that motor cortex stimulation may reduce pain by modulating activity in networks of brain areas involved in pain processing, such as the thalamus, and by facilitating descending pain inhibitory mechanisms (Garcia-Larrea 1997; Garcia-Larrea 1999; Peyron 2007).

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 patient blinding, particularly in cross-over design studies. Lisanby 2001 and Loo 2000 suggest that an ideal sham condition for rTMS should:

  1. not stimulate the cortex;

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

  3. 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.

Why it is important to do this review

This approach to pain treatment is relatively novel. It is important to assess the existing literature robustly to ascertain the current level of supporting evidence and to inform future research and potential clinical use. Recent reviews have addressed this area and concluded that non-invasive brain stimulation can exert a significant effect on chronic pain, but they have restricted their findings to specific cortical regions, types of painful condition or types of stimulation and did not carry out a thorough assessment of study quality or risk of bias (Lefaucheur 2008b; Leung 2009; Lima 2008).

Objectives

To review all randomised and quasi-randomised studies of non-invasive cortical stimulation techniques in the treatment of chronic pain. The key aims of the review were:

  1. to critically evaluate the efficacy of non-invasive cortical stimulation techniques compared to sham controls for chronic pain; and

  2. to critically evaluate the influence of altered treatment parameters (i.e. stimulation method, parameters, dosage, site) on the efficacy of non-invasive cortical stimulation for chronic pain.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-randomised trials (e.g. by order of entry or date of birth) that utilise a sham control group were included. 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 are 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 or RINCE). 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. 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, were also not included. 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

Primary outcomes

The primary outcome measure was change in self reported pain using validated measures of pain intensity such as visual analogue scales (VAS), verbal rating scales (VRS) or numerical rating scales (NRS).

Secondary outcomes

Secondary outcomes that we extracted when available included self reported disability data, quality of life measures and the incidence/nature of adverse events.

Search methods for identification of studies

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 (Higgins 2011). We have slightly adapted this filter to include the term 'sham' in the title or abstract. The search strategies 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.

Electronic databases

We ran the original search for the review in November 2009 and searched all databases from their inception. To identify studies for inclusion in this update we searched the following electronic databases from 2009 to July 2013 to identify additional published articles:

  • the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 6);

  • OVID MEDLINE & MEDLINE in Process to 23 July 2013;

  • OVID EMBASE to 2013 week 29;

  • PsycINFO to July week 3 2013;

  • CINAHL to July 2013;

  • LILACS to January 2013;

For full details of the search parameters including dates for this update see Appendix 1; Appendix 2; Appendix 3.

Searching other resources

Reference lists

We searched reference lists of all eligible trials, key textbooks and previous systematic reviews to identify additional relevant articles.

Unpublished data

We searched the National Research Register (NRR) Archive, Health Services Research Projects in Progress (HSRProj), Current Controlled Trials register (incorporating the meta-register of controlled trials and the International Standard Randomised Controlled Trial Number (ISRCTN)) to January 2013 to identify research in progress and unpublished research.

Language

The search attempted to identify all relevant studies irrespective of language. We assessed non-English papers and, if necessary, translated with the assistance of a native speaker.

We sent a final list of included articles to two experts in the field of therapeutic brain stimulation with a request that they review the list for possible omissions.

Data collection and analysis

Selection of studies

Two review authors (NOC and BW) independently checked the search results and 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 post-intervention 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 2011).

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.

For this update, in compliance with new author guidelines from the Cochrane Pain, Palliative and Supportive Care review group 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.

Assessment of sham credibility

We rated the type of sham used in studies of rTMS for credibility: as optimal (the sham controls for the auditory and sensory characteristics of stimulation and is visually indistinguishable from real stimulation (Lisanby 2001; Loo 2000)) and sub-optimal (fails to account for either the auditory and sensory characteristics of stimulation, or is visually distinguishable from the active stimulation, or fails on more than one of these criteria). We made a judgement of 'unclear' where studies did not adequately describe the sham condition.

In light of empirical evidence that tDCS may be inadequately blinded at intensities of 2 mA (O'Connell 2012), and of detectable differences in the experience of tDCS at 1.5 mA (Kessler 2013), for this update we assessed studies that used these stimulation intensities to be at unclear risk of bias for participant and assessor blinding. We chose 'unclear' instead of 'high' risk of bias as the available evidence demonstrates the potential for inadequate blinding rather than providing clear evidence that individual studies were effectively unblinded. We applied this rule to all newly identified studies and retrospectively to studies identified in the previous version of this review.

Two independent review authors (NOC and BW) performed rating of sham credibility. We resolved disagreement between review authors through consensus. Where resolution was not achieved a third review author (LDS) considered the paper(s) in question. Where sham credibility was assessed as unclear or sub-optimal we made a judgement of 'unclear' for the criterion 'adequate blinding of participants' in the 'Risk of bias' assessment.

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 100 mm VAS format on the basis of the mean standard deviation from trials using 0 to 100 mm 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 < 15% as no important change, ≥ 15% as a minimally important change, ≥ 30% as a moderately important change and ≥ 50% 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 2011). We imputed the post-treatment between-condition correlation coefficient from an included cross-over study that presented individual patient 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 times data from that trial were entered in the meta-analysis. We calculated the SMD(SE) for parallel studies in RevMan. 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.

Data synthesis

We performed pooling of results where adequate data supported this using RevMan 5 software (version 5.2) (RevMan 2012), 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 and RINCE) and for short-term (0 to < 1 week post-intervention), mid-term (≥ 1 to 6 weeks post-intervention) and long-term (≥ 6 weeks post-intervention) outcomes where adequate data were identified.

Where more than one data point was available for short-term outcomes, we used the first post-stimulation 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'.

For this update we utilised the GRADE approach to assessing the quality of a body of evidence (Guyatt 2008). 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 'Risk of bias' criteria.

  • Inconsistency: downgrade once if heterogeneity is statistically significant 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 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.

While we had planned to use GRADE in our initial protocol we introduced these criteria specifically for this update.

Subgroup analysis and investigation of heterogeneity

We assessed heterogeneity using the Chi2 test to investigate its statistical significance and the I2 statistic to estimate the amount. Where significant heterogeneity (P < 0.1) was present we explored subgroup analysis. Pre-planned comparisons included site of stimulation, frequency of TMS stimulation (low ≤ 1 Hz, high ≥ 5 Hz), multiple 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

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Published data

In our original review the search strategy identified 1148 citations, including 305 duplicates. See Appendix 4 and Appendix 5 for full details of the search results from the original review. Screening of the 843 unique citations by title and abstract identified 39 as potentially eligible for the review. Three studies were identified from handsearching of the reference lists of included studies of which two were not retrievable in abstract or full manuscript form. The level of agreement between review authors, calculated using the kappa statistic for study eligibility based on title and abstract alone, was 0.77. We identified three more papers that were not picked up from the search strategy. We also deemed these to be potentially eligible for the review. One of the experts contacted to review the search results for possible omissions identified one additional study. The full-text screening of the 44 citations identified 33 eligible studies (19 of rTMS, 422 participants randomised; six of tDCS, 124 participants randomised; eight of CES, 391 participants randomised) (André-Obadia 2006; André-Obadia 2008; Boggio 2009; Borckardt 2009; Capel 2003; Carretero 2009; Cork 2004; Defrin 2007; Fenton 2009; Fregni 2005; Fregni 2006a; Fregni 2006b; Gabis 2003; Gabis 2009; Hirayama 2006; Irlbacher 2006; Kang 2009; Katsnelson 2004; Khedr 2005; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Lichtbroun 2001; Mori 2010; Passard 2007; Pleger 2004; Rollnik 2002; Saitoh 2007; Tan 2000; Tan 2006; Valle 2009). The kappa level of agreement between authors for eligibility from full-text screening was 0.87.

In this update we conducted a full search in February 2013 and updated the search of the main databases on 12 June 2013 and again on 24 July 2013. We included a further 23 completed studies with 773 participants randomised (range of n = 3 to 105, see Figure 2 for a flow chart of the search process). Of these, 11 studies (324 participants randomised) investigated rTMS (Ahmed 2011; André-Obadia 2011; Avery 2013, Fregni 2011; Hosomi 2013; Jensen 2013; Lee 2012; Mhalla 2011; Picarelli 2010; Short 2011; Tzabazis 2013), eight studies (177 participants randomised) investigated tDCS (Antal 2010; Jensen 2013; Mendonca 2011; Portilla 2013; Riberto 2011; Soler 2010; Villamar 2013; Wrigley 2014), three studies (181 participants randomised) investigated CES (Rintala 2010; Tan 2011; Taylor 2013), and one study investigated a novel form of stimulation (reduced impedance non-invasive cortical electrostimulation (RINCE)) that did not fit neatly into any of the three broad categories (Hargrove 2012, 91 participants)). Overall this updated review included 56 studies (1710 participants randomised), with 30 trials of rTMS (746 participants randomised), 14 trials of tDCS (301 participants randomised), 11 studies of CES (572 participants randomised) and one study of RINCE stimulation (91 participants randomised).

Figure 2.

Study flow diagram for updated search.

We identified an additional 11 conference abstracts that were not related to full published studies (Acler 2012; Albu 2011; Ansari 2013; Fricova 2009; Fricova 2011; Klirova 2010; Klirova 2011; Knotkova 2011; Pellaprat 2012; Schneider 2012; Yaĝci 2013). We contacted the authors of these abstracts to try to ascertain whether they were unique studies or duplicates and to acquire full study reports. Where we were unable to obtain this information we placed these records in Studies awaiting classification. For two of these abstracts the authors confirmed that they referred to studies that are either in the analysis/write-up stage or under review for publication, and as such were unavailable for this review update (Knotkova 2011; Schneider 2012). For the remaining abstracts identified in this update our attempts to contact the authors were not successful (Acler 2012; Albu 2011; Ansari 2013 Fricova 2009; Fricova 2011; Klirova 2010; Klirova 2011; Pellaprat 2012; Yaĝci 2013). We sent requests by email where possible in February 2013, with a follow-up email in April and June 2013, for those identified in the first search of this update, and in June 2013 for those identified by the second round of searching.

Unpublished data

In our original review the search strategy identified 5920 registered studies. Screening of the studies by the register records identified 23 studies that might potentially produce relevant data. Of these, seven were duplicated across trials registers, leaving 16 unique registered studies. We contacted the contact author for each of these studies by post or email with a request for any relevant data that might inform the review. No data were available from any of these studies for inclusion in this review.

In this update our search of the trials registers identified 599 records from which 11 relevant ongoing trials were identified. In addition to the two ongoing studies remaining from the last update (NCT00947622; NCT00815932); this makes a total of 13 ongoing studies identified. We contacted the contact author for each of these studies by post or email with a request for any relevant data that might inform the review. No data were available from any of these studies for inclusion in this review. We sent initial request emails for this update in April, and where no response was received also in May and in June 2013. Unpublished data and a full study report was provided for one study of rTMS identified from the trials registers search of the last update of this review (reference was Wajdik 2009, now Avery 2013).

Included studies

See Characteristics of included studies.

Country of origin and language of publication

All but one of the studies (Irlbacher 2006, written in German) were written in English. Studies were undertaken in Brazil, Egypt, Europe (France, Germany, Italy, Spain and the UK), Israel, Japan, Russia, South Korea and the USA. Most studies were based in a laboratory or outpatient pain clinic setting.

Type of stimulation, application and use

In total 30 studies investigated rTMS (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Avery 2013; Borckardt 2009; Carretero 2009; Defrin 2007; Fregni 2005; Fregni 2011; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Kang 2009; Khedr 2005; Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Mhalla 2011; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011; Tzabazis 2013). Eleven studies investigated CES (Capel 2003; Cork 2004; Gabis 2003; Gabis 2009; Katsnelson 2004; Lichtbroun 2001; Rintala 2010; Tan 2000; Tan 2006; Tan 2011; Taylor 2013), 14 studies investigated tDCS (Antal 2010; Boggio 2009; Fenton 2009; Fregni 2006a; Fregni 2006b; Jensen 2013; Mendonca 2011; Mori 2010; Portilla 2013; Riberto 2011; Soler 2010; Valle 2009; Villamar 2013; Wrigley 2014), and one study investigated RINCE stimulation (Hargrove 2012). We had not been aware of RINCE therapy until it was identified in this search update. While it bears similarities with CES the author of the included trial suggested that due to the specific unique stimulation parameters that differ from conventional forms of CES, it represents a novel form of cortical stimulation (Hargrove 2012).

Study designs

There were a mixture of parallel and cross-over study designs. For rTMS there were 12 parallel studies (Ahmed 2011; Avery 2013; Carretero 2009; Defrin 2007; Fregni 2011; Khedr 2005; Lee 2012; Mhalla 2011; Passard 2007; Picarelli 2010; Short 2011; Tzabazis 2013), and 18 cross-over studies (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011, Borckardt 2009; Fregni 2005; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Kang 2009; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Onesti 2013; Pleger 2004; Rollnik 2002; Saitoh 2007). For CES there were eight parallel studies (Gabis 2003; Gabis 2009; Katsnelson 2004; Lichtbroun 2001; Rintala 2010; Tan 2006; Tan 2011; Taylor 2013), and three cross-over studies (Capel 2003; Cork 2004; Tan 2000), of which we considered two as parallel studies, with only the opening phase of the study considered in this review because subsequent phases were unblinded (Capel 2003; Cork 2004). For tDCS there were seven parallel studies (Fregni 2006a; Fregni 2006b; Mendonca 2011; Mori 2010; Riberto 2011; Soler 2010; Valle 2009), and seven cross-over studies (Antal 2010; Boggio 2009; Fenton 2009; Jensen 2013; Portilla 2013; Villamar 2013; Wrigley 2014), of which we considered one as a parallel study with only the opening phase of the study considered in this review due to excessive attrition after the first phase (Antal 2010).

Study participants

The included studies were published between 2000 and 2013. In rTMS studies sample sizes at the study outset ranged from four to 70 participants. In CES studies sample size ranged from 19 to 105 participants, in tDCS studies sample size ranged from three to 41 participants and the single RINCE study recruited 91 participants.

Studies included a variety of chronic pain conditions. Nine rTMS studies included participants with neuropathic pain of mixed origin; of these seven included a mix of central, peripheral and facial neuropathic pain patients (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Hirayama 2006; Hosomi 2013, Lefaucheur 2004; Lefaucheur 2008), two included a mix of central and peripheral neuropathic pain patients (Lefaucheur 2006; Saitoh 2007), of which one study included a patient with phantom limb pain (Saitoh 2007). One study included a mix of central neuropathic pain and phantom limb pain patients (Irlbacher 2006). One study included a mix of central and facial neuropathic pain patients (Lefaucheur 2001a), two rTMS studies included only central neuropathic pain patients (Defrin 2007; Kang 2009), one included only peripheral neuropathic pain patients (Borckardt 2009), and nine studies included non-neuropathic chronic pain including fibromyalgia (Carretero 2009; Lee 2012; Mhalla 2011; Passard 2007; Short 2011; Tzabazis 2013), chronic widespread pain (Avery 2013), chronic pancreatitis pain (Fregni 2005; Fregni 2011), and complex regional pain syndrome type I (CRPSI) (Picarelli 2010; Pleger 2004). One study included only phantom limb pain (Ahmed 2011). Finally one study included a mix of peripheral neuropathic and non-neuropathic chronic pain (Rollnik 2002), including one participant with phantom limb pain and one with osteomyelitis. The majority (17) of rTMS studies specified chronic pain that was refractory to current medical management (André-Obadia 2006; André-Obadia 2008, André-Obadia 2011; Defrin 2007; Hirayama 2006; Hosomi 2013; Kang 2009; Khedr 2005; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Onesti 2013; Picarelli 2010; Rollnik 2002; Saitoh 2007). This inclusion criterion was varyingly described as intractable, resistant to medical intervention or drug management.

Of the studies investigating CES, one study included participants with pain related to osteoarthritis of the hip and knee (Katsnelson 2004), and two studied chronic back and neck pain (Gabis 2003; Gabis 2009). Of these, the later study also included participants with chronic headache but these data were not considered in this review. Three studies included participants with fibromyalgia (Cork 2004; Lichtbroun 2001; Taylor 2013), and three studies included participants with chronic pain following spinal cord injury (Capel 2003; Tan 2006; Tan 2011), although only one of these reports specified that the pain was neuropathic (Tan 2011). One study included participants with a mixture of "neuromuscular pain" excluding fibromyalgia of which back pain was reportedly the most prevalent complaint (Tan 2000), although further details were not reported. One study included participants with chronic pain related to Parkinson's disease (Rintala 2010).

Of the studies of tDCS one study included participants with a mixture of central, peripheral and facial neuropathic pain (Boggio 2009), one study included participants with neuropathic pain secondary to multiple sclerosis (Mori 2010), three included participants with central neuropathic pain following spinal cord injury (Fregni 2006a; Soler 2010; Wrigley 2014), one with neuropathic or non-neuropathic pain following spinal cord injury (Jensen 2013), and six studies included non-neuropathic pain, specifically chronic pelvic pain (Fenton 2009), and fibromyalgia (Fregni 2006b; Mendonca 2011; Riberto 2011; Villamar 2013), or a mixed group (Antal 2010). One study included participants with neuropathic pain following burn injury (Portilla 2013). Four studies of tDCS specified recruiting participants with pain that was refractory to medical management (Antal 2010; Boggio 2009; Fenton 2009; Fregni 2006a). The study relating to RINCE stimulation included participants with fibromyalgia (Hargrove 2012).

Most studies included both male and female participants except the studies of Fenton 2009 (chronic pelvic pain) and Fregni 2006b, Valle 2009, Riberto 2011 and Mhalla 2011; Lee 2012 (fibromyalgia), which recruited females only and Fregni 2006a (post-spinal cord injury pain), which recruited only males. Two studies did not present data specifying the gender distribution of participants (Capel 2003; Katsnelson 2004).

Outcomes
Primary outcomes

All included studies assessed pain using self reported pain visual analogue or numerical rating scales. There was variation in the precise measure of pain (for example, current pain intensity, average pain intensity over 24 hours) and in the anchors used particularly for the upper limit of the scale (e.g. "worst pain imaginable", "unbearable pain", "most intense pain sensation"). Several studies did not specify the anchors used.

All studies assessed pain at the short-term (< 1 week post-treatment) follow-up stage. Twenty-three studies reported collecting medium-term outcome data (≥ 1 to 6 weeks post-treatment) (Ahmed 2011; André-Obadia 2008; Antal 2010; Borckardt 2009; Carretero 2009; Defrin 2007; Fenton 2009; Fregni 2006a; Fregni 2006b; Fregni 2011; Gabis 2009; Kang 2009; Khedr 2005; Lee 2012; Lefaucheur 2001a; Mori 2010; Passard 2007; Picarelli 2010; Short 2011; Soler 2010; Tzabazis 2013; Valle 2009; Wrigley 2014). Only three studies collected controlled outcome data on long-term (> 6 weeks post-treatment) follow-up (Avery 2013; Kang 2009; Passard 2007).

Secondary outcomes

We only considered secondary outcomes that distinctly measured self reported disability or quality of life for extraction and inclusion in the Characteristics of included studies table. Nine studies used measures of disability or pain interference (Avery 2013; Cork 2004; Kang 2009; Mhalla 2011; Passard 2007; Short 2011; Soler 2010; Tan 2000; Tan 2006), and 14 studies collected measures of quality of life (Avery 2013; Fregni 2006b; Lee 2012; Lichtbroun 2001; Mhalla 2011; Mori 2010; Passard 2007; Picarelli 2010; Riberto 2011; Short 2011; Tan 2011; Taylor 2013; Tzabazis 2013; Valle 2009).

Adverse event reporting

Seventeen studies did not report any information regarding adverse events (Ahmed 2011; André-Obadia 2011; Borckardt 2009; Cork 2004; Defrin 2007; Gabis 2009; Jensen 2013; Kang 2009; Katsnelson 2004; Khedr 2005; Lefaucheur 2006; Lefaucheur 2008; Lichtbroun 2001; Pleger 2004; Riberto 2011; Tan 2000; Tan 2006).

Studies of rTMS

See Table 1 for a summary of stimulation characteristics utilised in rTMS studies.

Table 1. rTMS studies - characteristics of stimulation
  1. 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

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, 190

20 Hz: 20

1Hz: 1

20 Hz: 4 sec

1 Hz: 26 min

20 Hz: 8416001
André-Obadia 2008M1 contralateral to painful side

Posteroanterior

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 2012

Right DLPFC (low-frequency)

Left M1 (high-frequency)

Not specified10, 1

10 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, 0.580

10 Hz: 20

0.5 Hz: 1

10 Hz: 5 sec

0.5 Hz: 20 min

10 Hz: 55

10 Hz: 1000

0.5 Hz: 600

1
Lefaucheur 2004M1 contralateral to painful sidePosteroanterior1080205 sec5510001
Lefaucheur 2006M1 contralateral to painful sidePosteroanterior10, 190

10 Hz: 20

1 Hz: 1

10 Hz: 6 sec

1 Hz: 20 min

10 Hz: 54

10 Hz: 1200

1 Hz: 1200

1
Lefaucheur 2008M1 contralateral to painful sidePosteroanterior10, 190

10 Hz: 20

1 Hz: 1

10 Hz: 6 sec

1 Hz: 20 min

10 Hz: 54

10 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, 190

10 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)
Stimulation location

The parameters for rTMS application varied significantly between studies including by site of stimulation, stimulation parameters and the number of stimulation sessions. The majority of rTMS studies targeted the primary motor cortex (M1) (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Defrin 2007; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Kang 2009; Khedr 2005; Lee 2012, Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Mhalla 2011; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007). Of these, one study specified stimulation of the right hemisphere (Kang 2009), one study specified the left hemisphere (Mhalla 2011), and two studies specified stimulation over the midline (Defrin 2007; Pleger 2004). One study used a novel H-coil to stimulate the motor cortex of the leg representation situated deep in the central sulcus (Onesti 2013), and the remainder stimulated over the contralateral cortex to the side of dominant pain. One of these studies also investigated stimulation of the supplementary motor area (SMA), pre-motor area (PMA) and primary somatosensory cortex (S1) (Hirayama 2006). Two studies stimulated the dorsolateral pre-frontal cortex (DLPFC), with two studies stimulating the left hemisphere (Borckardt 2009; Short 2011), and two studies the right (Carretero 2009; Lee 2012). One study investigated stimulation of the left and right secondary somatosensory cortex (SII) as separate treatment conditions (Fregni 2005), and another investigated stimulation to the right SII area (Fregni 2011). One study used a four-coil configuration to target the anterior cingulate cortex (Tzabazis 2013).

Stimulation parameters
Frequency

Eleven studies investigated low-frequency (< 5 Hz) rTMS (André-Obadia 2006; Carretero 2009; Fregni 2005; Fregni 2011; Irlbacher 2006; Lee 2012; Lefaucheur 2001b; Lefaucheur 2006; Lefaucheur 2008; Saitoh 2007; Tzabazis 2013). Of these, one study used a frequency of 0.5 Hz in one treatment condition (Lefaucheur 2001b), and the rest used a frequency of 1 Hz. Twenty-seven studies investigated high-frequency (≥ 5 Hz) rTMS (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Avery 2013; Borckardt 2009; Defrin 2007; Fregni 2005; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Kang 2009; Khedr 2005; Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Mhalla 2011; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011). While the study by Tzabazis 2013 did apply high-frequency stimulation to some participants, the allocation of the high-frequency groups was not randomised in that study (confirmed through correspondence with authors) and so those data will not be considered further in this review as they do not meet our inclusion criteria.

Other parameters

We observed wide variation between studies for various stimulation parameters. The overall number of rTMS pulses delivered varied from 120 to 4000. The study by Defrin 2007 reported a total number of pulses of 500 although the reported stimulation parameters of 500 trains, delivered at a frequency of 5 Hz for 10 seconds would imply 25,000 pulses. Eight studies specified a posteroanterior or parasagittal orientation of the stimulating coil (André-Obadia 2006; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Passard 2007; Picarelli 2010; Short 2011), two studies specified a coil orientation 45º to the midline (Ahmed 2011; Kang 2009), one study compared a posteroanterior coil orientation with a medial-lateral coil orientation (André-Obadia 2008), one used an H-coil (Onesti 2013), one used a four-coil configuration (Tzabazis 2013), and the remaining studies did not specify the orientation of the coil. Within studies that reported the information, the duration and number of trains and the inter-train intervals varied. Two studies did not report this information (Fregni 2005; Fregni 2011).

Type of sham

rTMS studies employed a variety of sham controls. In 11 studies the stimulating coil was angled away from the scalp to prevent significant cortical stimulation (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; Carretero 2009; Hirayama 2006; Kang 2009; Khedr 2005; Lee 2012; Pleger 2004; Rollnik 2002; Saitoh 2007), of which two studies also simultaneously electrically stimulated the skin of the scalp in both the active and sham stimulation conditions in order to mask the sensations elicited by active rTMS and thus preserve participants' blinding (Hirayama 2006; Saitoh 2007). The remaining studies utilised sham coils. Of these, eight studies specified that the sham coil made similar or identical sounds to those elicited during active stimulation (André-Obadia 2011; Borckardt 2009; Defrin 2007; Irlbacher 2006; Mhalla 2011; Passard 2007; Picarelli 2010; Tzabazis 2013), and five specified that the sham coil made similar sounds, looked the same and elicited similar scalp sensations as the real coil (Avery 2013; Fregni 2011; Hosomi 2013; Onesti 2013; Short 2011). Six studies did not specify whether the sham coil controlled for the auditory characteristics of active stimulation (Fregni 2005; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008).

Studies of CES

See Table 2 for a summary of stimulation characteristics utilised in CES studies.

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
Stimulation device, parameters and electrode location

Seven studies of CES used the 'Alpha-stim' CES device (Electromedical Products International, Inc, Mineral Wells, Texas, USA). This device uses two ear clip electrodes that attach to each of the participant's ears (Cork 2004; Lichtbroun 2001; Rintala 2010; Tan 2000; Tan 2006; Tan 2011; Taylor 2013), and these studies utilised stimulation intensities of 100 μA with a frequency of 0.5 Hz. One study (Capel 2003) used a device manufactured by Carex (Hemel Hempstead, UK) that also used earpiece electrodes and delivered a stimulus intensity of 12 μA.

Two studies used the 'Pulsatilla 1000' device (Pulse Mazor Instruments, Rehavol, Israel) (Gabis 2003; Gabis 2009). The electrode array for this device involved an electrode attached to each of the participant's mastoid processes and one attached to the forehead; current is passed to the mastoid electrodes. One study used the 'Nexalin' device (Kalaco Scientific Inc, Scottsdale, AZ, USA) (Katsnelson 2004). With this device current is applied to a forehead electrode and returned via electrodes placed behind the patient's ears. These three studies utilised significantly higher current intensities than those using ear clip electrodes with intensities of 4 mA (Gabis 2003; Gabis 2009), and 11 to 15 mA (Katsnelson 2004).

All CES studies gave multiple treatment sessions for each treatment group with variation between the number of treatments delivered.

Type of sham

Eight studies utilised inert sham units (Capel 2003; Cork 2004; Lichtbroun 2001; Rintala 2010; Tan 2000; Tan 2006; Tan 2011; Taylor 2013). These units were visually indistinguishable from the active devices. Stimulation at the intensities used is subsensation and as such it should not have been possible for participants to distinguish between the active and sham conditions.

Two studies utilised an "active placebo" treatment unit (Gabis 2003; Gabis 2009). This sham device was visually indistinguishable and delivered a current of much lower intensity (≤ 0.75 mA) than the active stimulator to evoke a similar sensation to ensure patient blinding. Similarly, Katsnelson 2004 utilised a visually indistinguishable sham device that delivered brief pulses of current of < 1 mA. The placebo conditions used in these three studies delivered current at much greater intensities than those used in the active stimulation conditions of the other CES studies.

Studies of tDCS

See Table 3 for a summary of stimulation characteristics utilised in tDCS studies.

Table 3. tDCS studies - characteristics of stimulation
  1. DLPFC: dorsolateral prefrontal cortex; M1: primary motor cortex

    HD-tDCS: High definition tDCS

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 2011

Group 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
Stimulation parameters and electrode location

Two studies of tDCS stimulated the dorsolateral prefrontal cortex in one treatment group (Fregni 2006b; Valle 2009). Thirteen studies stimulated the motor cortex (Antal 2010; Boggio 2009; Fenton 2009; Fregni 2006a; Fregni 2006b; Jensen 2013; Mori 2010; Portilla 2013; Riberto 2011; Soler 2010; Valle 2009; Villamar 2013; Wrigley 2014). Of these, nine stimulated the cortex contralateral to the side of worst pain (Boggio 2009; Fregni 2006a; Fregni 2006b; Mori 2010; Portilla 2013; Riberto 2011; Soler 2010; Villamar 2013; Wrigley 2014), of which six studies stimulated the opposite hemisphere to the dominant hand where pain did not have a unilateral dominance (Fregni 2006a; Fregni 2006b; Jensen 2013; Riberto 2011; Soler 2010; Wrigley 2014). Three studies stimulated the left hemisphere for all participants (Antal 2010; Valle 2009; Villamar 2013). One study of chronic pelvic pain stimulated the opposite hemisphere to the dominant hand in all participants (Fenton 2009). One study specifically investigated the use of tDCS in conjunction with transcutaneous electrical nerve stimulation (TENS) therapy (Boggio 2009). We extracted data comparing active tDCS and sham TENS with sham tDCS and sham TENS for the purposes of this review. One applied anodal or cathodal stimulation to the left motor cortex or to the right supraorbital area (Mendonca 2011).

Six studies delivered a current intensity of 2 mA for 20 minutes once a day for five days (Antal 2010; Fregni 2006a; Fregni 2006b; Mori 2010; Valle 2009; Wrigley 2014). One study applied a current intensity of 1 mA once a day for two days (Fenton 2009), and four studies applied one treatment per stimulation condition at an intensity of 2 mA for 20 minutes (Boggio 2009; Mendonca 2011; Jensen 2013; Villamar 2013). One study delivered 10 stimulation sessions of 20 minutes at 2 mA once weekly for 10 weeks (Riberto 2011), and another delivered 10 sessions once a day, with a visual illusion condition or a sham visual illusion condition for 10 consecutive weekdays (Soler 2010).

All studies of tDCS utilised a sham condition whereby active stimulation was ceased after 30 seconds without the participants' knowledge.

Excluded studies

See Characteristics of excluded studies.

In our original review we excluded 11 studies after consideration of the full study report. Of these, one was not a study of brain stimulation (Frentzel 1989), two did not assess self reported pain as an outcome (Belci 2004; Johnson 2006), four were not restricted to participants with chronic pain (Evtiukhin 1998; Katz 1991; Longobardi 1989; Pujol 1998), one study was unclear on the duration of participants' symptoms (Avery 2007), 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), and one did not employ a sham control (Evtiukhin 1998).

For this update we excluded a further 17 reports, after consideration of the full study report. Nine reports referred to studies which had already been included in the previous version of this review, one was not a study of brain stimulation (Carraro 2010), two were not clearly in a chronic pain population (Choi 2012a; Choi 2012b), one was not a randomised controlled trial (O'Connell 2013), one reported uncontrolled long-term follow-up data from an included study (Hargrove 2012a), 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). Finally one citation referred to a booklet of conference proceedings which contained no relevant citations.

Risk of bias in included studies

Risk of bias varied across studies for all of the assessment criteria. For a summary of 'Risk of bias' assessment across studies see Figure 1.

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 14 trials as having an unclear risk of bias (Antal 2010; Carretero 2009; Cork 2004; Defrin 2007; Hargrove 2012; Katsnelson 2004; Lee 2012; Mendonca 2011; Picarelli 2010; Riberto 2011; Rintala 2010; Tan 2006; Taylor 2013; Tzabazis 2013), 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 patients were allocated depending on the day of the week on which they were recruited, which we did not judge as being genuinely random.

Allocation concealment

We only considered for the criterion 'Adequate concealment of allocation' studies with parallel designs or from which only data from the first phase of the study were included (i.e. we them considered as parallel studies). Seventeen studies did not report concealment of allocation and we judged them as 'unclear' (Antal 2010; Carretero 2009; Cork 2004; Defrin 2007; Fregni 2011; Hargrove 2012; Katsnelson 2004; Lee 2012; Mendonca 2011; Passard 2007; Picarelli 2010; Riberto 2011; Rintala 2010; Soler 2010; Tan 2006; Taylor 2013; Tzabazis 2013), 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).

Blinding

Blinding of assessors

While many studies used self reported pain outcomes we considered that the complex nature of the intervention, and the level of interaction this entails between participants and assessors, suggested that a lack of blinding of the researchers engaged in the collection of outcomes might potentially introduce bias. As such, where blinding of assessors was not clearly stated we made a judgement of 'unclear' for this criterion.

Sixteen studies did not specify whether they blinded outcome assessors (André-Obadia 2011; Borckardt 2009; Hirayama 2006; Irlbacher 2006; Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Onesti 2013; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Tan 2000; Tzabazis 2013), while we judged the majority of studies of tDCS at unclear risk of bias on this criterion (Boggio 2009; Fregni 2006a; Fregni 2006b; Jensen 2013; Mori 2010; Portilla 2013; Riberto 2011; Soler 2010; Valle 2009; Villamar 2013; Wrigley 2014), since there is evidence that assessor blinding may be compromised at the stimulation intensities used (O'Connell 2012).

Blinding of participants
rTMS studies

All studies attempted to blind participants. However, due to the difficulties involved in producing a robust sham control in rTMS studies (see Assessment of risk of bias in included studies) we made an assessment of sham credibility. Where the coil was angulated or angulated and elevated away from the scalp, this is potentially distinguishable both visually and by the sensory effects of stimulation. Two studies simultaneously electrically stimulated the scalp during rTMS stimulation to mask the differences in sensation between conditions (Hirayama 2006; Saitoh 2007). However, by angulating the coil away from the scalp participants may have been able to visually distinguish between the conditions. Where sham coils were utilised they usually did not control for the sensory aspects of stimulation. We assessed most rTMS studies as having sub-optimal sham control conditions and we therefore assessed them as having an 'unclear' risk of bias. Four rTMS studies included in this update utilised modern sham coils that are visually indistinguishable, emit the same noise during stimulation and elicit similar scalp sensations (Avery 2013; Fregni 2011; Onesti 2013; Short 2011). These studies met the criteria for an optimal sham condition and as such we judged them at low risk of bias for participant blinding.

Similarly with tDCS studies, due to evidence that blinding of participants to the stimulation condition may be compromised at intensities of 1.5 mA and above, we judged the majority of tDCS studies at unclear risk of bias on this criterion (Boggio 2009; Fregni 2006a; Fregni 2006b; Jensen 2013; Mori 2010; Portilla 2013; Riberto 2011; Soler 2010; Valle 2009; Villamar 2013; Wrigley 2014).

We assessed all studies of CES as having a low risk of bias for this criterion.

Incomplete outcome data

We assessed 11 studies as having an unclear risk of bias for this criterion (Ahmed 2011; André-Obadia 2006; André-Obadia 2011; Boggio 2009; Cork 2004; Fregni 2011; Hargrove 2012; Katsnelson 2004; Lefaucheur 2006; Lichtbroun 2001; Tzabazis 2013). Ahmed 2011 and Fregni 2011 did not report the level of drop-out from their studies. 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. Five studies did not clearly report levels of drop-out (Cork 2004; Katsnelson 2004; Lefaucheur 2006; Lichtbroun 2001; Tzabazis 2013), of which one 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 (Schneider 2012). We assessed three studies as having a high risk of bias for this criterion (Antal 2010; Irlbacher 2006; Tan 2000). In the Antal 2010 study, of 23 participants recruited only 12 completed the full cross-over. In the study by Irlbacher 2006, only 13 of the initial 27 participants completed all of the treatment conditions. In the studies of 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. We considered this level of withdrawal unsustainable.

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, and these data were not made available upon request. We assessed 11 studies as having a high risk of bias for this criterion (Capel 2003; Cork 2004; Fregni 2005; Fregni 2011; Katsnelson 2004; Lichtbroun 2001; Mendonca 2011; Onesti 2013; Portilla 2013; Tzabazis 2013; Valle 2009). We judged two studies as being at unclear risk of bias (Fregni 2006a; Fregni 2006b). In the reports of these studies 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. We assessed the remaining studies as having a low risk of bias for this criterion. For this update, we first made requests for data (by email where possible) in February 2013, with repeat emails sent where necessary in March, April and June 2013. For studies identified in the second round of searches we made requests in June 2013 and we made the final round of requests on 1 August 2013. If these data are made available in time for future updates then we can revise judgements on this criterion accordingly.

Study size

We rated three studies at unclear risk of bias (Hosomi 2013; Lefaucheur 2004; Tan 2011), with all remaining studies rated at high risk of bias on this criterion.

Study duration

We rated seven studies at low risk of bias on this criterion (Ahmed 2011; Avery 2013; Gabis 2009; Mhalla 2011; Passard 2007; Picarelli 2010; Valle 2009), 19 studies at unclear risk of bias (André-Obadia 2008; André-Obadia 2011; Antal 2010; Borckardt 2009; Carretero 2009; Defrin 2007; Fenton 2009; Fregni 2006a; Fregni 2006b; Fregni 2011; Hosomi 2013; Kang 2009; Khedr 2005; Lee 2012; Mori 2010; Onesti 2013; Soler 2010; Tzabazis 2013; Wrigley 2014), and the remaining studies at high risk of bias (André-Obadia 2006; Boggio 2009; Capel 2003; Cork 2004; Fregni 2005; Gabis 2003; Hargrove 2012; Hirayama 2006; Irlbacher 2006; Jensen 2013; Katsnelson 2004; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Lichtbroun 2001; Mendonca 2011; Pleger 2004; Portilla 2013; Riberto 2011; Rintala 2010; Rollnik 2002; Saitoh 2007; Short 2011; Tan 2000; Tan 2006; Tan 2011; Taylor 2013; Villamar 2013) .

Other potential sources of bias

Carry-over effects in cross-over trials

We judged one study as unclear on this criterion as no pre-stimulation data were provided and no investigation of carry-over effects was discussed in the study report (Fenton 2009). In one cross-over study baseline differences between the sham and the 10 Hz stimulation condition were notable (Saitoh 2007). A paired t-test did not show a significant difference (P > 0.1) and we judged this study as having a low risk of bias for carry-over effects. We judged another study at unclear risk of bias on this criterion as the necessary data were not available in the study report from which to make a judgement (Portilla 2013).

Other sources of bias

Two studies did not present baseline data for key outcome variables and we judged them as 'unclear' (Fregni 2011; Tzabazis 2013). Three studies demonstrated baseline imbalances: one study on pain intensity levels (Defrin 2007), one study on Brief Pain Inventory pain interference, SF-36 pain sub-scale and coping strategies (Tan 2011) and one study on duration of pain, education, age and economic activity (Riberto 2011). We judged these studies at unclear risk of bias for these reasons. One study of CES did not clearly present relevant baseline group characteristics of the included participants and we judged it as being at high risk of bias for this criterion (Katsnelson 2004). 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 judged one study at high risk of bias on this criterion due to imbalances between the groups at baseline on the duration of pain, education, age and economic activity (Riberto 2011).

Effects of interventions

See: Summary of findings for the main comparison

For a summary of all core findings see Summary of findings for the main comparison.

Primary outcome: pain

Repetitive transcranial magnetic stimulation (rTMS) for short-term relief of chronic pain

The primary meta-analysis (Analysis 1.1) pooled data from all rTMS studies with low or unclear risk of bias (excluding the risk of bias criteria 'study size' and 'study duration') where data were available (n = 528), including cross-over and parallel designs, using the generic inverse variance method (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Borckardt 2009; Carretero 2009; Defrin 2007; Hirayama 2006; Hosomi 2013; Kang 2009; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Mhalla 2011; Passard 2007; Pleger 2004; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011). We excluded the studies by Ahmed 2011, Khedr 2005, Irlbacher 2006 and Lee 2012, as we classified them as having a high risk of bias on at least one criterion. We were unable to include data from five studies (Fregni 2005; Fregni 2011; Onesti 2013; Picarelli 2010; Tzabazis 2013 combined n = 86), as the necessary data were not available in the study report or upon request by the submission date of this update. We imputed the correlation coefficient used to calculate the standard error (SE) (standardised mean difference (SMD)) for cross-over studies (0.764) from data extracted from André-Obadia 2008 (as outlined in Unit of analysis issues) and we entered the SMD (SE) for each study into a generic inverse variance meta-analysis. We divided the number of participants in each cross-over study by the number of comparisons made by that study entered into the meta-analysis. For parallel studies we calculated the standard error of the mean (SEM) from the 95% confidence intervals of the standardised mean difference (SMD) and entered both the SMD and the SEM into the meta-analysis. We then entered this into the meta-analysis with the SMD using the generic inverse variance method.

We observed substantial heterogeneity (I2 = 67%, P < 0.01) and investigated this using pre-planned subgroup analysis. Categorising studies by high (≥ 5 Hz) or low (< 5 Hz) frequency rTMS demonstrated a significant difference between subgroups (P < 0.01) and reduced heterogeneity in the low-frequency group (n = 81, I2 = 0%). In this group there was no evidence of an effect of low-frequency rTMS for short-term relief of chronic pain (SMD 0.15, 95% confidence interval (CI) -0.01 to 0.3, P = 0.07). While high-frequency stimulation demonstrated a significant effect (SMD -0.27, 95% CI -0.35 to -0.20, P < 0.01), we observed substantial heterogeneity in this (n = 447, I2 = 64%). Separating studies that delivered a single treatment per condition from those that delivered multiple treatment sessions did not reduce heterogeneity substantially in multiple-dose studies (n = 225, I2 = 75%) or single-dose studies (n = 303, I2 = 61%) (Analysis 1.2).

There were insufficient data to support the planned subgroup analysis by the type of painful condition as planned. However, when the analysis was restricted to studies including only well-defined neuropathic pain populations (Analysis 1.3 excluding Carretero 2009; Mhalla 2011; Passard 2007; Pleger 2004; Rollnik 2002; Short 2011), there was little impact on heterogeneity (I2 = 71% P < 0.01). In the subgroup of non-neuropathic pain studies overall heterogeneity remained significant and high (I2 = 56%, P = 0.04) (Analysis 1.4).

rTMS motor cortex

Restricting the analysis to single-dose studies of high-frequency stimulation of the motor cortex (n = 233) reduced heterogeneity (I2 = 31%, P = 0.13) (Analysis 1.5). In this group the pooled SMD was -0.39 (95% confidence interval (CI) -0.51 to -0.27, P < 0.01). We back-transformed the SMD to a mean difference using the mean standard deviation of the post-treatment sham group score of the studies included in this analysis (1.87). We then used this to estimate the real percentage change on a 0 to 100 mm visual analogue scale (VAS) of active stimulation compared with the mean post-stimulation score from the sham groups of the included studies (6.2). This equated to a reduction of 7.3 mm (95% CI 5 mm to 9.5 mm), or a percentage change of 12% (95% CI 8% to 15%) of the control group outcome. This estimate does not reach the pre-established criteria for a minimal clinically important difference (≥ 15%). Of the included studies in this subgroup, nine did not clearly report blinding of assessors and we awarded them a judgement of 'unclear' risk of bias for this criterion (André-Obadia 2011; Hirayama 2006; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Pleger 2004; Rollnik 2002; Saitoh 2007). Sensitivity analysis removing these studies reduced heterogeneity to I2 = 0% although only three studies were preserved in the analysis (André-Obadia 2006; André-Obadia 2008; Lefaucheur 2008). There remained a statistically significant difference between sham and active stimulation although the SMD reduced to -0.31 (95% CI -0.49 to -0.13). This equates to a percentage change of 9% (95% CI 4% to 15%) in comparison with sham stimulation. For multiple-dose studies of high-frequency motor cortex stimulation heterogeneity was high (n = 157, I2 = 71%, P < 0.01), but the pooled effect was not significant (SMD -0.07, 95% CI -0.41 to 0.26, P = 0.68).

When the analysis was restricted to studies of single-dose, high-frequency motor cortex stimulation in well-defined neuropathic pain populations (excluding data from Pleger 2004; Rollnik 2002), there was little effect on the pooled estimate (SMD -0.43, 95% CI -0.57 to -0.30) or heterogeneity (I2 = 31%, not significant). When we applied the same process to multiple-dose studies of high-frequency motor cortex stimulation (excluding data from Passard 2007) heterogeneity remained high (I2 = 62%, P = 0.03) with no significant pooled effect.

Sensitivity analysis

To assess whether the imputation of standard errors for cross-over studies was robust we repeated the analysis with the correlation coefficient reduced to 0.66 and increased to 0.86. This had no marked effect on the overall analysis (Analysis 1.6; Analysis 1.7). The same process was applied to the subgroup analysis of single-dose studies of high-frequency motor cortex stimulation (Analysis 1.8; Analysis 1.9). This had a negligible impact on the effect size or the statistical significance of this subgroup.

To assess the impact of excluding the studies of Ahmed 2011, Irlbacher 2006, Khedr 2005 and Lee 2012, we performed the analysis with data from these studies included (Analysis 1.10). While this produced a modest increase in the SMD it increased heterogeneity from 69% to 74%. Inclusion of Ahmed 2011, Khedr 2005 and Lee 2012 to the multiple-dose studies of high-frequency motor cortex stimulation subgroup increased heterogeneity (I2 = 88%, P < 0.01), though the subgroup demonstrated an effect that approached statistical significance (SMD -0.50, 95% CI -0.99 to -0.01, P = 0.05) (Analysis 1.11). Inclusion of the Irlbacher 2006 study in the single-dose studies of high-frequency motor cortex stimulation subgroup caused a slight decrease in the pooled effect size (SMD -0.36, 95% CI -0.48 to -0.24) with no impact on heterogeneity.

Small study effects/publication bias

We investigated small study effects using Egger's test. The results are not suggestive of a significant influence of small study effects.

rTMS prefrontal cortex

Restricting the analysis to studies that stimulated the dorsolateral pre-frontal cortex (DLPFC) included four studies (n = 68) (Avery 2013; Borckardt 2009; Carretero 2009; Short 2011) (Analysis 1.12). We excluded the study by Lee 2012 due to its high risk of bias. The pooled effect was non-significant (P = 0.36) with substantial heterogeneity (I2 = 82%, P < 0.01). Restricting the analysis to high-frequency studies (Avery 2013; Borckardt 2009; Short 2011), the effect remained non-significant (P = 0.33) with high heterogeneity (I2 = 85%, P < 0.01). The only remaining low-frequency study (Carretero 2009, n = 26) was not suggestive of a significant effect (SMD 0.16, 95% CI -0.29 to 0.61). It is worthy of note that the only study in the analysis which individually demonstrated a significant effect was very small (n = 4) and its removal from the analysis makes heterogeneity non-significant (Borckardt 2009).

Sensitivity analysis

To assess the impact of excluding the study of Lee 2012, we performed the analysis with data from this study included (Analysis 1.13). The overall effect remained non-significant (P = 0.27) with high heterogeneity (I2 = 76%, P < 0.01). Restricting this to low-frequency studies (Carretero 2009; Lee 2012) brought heterogeneity down to a non-significant level (I2 = 16%, P = 0.28), though the effect remained non-significant. Restricting the analysis to high-frequency studies (Borckardt 2009; Lee 2012; Short 2011), the effect remained non-significant (P = 0.25) though heterogeneity remained high (I2 = 74%, P < 0.01). Restricting the analysis to low-frequency studies (Carretero 2009; Lee 2012), the effect remained non-significant (P = 0.92) with no heterogeneity (I2 = 16%, P = 0.28).

rTMS for medium-term relief of chronic pain (< 6 weeks post-treatment)

Seven studies provided data on medium-term pain outcomes (Avery 2013; Carretero 2009; Hosomi 2013; Lefaucheur 2001a; Kang 2009; Passard 2007; Short 2011). We excluded the studies by Ahmed 2011, Khedr 2005 and Lee 2012 as we classified them as having a high risk of bias. The analysis included 184 participants (Analysis 1.14). Overall heterogeneity was high (I2 = 57%, P = 0.02) and no significant effect was observed (SMD -0.18, 95% CI -0.43 to 0.06, P = 0.15). Restricting the analysis to studies of prefrontal cortex stimulation (Avery 2013; Carretero 2009; Short 2011) demonstrated no significant effect (SMD -0.03, 95% CI -0.52 to 0.35). Studies of motor cortex stimulation also demonstrated no significant effect (SMD -0.22, 95% CI -0.52 to 0.07, P = 0.14) although heterogeneity was high (I2 = 72%, P < 0.01). We performed sensitivity analysis to assess the impact of excluding the studies by Ahmed 2011, Khedr 2005 and Lee 2012 on the basis of risk of bias (Analysis 1.15). Including these studies increased heterogeneity (I2 = 76%, P < 0.01) though the effect reached significance overall (SMD -0.43, 95% CI -0.76 to -0.10) and specifically for high-frequency studies (SMD -0.48, 95% CI -0.83 to -0.13) (I2 = 79%, P < 0.01).

rTMS for long-term relief of chronic pain (≥ 6 weeks post-treatment)

Three studies provided data for long-term pain relief (Avery 2013; Kang 2009; Passard 2007) (Analysis 1.16). The analysis included 59 participants. There was no heterogeneity (I2 = 0%, P = 0.95). The analysis demonstrated no significant effect (SMD -0.12, 95% CI -0.46 to 0.21, P = 0.47). Sensitivity analysis to assess the impact of excluding the study of Ahmed 2011 due to its high risk of bias continued to demonstrate no significant effect, though heterogeneity was introduced (Analysis 1.17, I2 = 68%, P = 0.03).

Cranial electrotherapy stimulation (CES) for short-term pain relief

Six studies provided data for this analysis (Gabis 2003; Gabis 2009; Rintala 2010; Tan 2006; Tan 2011; Taylor 2013) (Analysis 2.1, n = 270). We excluded the study by Rintala 2010 due to high risk of attrition bias. All studies utilised a parallel-group design and so we used a standard inverse variance meta-analysis using SMD. Four studies did not provide the necessary data to enter into the analysis (Capel 2003; Cork 2004; Katsnelson 2004; Lichtbroun 2001, combined n = 228) and we classified two studies as being at high risk of bias on criteria other than 'free of selective outcome reporting' (Katsnelson 2004; Tan 2000). The studies by Gabis 2003 and Gabis 2009 differ substantially from the other included studies on the location of electrodes and the intensity of the current provided. Despite this, there was no heterogeneity (I2 = 0%). No individual study in this analysis demonstrates superiority of active stimulation over sham and the results of the meta-analysis do not demonstrate statistical significance (SMD -0.24, 95% CI -0.48 to 0.01, P = 0.06). Sensitivity analysis, including the study by Rintala 2010, did not meaningfully affect the results (SMD -0.21, 95% CI -0.45 to 0.02, P = 0.07).

There were insufficient data to perform a meta-analysis for medium or long-term pain outcomes for CES.

Transcranial direct current stimulation (tDCS) for short-term pain relief

Adequate data were available from 11 studies (Antal 2010; Boggio 2009; Fenton 2009; Fregni 2006a; Fregni 2006b; Jensen 2013; Mori 2010; Riberto 2011; Soler 2010; Villamar 2013; Wrigley 2014) for this analysis (n = 193). We were unable to include data from Mendonca 2011 and Valle 2009 (combined n = 71) as the necessary data were not reported in the study report or available upon request to the authors. We only included first-stage data from the study of Antal 2010 (n = 12) due to the unsustainable level of attrition following this stage. 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). Combining the treatment conditions was considered 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. The overall meta-analysis did not demonstrate a significant effect of active stimulation (SMD -0.18, 95% CI -0.46 to 0.09, P = 0.19) (Analysis 3.1), but heterogeneity was significant (I2 = 49%, P = 0.02). Subgrouping studies by multiple or single dose did not demonstrate a significant subgroup difference (test for subgroup differences P = 0.89) and decreased heterogeneity in the single-dose subgroup (I2 = 0%, P = 0.53) but increased heterogeneity in the multiple-dose subgroup (I2 = 62%, P < 0.01). Analysis restricted to comparisons of active motor cortex stimulation (single and multiple-dose studies (n = 183, Analysis 3.2) reduced heterogeneity substantially (I2 = 33%, P = 0.13) but did not demonstrate a statistically significant effect (SMD -0.23, 95% CI -0.48 to 0.01, P = 0.06). This lack of effect was consistent for the subgroups of single-dose studies (SMD -0.18, 95% CI -0.41 to 0.05, P = 0.13) and multiple-dose studies (SMD -0.35, 95% CI -0.79 to 0.09, P = 0.12).

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 3.3; Analysis 3.4; Analysis 3.5; Analysis 3.6). When the correlation was decreased the analysis including both single and multiple-dose studies of motor cortex tDCS stimulation only approached, but did not reach, statistical significance (SMD -0.24, 95% CI -0.48 to 0.00, P = 0.05).

Small study effects/publication bias

We investigated small study effects using Egger's test. The results are not suggestive of a significant influence of small study effects.

tDCS for medium-term pain relief (1 to < 6 weeks post-treatment)

Five studies provided adequate data for this analysis (Antal 2010; Fenton 2009; Mori 2010; Soler 2010, Wrigley 2014, pooled n = 87) (Analysis 3.7). There was no significant heterogeneity (I2 = 31%, P = 0.21) and the pooled effect was not statistically significant (SMD -0.20, 95% CI -0.63 to 0.24, P = 0.37).

Reduced impedance non-invasive cortical electrostimulation (RINCE) for short-term pain relief

The one study that investigated RINCE stimulation demonstrated a positive effect on pain (mean difference (0 to 10 pain scale) -1.41, 95% CI -2.48 to -0.34, P < 0.01) (Analysis 4.1; Hargrove 2012).

Secondary outcomes: disability and quality of life

rTMS for disability/pain interference: short-term follow-up

Five studies provided data on disability/pain interference at short-term follow-up (Avery 2013; Kang 2009; Mhalla 2011; Passard 2007; Short 2011). Pooling of these studies (Analysis 1.18; n = 119) demonstrated no significant effect on pain interference (SMD -0.29, 95% CI -0.87 to 0.29, P = 0.33) with substantial heterogeneity (I2 = 71%, P < 0.01). All of these studies delivered multiple doses of high-frequency stimulation. Two studies stimulated the DLPFC (Avery 2013; Short 2011) and three stimulated the motor cortex (Kang 2009; Mhalla 2011; Passard 2007). Subgrouping studies by stimulation site had no impact on heterogeneity.

rTMS for disability/pain interference: medium-term follow-up (1 to < 6 weeks post-treatment)

Four studies provided data on disability/pain interference at medium-term follow-up (Avery 2013; Kang 2009; Mhalla 2011; Passard 2007). Pooling of these studies (Analysis 1.19; n = 99) demonstrated no significant effect (SMD -0.37, 95% CI -1.07 to 0.33, P = 0.3) with significant heterogeneity (I2 = 78%, P < 0.01). All studies delivered multiple sessions of high-frequency stimulation. Of these, one study stimulated the DLPFC (Avery 2013) and the remaining studies stimulated the motor cortex (Kang 2009; Mhalla 2011; Passard 2007). Removing the study of Avery 2013 did not decrease heterogeneity (I2 = 85%, P < 0.01).

rTMS for disability/pain interference: long-term follow-up (≥ 6 weeks post-treatment)

Three studies provided data on disability/pain interference at long-term follow-up (Avery 2013; Kang 2009; Passard 2007). Pooling of these studies demonstrated no significant effect (SMD -0.23, 95% CI -0.62 to 0.16, P = 0.24) without significant heterogeneity (I2 = 15%, P = 0.31) (Analysis 1.20).

rTMS for quality of life: short-term follow-up

Three studies provided data on quality of life at short-term follow-up (Mhalla 2011; Passard 2007; Short 2011). We were unable to include data from Tzabazis 2013, as the size of the treatment groups was not clear from the study report. All studies used the Fibromyalgia Impact Questionnaire so we were able to use the mean difference as the measure of effect. Pooling data from these studies (Analysis 1.21; n = 80) demonstrated a significant effect (mean difference (MD) -10.38, 95% CI -14.89 to -5.87, P < 0.01) with no heterogeneity (I2 = 0%, P = 0.99). Expressed as a percentage of the mean post-stimulation score in the sham groups from the included studies (58.3) this equates to a 18% (95% CI 10% to 26%) reduction in fibromyalgia impact.

rTMS for quality of life: medium-term follow-up (1 to < 6 weeks post-treatment)

The same three studies provided data on quality of life at medium-term follow-up (Mhalla 2011; Passard 2007; Short 2011). All studies used the Fibromyalgia Impact Questionnaire so we were able to use the mean difference as the measure of effect. Pooling data from these studies (Analysis 1.22; n = 80) demonstrated a significant effect (MD -11.49, 95% CI -17.04 to -5.95, P < 0.01) with no heterogeneity (I2 = 0%, P = 0.63). Expressed as a percentage of the mean post-stimulation score in the sham groups from the included studies (57.8) this equates to a 20% (95% CI 10% to 29%) reduction in fibromyalgia impact.

rTMS for quality of life: long-term follow-up (≥ 6 weeks post-treatment)

Data were only available from one study (Passard 2007, n = 30) for quality of life at long-term follow-up. This study demonstrated no significant effect (MD -0.61, 95% CI -1.34 to 0.12) (Analysis 1.23).

CES for quality of life: short-term follow-up

Two studies provided quality of life data for this analysis (Tan 2011; Taylor 2013). One study used the physical component score of the SF-12 and the other used the Fibromyalgia Impact Questionnaire. However, one study demonstrated a baseline imbalance of the SF-12 that exceeded in size any pre-post stimulation change (Tan 2011). Therefore we considered it inappropriate to enter this into a meta-analysis. The study by Taylor 2013 (n = 36) demonstrated a positive effect on this outcome (SMD -1.25, 95% CI -1.98 to -0.53) (Analysis 2.3).

tDCS for quality of life

Two studies provided adequate data for this analysis (Mori 2010; Riberto 2011, pooled n = 32). Of these, Mori 2010 used the Multiple Sclerosis Quality of Life 54 scale (MS-QoL-54) and Riberto 2011 used the SF-36 (total score). The pooled effect was significant (SMD 0.88, 95% CI 0.24 to 1.53, P < 0.01) with no heterogeneity (I2 = 0%, P = 0.41) (Analysis 3.9). At medium-term follow-up only Mori 2010 (n = 19) provided data and the effect of tDCS on quality of life was not significant.

RINCE for quality of life

The one study of RINCE therapy demonstrated no significant effect on quality of life (Fibromyalgia Impact Questionnaire) (Analysis 4.2) .

Adverse events

rTMS
Minor

Of the rTMS studies that reported adverse events, nine studies reported none (André-Obadia 2006; André-Obadia 2008; Fregni 2005; Hirayama 2006; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Onesti 2013; Saitoh 2007). Carretero 2009 reported neck pain or headache symptoms in six out of 14 participants in the active stimulation group compared with two out of 12 in the sham group. One participant in the active stimulation group reported worsening depression and four participants in the sham group reported symptoms of nausea and tiredness. Passard 2007 reported incidence of headaches (four out of 15 participants in the active group versus five out of 15 in the sham group), feelings of nausea (one participant in the active group), tinnitus (two participants in the sham group) and dizziness (one participant in the sham group). Rollnik 2002 reported that one participant experienced headache, but it is unclear in the report whether this was following active or sham stimulation. Avery 2013 reported a range of reported sensations including headache, pain at the stimulation site, muscle aches/fatigue, dizziness and insomnia, though there were no clear differences in the frequency of these events between the two groups. Mhalla 2011 reported that nine patients (five following active stimulation and four following sham stimulation) reported transient headache, and one participant reported transient dizziness after active stimulation. Picarelli 2010 found six reports of headache following active stimulation and four following sham stimulation, and two reports of neck pain following active stimulation with four reports following sham stimulation. Short 2011 reported that there were few side effects and Hosomi 2013 reported no difference between real and sham rTMS for minor adverse events. In the study by Fregni 2011, the incidence of headache and neck pain was higher in the active stimulation group than in the sham group. Forty-one participants reported headache after active stimulation compared to 19 after sham and 18 participants reported neck pain after active stimulation compared with three after sham. Following four-coil rTMS, Tzabazis 2013 reported no serious adverse events. The incidence of scalp pain, headache, lightheadedness, back pain, otalgia, hot flashes and pruritis was more commonly reported following sham stimulation than active stimulation. Neck pain (14% of participants following active stimulation versus no participants following sham) and nausea (19% of participants following active stimulation verus 11% following sham) were more common with active stimulation.

Major

Both Lee 2012 and Picarelli 2010 reported one incidence of seizure following high-frequency active stimulation.

CES

Four studies of CES reported the incidence of adverse events (Capel 2003; Gabis 2003; Rintala 2010; Tan 2011). In these studies no adverse events were reported. Rintala 2010 reported no major adverse events. In the active stimulation group they reported incidences of pulsing, tingling, tickling in ears (three participants), tender ears (one participant) and pins and needles feeling near bladder (one participant). In the sham group they reported drowsiness (one participant), warm ears (one participant) and headache after one session (one participant). Tan 2011 reported only mild adverse events with a total of 41 reports in the active stimulation group and 56 in the sham group. Of note, sensations of ear pulse/sting/itch/electric sensations or ear clip tightness seemed more common in active group than the sham group (12 versus six incidents). Through correspondence with the authors of Taylor 2013, we confirmed that there were no adverse events reported.

tDCS

Most studies of tDCS reported the incidence of adverse events. Of these, four studies reported none (Fregni 2006a; Mendonca 2011; Mori 2010; Portilla 2013). Boggio 2009 reported that one participant experienced headache with active stimulation. The study by Fenton 2009 reported three cases of headache, two of neck ache, one of scalp pain and five of a burning sensation over the scalp in the active stimulation group versus one case of headache in the sham stimulation group. Fregni 2006b reported one case of sleepiness and one of headache in response to active stimulation of the DLPFC, three cases of sleepiness and three of headache with active stimulation of M1 and one case of sleepiness and two of headache in response to sham stimulation. Soler 2010 recorded three reports of headache, all following active stimulation. Villamar 2013 reported that the vast majority of participants reported a mild to moderate tingling or itching sensation during both active and sham stimulation that faded over a few minutes but no other adverse effects. Valle 2009 reported "minor and uncommon" side effects, such as skin redness and tingling, which where equally distributed between active and sham stimulation. Antal 2010 recorded reports of tingling, moderate fatigue, tiredness, headache and sleep disturbances, though there were no large differences in the frequency of these between the active and sham stimulation groups. Wrigley 2014 reported only "mild to moderate" side effects with no significant difference between active and sham over the 24-hour post-stimulation period. These included sleepiness (70% of participants following active, 60% following sham), fatigue, inertia (60% of participants following active, 30% following sham), lightheadedness (20% of participants during active and sham treatment) and headache (10% of participants during active and sham treatment).

Four studies monitored for possible effects on cognitive function using the Mini Mental State Examination questionnaire (Boggio 2009; Fregni 2006a; Fregni 2006b; Valle 2009) and three of these also used a battery of cognitive tests including the digit-span memory test and the Stroop word-colour test (Boggio 2009; Fregni 2006a; Fregni 2006b) and simple reaction time tasks (Fregni 2006a). No studies demonstrated any negative influence of stimulation on these outcomes. No studies of tDCS reported severe or lasting side effects. Jensen 2013 and Riberto 2011 did not consider adverse events in their study reports.

RINCE

Hargrove 2012 reported a low incidence of side effects from RINCE stimulation including short-lived headache (two participants in the active group, one in the sham group), eye movement/flutter during stimulation (one active, one sham), restlessness (one active and none sham) and nausea (one active and none sham).

GRADE judgements

GRADE judgements for all core comparisons of the primary outcome can be found in Table 4. For all comparisons the highest rating of the quality of evidence was 'low'.

Table 4. GRADE judgements for core comparisons
  1. 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

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

Discussion

Summary of main results

This update has included a substantial number of new studies. Despite this, for rTMS and CES our findings have not altered substantially from the previous version of this review. However, for tDCS the inclusion of these new data have altered the outcome of our analyses, which no longer suggest a statistically significant effect of tDCS over sham. We recommend that previous readers should re-read this update.

Repetitive transcranial magnetic stimulation (rTMS) for chronic pain

Meta-analysis of all rTMS studies in chronic pain demonstrated significant 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 significance. 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 pre-frontal 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 suggest a significant effect of rTMS in the medium term. The limited evidence at long-term follow-up consistently suggests no effect of rTMS.

Cranial electrotherapy stimulation (CES) for chronic pain

The evidence from trials where it is possible to extract data is not suggestive of a significant 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.

Transcranial direct current stimulation (tDCS) for chronic pain

Meta-analysis of all tDCS studies in chronic pain demonstrated significant heterogeneity. Predetermined subgroup analyses did not demonstrate a statistically significant effect of tDCS on chronic pain despite many of the studies included in this review being at unclear risk of bias for participant and assessor blinding. The evidence available at medium-term follow-up does not suggest a significant effect of tDCS.

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

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

Adverse effects

rTMS, CES, tDCS 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.

Secondary outcome measures

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

Limited evidence suggests that rTMS and tDCS have positive effects on quality of life. This finding in rTMS is difficult to interpret as it arises from multiple-dose studies which together do not demonstrate an effect on pain intensity levels. Any hypothesised effects of non-invasive brain stimulation techniques on quality of life would presumably be through the reduction of pain. Given this inconsistency between outcomes for rTMS and the limited amount of data available to these analyses, we would recommend that this finding should be interpreted with caution.

Overall completeness and applicability of evidence

For rTMS we were unable to include data from five full published studies (Fregni 2005; Fregni 2011, Onesti 2013; Picarelli 2010; Tzabazis 2013, combined n = 86). In addition, we identified six studies of rTMS published in abstract format for which we have not been able to acquire full study reports. A conservative estimate of the combined number of participants that those studies might add, assuming that some reports refer to the same study, is 243.

We were unable to extract the relevant data from four studies of CES (Capel 2003; Cork 2004; Katsnelson 2004; Lichtbroun 2001). This may have impacted upon the results of our meta-analysis although one of those studies would have been excluded from the meta-analysis as we judged it as being at risk of bias on criteria other than selective outcome reporting (Katsnelson 2004).

We were also unable to extract the relevant data from two studies of tDCS (Mendonca 2011; Valle 2009), and these data were not made available upon request to the study authors. These data would have significantly contributed to the power of the meta-analysis by the introduction of a further 71 participants and may have altered our conclusions. In addition, we identified three studies of tDCS (Acler 2012; Albu 2011; Knotkova 2011, combined n = 87) published in abstract format, one of which is currently being re-analysed by the study authors and as such the data were not available (Knotkova 2011), and for two of which we were unsuccessful in our efforts to contact the authors (Acler 2012; Albu 2011).

For both rTMS and tDCS there are a number of ongoing studies identified through the trials registers searches. Of these, two registered trials that were identified in the original version of this review have not yet been published and our attempts to contact the authors were unsuccessful (NCT00947622; NCT00815932). We hope that future updates of this review will include the aforementioned data.

Quality of the evidence

Using the GRADE criteria we judged the quality of evidence for all comparisons as low or very low-quality. In large part this is due to issues of blinding and of precision and to a degree it reflects the early stage of research development that these technique are at. The majority of studies of rTMS were at unclear risk of bias. The predominant reason for this was the use of sub-optimal sham controls that were unable to control for all possible sensory cues associated with active stimulation. A number of studies did not clearly report blinding of assessors and sensitivity analysis excluding those studies reduced both heterogeneity and the pooled effect size. It could be reasonably argued that the presence of a subgroup of single-dose studies of high-frequency stimulation specific to the motor cortex that does demonstrate superiority over sham with acceptable levels of heterogeneity is evidence for a specific clinical effect of rTMS. It should be considered, however, that high-frequency rTMS is associated with more intense sensory and auditory cues that might plausibly elicit a larger placebo response, and many of the included studies were unable to control conclusively for these factors. The pooled effect size for the high-frequency studies of motor cortex rTMS does not meet our predetermined threshold for clinical significance. This estimate is based solely on studies that delivered a single dose of rTMS. It is feasible that a single dose may be insufficient to induce clinically meaningful improvement. These single-dose studies included in the analysis are best characterised as proof of principle studies which sought to test whether rTMS could modulate pain, rather than full-scale clinical studies with the aim of demonstrating clinical utility. However the combined evidence from studies of rTMS that delivered multiple doses (excluding studies judged as being at high risk of bias), while demonstrating substantial heterogeneity, does not indicate a significant effect on pain.

Similarly, we judged no study of tDCS as having a low risk of bias on all criteria. While there is evidence that the sham control used in tDCS does achieve effective blinding of participants at stimulation intensities of 1 mA (Gandiga 2006), evidence has emerged since the last version of this review which indicates that at 1.5 mA the sensory profile of stimulation differs between active and sham stimulation (Kessler 2013), and at 2 mA participant and assessor blinding may be compromised (O'Connell 2012). Meta-epidemiological evidence demonstrates that incomplete blinding in controlled trials that measure subjective outcomes may exaggerate the observed effect size by around 25% (Wood 2008). It is therefore reasonable to expect that incomplete blinding may have exaggerated the effect sizes seen in the current analyses of rTMS and tDCS. The non-significant trend towards a positive effect of CES and tDCS over sham should be considered in this light.

No study of CES could be judged as having a low risk of bias across all criteria. Despite this, no study from which data were available demonstrated a clear advantage of active over sham stimulation. There was substantial variation in the stimulation parameters used between studies. Notably three studies utilised an "active placebo" control in which stimulating current was delivered but at much lower intensities (Gabis 2003; Gabis 2009; Katsnelson 2004). These intensities well exceed those employed in the active stimulation condition of other studies of CES devices and as such it could be hypothesised that they might induce a therapeutic effect themselves. This could possibly disadvantage the active stimulation group in these studies. However, the data available in the meta-analysis do not suggest such a trend and statistical heterogeneity between studies entered into the analysis was low.

All of the included studies may be considered to be small in terms of sample size and we reflected this in our 'Risk of bias' assessment. The prevalence of small studies increases the risk of publication or small study bias, wherein there is a propensity for negative studies to not reach full publication. There is evidence that this might lead to an overly positive picture for some interventions (Dechartres 2013; Moore 2012; Nüesch 2010). In a review of meta-analyses, Dechartres 2013 demonstrated that trials with fewer than 50 participants, which reflects the majority of studies included in this review, returned effect estimates that were on average 48% larger than the largest trials and 23% larger than estimates from studies with sample sizes of more than 50. Similarly, in a recent Cochrane review of amitriptyline neuropathic pain and fibromyalgia (Moore 2012), smaller studies were associated with substantially lower numbers needed to treat (NNTs) for treatment response than larger studies. In their recommendations for establishing best practice in chronic pain systematic reviews, the authors of Moore 2010 suggest that study size should be considered an important source of bias. It is therefore reasonable to consider that the evidence base for all non-invasive brain stimulation techniques is at risk of bias on the basis of sample size. We did not downgrade any of the GRADE judgements on the basis of publication bias as there was no direct evidence. However, it is accepted that existing approaches to detecting publication bias are unsatisfactory. To an extent our GRADE judgements reflect this risk through the assessment of imprecision and the limitations of included studies. It should be noted that even where a pooled estimate includes a large number of participants, if it is dominated by small studies, as are all comparisons in this review, then it is prone to small study effects.

Potential biases in the review process

There is substantial variation between the included studies of rTMS and tDCS. Studies varied in terms of the clinical populations included, the stimulation parameters and location, the number of treatment sessions delivered and in the length of follow-up employed. This heterogeneity is reflected in the I2 statistic for the overall rTMS and tDCS meta-analyses. However, pre-planned subgroup investigation significantly reduced this heterogeneity.

The majority of rTMS and tDCS studies specifically recruited participants whose symptoms were resistant to current clinical management and most rTMS studies specifically recruited participants with neuropathic pain. As such it is important to recognise that this analysis in large part reflects the efficacy of rTMS and tDCS for refractory chronic pain conditions and may not accurately reflect their efficacy across all chronic pain conditions.

One study included in the in the analysis of rTMS studies demonstrated a difference in pain levels between the two groups at baseline that exceeded the size of the difference observed at follow-up (Defrin 2007). Specifically, the group that received sham stimulation reported less pain at baseline than those in the active stimulation group. The use in the current analysis of a between-groups rather than a change from baseline comparison is likely to have affected the results although the study contributes only 1.5% weight to the overall meta-analysis and the study itself reported no difference in the degree of pain reduction between the active and sham stimulation groups.

The method used to back-transform the pooled standardised mean difference (SMD) to a visual analogue scale and subsequent calculation of the effect as a percentage improvement rests upon the assumption that the standard deviation and the pain levels used are representative of the wider body of evidence and should be considered an estimate at best. Representing average change scores on continuous scales is problematic in chronic pain studies since response to treatments has been found to display a bimodal distribution (Moore 2013). More plainly, some participants demonstrate a substantial response to pain therapies while many demonstrate little or no response with few individual participants demonstrating a response similar to the average. As a consequence the meaning of the average effect sizes seen in this review is difficult to interpret. This had led to the recommendation that chronic pain trials employ responder analysis based on predetermined cut-offs for a clinically important response (≥ 30% reduction in pain for a moderate benefit, ≥ 50% reduction for a substantial benefit) (Dworkin 2008; Moore 2010). Very few studies identified in this review presented the results of responder analyses and so this type of meta-analysis was not possible. However, where statistically significant effects were observed in this review they were small, which would indicate that if there is a subgroup of 'responders' to active stimulation who demonstrate moderate or substantial benefits it is likely to include a small number of participants.

Agreements and disagreements with other studies or reviews

The European Federation of Neurological Societies (EFNS) published guidelines on the use of neurostimulation therapy for chronic neuropathic pain in 2007 (Cruccu 2007), following a review of the existing literature. Using a narrative synthesis of the evidence they similarly concluded that there was moderate evidence (two randomised controlled trials) that high-frequency rTMS (≥ 5 Hz) of the motor cortex induces significant pain relief in central post-stroke pain and several other neuropathic conditions, but that the effect is modest and short-lived. They did not recommend its use as a sole clinical treatment but suggested that it might be considered in the treatment of short-lasting pain.

Leung 2009 performed a meta-analysis of individual patient data from studies of motor cortex rTMS for neuropathic pain conditions. Whilst the analysis was restricted to studies that clearly reported the neuroanatomical origin of participants' pain (and therefore excluded some of the studies included in the current analysis) the overall analysis suggests a similar effect size of 13.7% improvement in pain (excluding the study of Khedr 2005). The authors also performed an analysis of the influence of the neuro-anatomical origins of pain on the effect size. They noted a trend suggestive of a larger treatment effect in central compared with peripheral neuropathic pain states although this did not reach statistical significance. While the data in the current review were not considered sufficient to support a detailed subgroup analysis by neuro-anatomical origin of pain, the exclusion of studies that did not specifically investigate neuropathic pain did not significantly affect the overall analysis and the two multiple-dose studies of motor cortex rTMS for central neuropathic pain that were included failed to demonstrate superiority of active over sham stimulation (Defrin 2007; Kang 2009).

All but one of the included studies in the review by Leung 2009 delivered high-frequency (≥ 5 Hz) rTMS and no clear influence of frequency variations was observed within this group. The authors suggest that the number of doses delivered may be more crucial to the therapeutic response than the frequency (within the high-frequency group), based on the larger therapeutic response seen in the study of Khedr 2005 that was excluded from the current analysis. This review preceded the studies by Defrin 2007 and Kang 2009 that did not demonstrate superiority of active over sham stimulation. While there are limited data to test this proposition robustly the result of our subgroup analysis of studies of high-frequency motor cortex rTMS does not suggest a benefit of active stimulation over sham.

Lima and Fregni undertook a systematic review and meta-analysis of motor cortex stimulation for chronic pain (Lima 2008). They pooled data from rTMS and tDCS studies. While the report states that data were collected on mean between-group pain scores they are not presented. The authors present the pooled data for the number of responders to treatment across studies. They conclude that the number of responders is significantly higher following active stimulation compared with sham (risk ratio 2.64, 95% confidence interval (CI) 1.63 to 4.30). In their analysis the threshold for treatment response is defined as a global response according to each study's own definition and as such it is difficult to interpret and may not be well standardised. They note a greater response to multiple doses of stimulation, an observation that is not reliably reflected in the current review. Additionally they included the study of Khedr 2005 (excluded from this review due to high risk of bias) and Canavero 2002 (excluded on title and abstract as it is not a randomised or quasi-randomised study). The current review also includes a number of motor cortex rTMS studies published since that review (André-Obadia 2008; Defrin 2007; Kang 2009; Lefaucheur 2006; Lefaucheur 2008; Passard 2007; Saitoh 2007). Neither the review of Leung 2009 nor Lima 2008 applied a formal quality or 'Risk of bias' assessment. While the current review also suggests a small, significant short-term benefit of high-frequency motor cortex rTMS in the treatment of chronic pain the effect is small, appears short-term and although the pooled estimate approaches the threshold of minimal clinical significance it is possible that it might be inflated by methodological biases in the included studies.

A recent systematic review of tDCS and rTMS for the treatment of fibromyalgia concluded that the evidence demonstrated reductions in pain similar to US Food and Drug Administration (FDA) approved pharmaceuticals for this condition and recommended that rTMS or tDCS should be considered, particularly where other therapies have failed (Marlow 2013). This review included randomised and non-randomised studies, did not undertake meta-analysis and took a "vote-counting" approach to identifying significant effects based primarily on each included study's report of statistical testing. While our analysis did not specifically investigate a subgroup of studies in fibromyalgia participants, we would suggest that the methodology chosen by Marlow 2013 does not offer the most rigorous approach to establishing effect size, particularly in light of the inconsistency seen among the included studies of that review. Indeed given the degree of uncertainty that remains regarding the efficacy these interventions it could be suggested that the application of tDCS or rTMS for this or other conditions would ideally be limited to the clinical research situation.

Luedtke 2012 systematically reviewed studies of tDCS for chronic pain and experimental pain. Unlike our review they excluded the study by Fenton 2009, as it was judged to be at high risk of bias on the grounds of unclear randomisation procedure and due to a lack of clarity of participant withdrawal, and Boggio 2009 due to the level of drop-out. The results of their meta-analysis are broadly consistent with those presented in the last iteration of this review and similarly conclude that the evidence is insufficient to allow definite conclusions but that there is low-level evidence that tDCS may be effective for chronic pain. However, the inclusion of new studies in this update has rendered these analyses non-significant. Moreno-Duarte 2013 recently reviewed the evidence for a variety of electrical and magnetic neural stimulation techniques for the treatment for chronic pain following spinal cord injury, including rTMS, tDCS and CES, including both randomised and non-randomised studies. They found that the results varied across studies, though trials of tDCS were consistently positive, and concluded that further research is needed and that there is a need to develop methods to decrease the variability of treatment response to these interventions. However, it is worth noting that this review did not include the recent negative study of tDCS for post-spinal cord injury pain by Wrigley 2014, and also that variability in observed treatment "responses" may simply represent the play of chance rather than evidence of a specific group of responders.

Kirsch 2000 reviewed studies of CES in the management of chronic pain and concluded in favour of its use. The review did not report any formalised search strategy, inclusion criteria or quality assessment and discussed a number of unpublished studies that remain unpublished at the time of the current review. Using a more systematic methodology and including papers published since that review, we found that the data that were available for meta-analysis do not suggest a statistically or clinically important benefit of active CES over sham. Our analysis included 270 participants. While this is not particularly large it does suggest that if there is an effect of CES on chronic pain it is either small, or that the number of responders is likely to be small.

Authors' conclusions

Implications for practice

Low or very low-quality evidence suggests that low-frequency repetitive transcranial magnetic stimulation (rTMS), or rTMS applied to the prefrontal cortex, are not effective for the treatment of chronic pain. Subgroup analysis suggests that single doses of high-frequency rTMS of the motor cortex have small short-term effects on chronic pain that do not meet our threshold of minimum clinical importance (low-quality evidence) and may be exaggerated by the dominance of small studies and other sources of bias. The pooled evidence from multiple-dose studies of high-frequency rTMS is heterogenous but does not demonstrate a significant effect (very low-quality evidence). As such it is not currently clear whether rTMS represents a useful clinical tool. Very low-quality evidence suggests that transcranial direct current stimulation (tDCS) is not effective for treating chronic pain and low-quality evidence suggests that tDCS applied to the motor cortex is not effective. Low-quality evidence suggests that cranial electrotherapy stimulation (CES) is not effective. Due to various biases and limitations within the evidence base it is likely that future studies may have a substantial impact upon the estimates of effects presented. Due to this uncertainty, any clinical application of non-invasive brain stimulation techniques would be most appropriate within a clinical research setting rather than in routine clinical care.

Implications for research

The existing evidence across all forms of non-invasive brain stimulation is dominated by small studies with unclear risk of bias and there is a need for larger, rigorously controlled trials. All studies of non-invasive brain stimulation techniques should measure, record and clearly report adverse events from both active and sham stimulation. Future trials should also consider the IMMPACT recommendations for the design of trials in chronic pain (Dworkin 2008; Dworkin 2009; Dworkin 2010; Turk 2008), to ensure that outcomes, thresholds for clinical importance and study designs are optimal, and should endeavour to ensure that published study reports are compliant with the CONSORT statement (Schulz 2010).

In rTMS the evidence base is dominated by studies of intractable neuropathic pain and there is little evidence from which to draw conclusions regarding other types of chronic pain. Most of the included rTMS studies are affected by the use of sub-optimal sham conditions that may adversely impact upon blinding. Future rTMS research should consider employing recently developed sham coils that control for all of the sensory aspects of stimulation. Such coil systems should be robustly validated as reliable and valid sham controls. We have recently recommended that while there remains a case for exploring alternative stimulation targets and parameters, there is a more urgent need to examine robustly the more promising findings within the existing data through large, rigorous, adequately blinded trials that deliver a reasonable dose and investigate effects over a meaningful timescale (O'Connell 2011). A data-led approach suggests that high-frequency stimulation of the motor cortex is a logical focus for this effort. Until a body of this type of research is generated there will be continued uncertainty as to whether rTMS has genuine clinical utility for chronic pain.

Future studies of tDCS should give consideration to the integrity of participant blinding, particularly when utilising stimulation intensities that exceed 1 mA and should possess adequate sample sizes to reduce uncertainty.

Acknowledgements

The authors would like to thank James Langridge of the Brunel University library for sharing his expertise in the use of electronic databases, Arturo Lawson, Ana Bela Nascimento, Andrea Wand, Pete and Maria Heine and Dr Evgeny Makarov for assistance with interpretation. We would like to extend particular thanks to the Cochrane Pain, Palliative and Supportive Care Group for their assistance throughout the review, in particular Anna Hobson and Joanne Abbott.

We would also like to thank the following authors for generously providing additional data for this review upon request: Dr David Avery, Dr Nathalie André-Obadia, Dr Andrea Antal, Dr Didier Bouhassira, Dr Ruth Defrin, Dr Bradford Fenton, Dr Felipe Fregni, Dr Linda Gabis/Dr Ranann Raz, Dr Jeffrey Hargrove, Dr Eman Khedr, Prof. Jean-Pascale Lefaucheur, Dr Francesco Mori, Dr Burkhard Pleger, Dr Marcelo Riberto, Prof. Jens Rollnik, Prof Youichi Saitoh and Ann Gillian Taylor.

Data and analyses

Download statistical data

Comparison 1. Repetitive transcranial magnetic stimulation (rTMS)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain: short-term follow-up21 Std. Mean Difference (Fixed, 95% CI)-0.20 [-0.26, -0.13]
1.1 Low-frequency ≤ 1 Hz6 Std. Mean Difference (Fixed, 95% CI)0.15 [-0.01, 0.31]
1.2 High-frequency ≥ 5 Hz20 Std. Mean Difference (Fixed, 95% CI)-0.27 [-0.35, -0.20]
2 Pain: short-term follow-up, subgroup analysis: multiple-dose vs single-dose studies21 Std. Mean Difference (Random, 95% CI)-0.19 [-0.33, -0.06]
2.1 Single-dose studies12 Std. Mean Difference (Random, 95% CI)-0.23 [-0.37, -0.09]
2.2 Multiple-dose studies9 Std. Mean Difference (Random, 95% CI)-0.12 [-0.47, 0.23]
3 Pain: short-term follow-up, subgroup analysis, neuropathic pain participants only14 Std. Mean Difference (Fixed, 95% CI)-0.20 [-0.27, -0.12]
3.1 Low-frequency ≤ 1 Hz5 Std. Mean Difference (Fixed, 95% CI)0.15 [-0.02, 0.32]
3.2 High-frequency ≥ 5 Hz14 Std. Mean Difference (Fixed, 95% CI)-0.27 [-0.35, -0.19]
4 Pain: short-term follow-up, subgroup analysis, non-neuropathic pain participants only6 Std. Mean Difference (Fixed, 95% CI)-0.19 [-0.44, 0.05]
4.1 Low-frequency ≤ 1 Hz1 Std. Mean Difference (Fixed, 95% CI)0.16 [-0.29, 0.61]
4.2 High-frequency ≥ 5 Hz5 Std. 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 excluded17 Std. Mean Difference (Random, 95% CI)-0.32 [-0.46, -0.17]
5.1 Single-dose studies12 Std. Mean Difference (Random, 95% CI)-0.39 [-0.51, -0.27]
5.2 Multiple-dose studies5 Std. Mean Difference (Random, 95% CI)-0.07 [-0.41, 0.26]
6 Sensitivity analysis - imputed correlation coefficient increased. Pain: short-term follow-up23 Std. Mean Difference (Random, 95% CI)-0.21 [-0.34, -0.08]
6.1 Low-frequency ≤ 1 Hz7 Std. Mean Difference (Random, 95% CI)0.15 [0.01, 0.29]
6.2 High-frequency ≥ 5 Hz22 Std. Mean Difference (Random, 95% CI)-0.30 [-0.44, -0.16]
7 Sensitivity analysis - imputed correlation coefficient decreased. Pain: short-term follow-up22 Std. Mean Difference (Random, 95% CI)-0.20 [-0.34, -0.06]
7.1 Low-frequency ≤ 1 Hz6 Std. Mean Difference (Random, 95% CI)0.17 [-0.03, 0.37]
7.2 High-frequency ≥ 5 Hz21 Std. 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 excluded17 Std. Mean Difference (Random, 95% CI)-0.33 [-0.47, -0.20]
8.1 Single-dose studies12 Std. Mean Difference (Random, 95% CI)-0.41 [-0.53, -0.29]
8.2 Multiple-dose studies5 Std. 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 excluded17 Std. Mean Difference (Random, 95% CI)-0.31 [-0.46, -0.17]
9.1 Single-dose studies12 Std. Mean Difference (Random, 95% CI)-0.38 [-0.49, -0.27]
9.2 Multiple-dose studies5 Std. 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-up25 Std. Mean Difference (Fixed, 95% CI)-0.23 [-0.31, -0.16]
10.1 Low-frequency ≤ 1 Hz9 Std. Mean Difference (Fixed, 95% CI)0.09 [-0.05, 0.24]
10.2 High-frequency ≥ 5 Hz23 Std. 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 excluded21 Std. Mean Difference (Random, 95% CI)-0.39 [-0.56, -0.23]
11.1 Single-dose studies14 Std. Mean Difference (Random, 95% CI)-0.36 [-0.48, -0.24]
11.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.50 [-0.99, -0.01]
12 Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only4 Std. Mean Difference (Random, 95% CI)-0.47 [-1.48, 0.54]
12.1 Multiple-dose studies4 Std. 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 only5 Std. Mean Difference (Random, 95% CI)-0.48 [-1.32, 0.37]
13.1 Multiple-dose studies5 Std. Mean Difference (Random, 95% CI)-0.48 [-1.32, 0.37]
14 Pain: medium-term follow-up7 Std. Mean Difference (Random, 95% CI)-0.18 [-0.43, 0.06]
14.1 Low-frequency ≤ 1 Hz1 Std. Mean Difference (Random, 95% CI)0.36 [-0.41, 1.13]
14.2 High-frequency ≥ 5 Hz6 Std. 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-up10 Std. Mean Difference (Random, 95% CI)-0.43 [-0.76, -0.10]
15.1 Low-frequency ≤ 1 Hz2 Std. Mean Difference (Random, 95% CI)-0.08 [-1.26, 1.10]
15.2 High-frequency ≥ 5 Hz9 Std. Mean Difference (Random, 95% CI)-0.48 [-0.83, -0.13]
16 Pain: long-term follow-up3 Std. 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-up4 Std. Mean Difference (Random, 95% CI)-0.46 [-1.10, 0.17]
18 Disability/pain interference: short-term follow-up5 Std. Mean Difference (Random, 95% CI)-0.29 [-0.87, 0.29]
19 Disability/pain interference: medium-term follow-up4 Std. Mean Difference (Random, 95% CI)-0.37 [-1.07, 0.33]
20 Disability/pain interference: long-term follow-up3 Std. 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-up1 Std. Mean Difference (Random, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 1 Pain: short-term follow-up.

Analysis 1.2.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 2 Pain: short-term follow-up, subgroup analysis: multiple-dose vs single-dose studies.

Analysis 1.3.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 3 Pain: short-term follow-up, subgroup analysis, neuropathic pain participants only.

Analysis 1.4.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 4 Pain: short-term follow-up, subgroup analysis, non-neuropathic pain participants only.

Analysis 1.5.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded.

Analysis 1.6.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 6 Sensitivity analysis - imputed correlation coefficient increased. Pain: short-term follow-up.

Analysis 1.7.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 7 Sensitivity analysis - imputed correlation coefficient decreased. Pain: short-term follow-up.

Analysis 1.8.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 8 Sensitivity analysis - imputed correlation increased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded.

Analysis 1.9.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 9 Sensitivity analysis - imputed correlation decreased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded.

Analysis 1.10.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 10 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up.

Analysis 1.11.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 11 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded.

Analysis 1.12.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 12 Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only.

Analysis 1.13.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 13 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only.

Analysis 1.14.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 14 Pain: medium-term follow-up.

Analysis 1.15.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 15 Sensitivity analysis - inclusion of high risk of bias studies. Pain: medium-term follow-up.

Analysis 1.16.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 16 Pain: long-term follow-up.

Analysis 1.17.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 17 Sensitivity analysis - inclusion of high risk of bias studies. Pain: long-term follow-up.

Analysis 1.18.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 18 Disability/pain interference: short-term follow-up.

Analysis 1.19.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 19 Disability/pain interference: medium-term follow-up.

Analysis 1.20.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 20 Disability/pain interference: long-term follow-up.

Analysis 1.21.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 21 Quality of life: short-term follow-up (Fibromyalgia Impact Questionnaire).

Analysis 1.22.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 22 Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire).

Analysis 1.23.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 23 Quality of life: long-term follow-up.

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 interference1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3 Quality of life1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
Analysis 2.1.

Comparison 2 Cranial electrotherapy stimulation (CES), Outcome 1 Pain: short-term follow-up.

Analysis 2.2.

Comparison 2 Cranial electrotherapy stimulation (CES), Outcome 2 Disability/function/pain interference.

Analysis 2.3.

Comparison 2 Cranial electrotherapy stimulation (CES), Outcome 3 Quality of life.

Comparison 3. Transcranial direct current stimulation (tDCS)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain: short-term follow-up11 Std. Mean Difference (Random, 95% CI)-0.18 [-0.46, 0.09]
1.1 Single-dose studies3 Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]
1.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.22 [-0.69, 0.25]
2 Pain: short-term follow-up, subgroup analysis: motor cortex studies only11 Std. Mean Difference (Random, 95% CI)-0.23 [-0.48, 0.01]
2.1 Single-dose studies3 Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]
2.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.35 [-0.79, 0.09]
3 Pain: short-term sensitivity analysis: correlation increased11 Std. Mean Difference (Random, 95% CI)-0.20 [-0.47, 0.06]
4 Pain: short-term sensitivity analysis: correlation decreased11 Std. 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 increased11 Std. Mean Difference (Random, 95% CI)-0.23 [-0.48, 0.02]
5.1 Single-dose studies3 Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]
5.2 Multiple-dose studies8 Std. 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 decreased11 Std. Mean Difference (Random, 95% CI)-0.24 [-0.48, -0.00]
6.1 Single-dose studies3 Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]
6.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.36 [-0.79, 0.07]
7 Pain: medium-term follow-up5 Std. Mean Difference (Random, 95% CI)-0.20 [-0.63, 0.24]
8 Disability (pain interference): short-term follow-up1 Mean 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-up1 Std. Mean Difference (IV, Random, 95% CI)Totals not selected
11 Pain: short-term follow-up, subgroup analysis: motor cortex studies only11 Std. Mean Difference (Random, 95% CI)-0.26 [-0.49, -0.03]
11.1 Single-dose studies3 Std. Mean Difference (Random, 95% CI)-0.18 [-0.41, 0.05]
11.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.38 [-0.80, 0.03]
Analysis 3.1.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 1 Pain: short-term follow-up.

Analysis 3.2.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 2 Pain: short-term follow-up, subgroup analysis: motor cortex studies only.

Analysis 3.3.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 3 Pain: short-term sensitivity analysis: correlation increased.

Analysis 3.4.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 4 Pain: short-term sensitivity analysis: correlation decreased.

Analysis 3.5.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation increased.

Analysis 3.6.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 6 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation decreased.

Analysis 3.7.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 7 Pain: medium-term follow-up.

Analysis 3.8.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 8 Disability (pain interference): short-term follow-up.

Analysis 3.9.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 9 Quality of life: short-term follow-up.

Analysis 3.10.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 10 Quality of life: medium-term follow-up.

Analysis 3.11.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 11 Pain: short-term follow-up, subgroup analysis: motor cortex studies only.

Comparison 4. Reduced impedance non-invasive cortical electrostimulation (RINCE)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain: short-term follow-up1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2 Fibromyalgia Impact Questionnaire total score1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
Analysis 4.1.

Comparison 4 Reduced impedance non-invasive cortical electrostimulation (RINCE), Outcome 1 Pain: short-term follow-up.

Analysis 4.2.

Comparison 4 Reduced impedance non-invasive cortical electrostimulation (RINCE), Outcome 2 Fibromyalgia Impact Questionnaire total score.

Appendices

Appendix 1. Main database search strategies for current update

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

Appendix 2. Trials register search results for current update

RegisterDate of searchSearch termsNumber of recordsNumber of relevant records
NRR archive7 February 2013(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 or sciatica or back-ache or back*ache or lumbago or fibromyalg* or trigem* 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) AND (brain* or cortex or cortical or transcranial* or cranial or magneti* or direct current or DC or electric or crani* or electrostim* or electrotherap* or electro-therap* or non-invasive or non*invasive or theta burst stimulat* or iTBS or Ctbs or transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy or electrosleep or electronarco*) al fields AND (2009 OR 2010 OR 2011 OR 2012 OR 2013) date started20
Clinical trials.gov7 February 2013

Field -  Interventional studies

 

CONDITION: 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 OR sciatica OR back-ache OR back*ache OR lumbago

 

INTERVENTION: brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS OR Ctbs

 

OUTCOME:  pain

01/01/2009 to 07/02/2013

adult

8910
Clinical trials.gov7 February 2013

Field -  Interventional studies

 

CONDITION: 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 OR sciatica OR back-ache OR back*ache OR lumbago

 

INTERVENTION: transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*

 

OUTCOME:  pain 

20
Clinical trials.gov7 February 2013

Field -  Interventional studies

 

CONDITION: fibromyalg* OR trigem* 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

 

INTERVENTION: brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS OR Ctbs

 

OUTCOME:  pain

 

 

2
Clinical trials.gov7 February 2013

 

Field -  Interventional studies

 

CONDITION: fibromyalg* OR trigem* 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

 

INTERVENTION: transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*

 

OUTCOME:  pain

0
HSRProj11 February 2013((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 or sciatica or back-ache or back*ache or lumbago or fibromyalg* or trigem* 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) AND (brain* or cortex or cortical or transcranial* or cranial or magneti* or direct current or DC or electric or crani* or electrostim* or electrotherap* or electro-therap* or non-invasive or non*invasive or theta burst stimulat* or iTBS or Ctbs or transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy or electrosleep or electronarco*))1520
Current controlled trials (excl clinicatrials.gov)11 February 2013(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (cranial electrotherapy OR electrosleep OR electronarco*)01
Current controlled trials (excl clinicatrials.gov)11 February 2013(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (Ctbs OR transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation)0
Current controlled trials (excl clinicatrials.gov)25 February 2013TRANSCRANIAL and PAIN1
Current controlled trials (excl clinicatrials.gov)25 February 2013CRANIAL AND PAIN4
Current controlled trials (excl clinicatrials.gov)25/2/13STIMULATION AND PAIN75
Current controlled trials (excl clinicatrials.gov)25 February 2013(Cortex or cortical) and pain8
Current controlled trials (excl clinicatrials.gov)25 February 2013Brain and pain33
Current controlled trials (excl clinicatrials.gov)25 February 2013(Electro or electrical) and pain46
Total current controlled trials25 February 2013 167
Total relevant trial records, all databases11

Appendix 3. Search results summary table for current update: July 2013 search

Database searched Date searched Number of results
CENTRAL Issue 6 of 12, 2013 (The Cochrane Library)24 July 20132

MEDLINE (OVID) June 2013 to 19/7/2013

MEDLINE In Process (OVID) – current week

24 July 2013

24 July 2013

5

19

EMBASE (OVID) June 2013 to 2013 week 2924 July 20138
PsycINFO (OVID) June 2013 to July week 3 201324 July 20131
CINAHL (EBSCO) June 2013 to July 201324 July 20134
Total 39
After de-duplication 35
After title abstract screening 0
After expert checking 2

Appendix 4. Full list of searches and results for 2009 version of review

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>

1exp PAIN/ 64959
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) AND pain*).ti,ab 25127
3(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*").ti,ab 4111
41 OR 2 OR 3 75018
5ELECTRONARCOSIS/ 1
6ELECTRIC STIMULATION/ 3829
7((brain* OR cortex OR cortical OR transcranial* OR cranial OR "magneti*) AND stimulat*).ti,ab 545
8((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)).ti,ab 26
9(("non-invasive brain" OR "non*invasive brain") AND stimulat*).ti,ab 12
10("theta burst stimulat*" OR iTBS OR cTBS).ti,ab 16
11("transcranial magnetic stimulation" OR rTMS OR "transcranial direct current stimulation" OR tDCS OR "cranial electrostimulation" OR "cranial electrotherapy").ti,ab 437
12(electrosleep OR electronarco*).ti,ab 1
135 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 4387
144 AND 13 836
15exp CLINICAL TRIALS/ 79642
16(clinical AND trial*).af 148411
17((singl* OR doubl* OR trebl* OR tripl*) AND (blind* OR mask*)).ti,ab 11736
18(Randomi?ed AND control* AND trial*).af 65515
19RANDOM ASSIGNMENT/ 22506
20(Random* AND allocat*).ti,ab 3666
21placebo*.af 34556
22PLACEBOS/ 5386
23QUANTITATIVE STUDIES/ 5131
2415 OR 16 OR17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 176918
2514 AND 24 226

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)

Appendix 5. Trials register search results for 2009 version of review

DatabaseDate of searchSearch strategyNo. hitsAgreed potential studies
National Research Register (NRR) Archive (NIHR)23 October 2009(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 or sciatica or back-ache or back*ache or lumbago or fibromyalg* or trigem* 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) AND (brain* or cortex or cortical or transcranial* or cranial or magneti* or direct current or DC or electric or crani* or electrostim* or electrotherap* or electro-therap* or non-invasive or non*invasive or theta burst stimulat* or iTBS or Ctbs or transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy or electrosleep or electronarco*) IN “TITLE” Field 366 2
Clinicaltrials.gov

23 October 2009

Search 1

Field -  Interventional studies

CONDITION: 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 OR sciatica OR back-ache OR back*ache OR lumbago

INTERVENTION: brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS OR Ctbs

OUTCOME:  pain

62 
Clinicaltrials.gov

23 October 2009

Search 2

Field -  Interventional studies

CONDITION: 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 OR sciatica OR back-ache OR back*ache OR lumbago

INTERVENTION: transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*

OUTCOME:  pain 

8 (all also picked up in search 1) 
Clinicaltrials.gov

23 October 2009

Search 3

Field -  Interventional studies

CONDITION: fibromyalg* OR trigem* 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

INTERVENTION: brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS OR Ctbs

OUTCOME:  pain

0 
Clinicaltrials.gov

23 October 2009

Search 4

Field -  Interventional studies

CONDITION: fibromyalg* OR trigem* 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

INTERVENTION: transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*

OUTCOME:  pain

0 
    TOTAL UNIQUE RESULTS FOR CLINICAL TRIALS.GOV 62 7
HSRProj (Health Services Research Projects in Progress)23 October 2009(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 or sciatica or back-ache or back*ache or lumbago or fibromyalg* or trigem* 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) AND (brain* or cortex or cortical or transcranial* or cranial or magneti* or direct current or DC or electric or crani* or electrostim* or electrotherap* or electro-therap* or non-invasive or non*invasive or theta burst stimulat* or iTBS or Ctbs or transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy or electrosleep or electronarco*) 77 0
Current Controlled Trials

23 October 2009

Search 1

(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (cranial electrotherapy OR electrosleep OR electronarco*)0 
Current Controlled Trials

23 October 2009

Search 2

(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (Ctbs OR transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation)0 
Current Controlled Trials

23 October 2009

Search 3

(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS)4 
Current Controlled Trials

23 October 2009

Search 4

(sudeck* atroph* OR causalg* OR whip-lash OR whip*lash OR polymyalg* OR failed back surg* OR failed back syndrome) AND (brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC)13 
Current Controlled Trials

23 October 2009

Search 5

(back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (cranial electrostimulation  OR cranial electrotherapy OR electrosleep OR electronarco*)0 
Current Controlled Trials

23 October 2009

Search 6

(back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (Ctbs OR transcranial magnetic stimulation OR rTMS OR transcranial direct current stimulation OR tDCS )9 
Current Controlled Trials

3 November 2009

Search 7

(back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (crani* OR electrostim* OR electrotherap* OR electro-therap*)36 
Current Controlled Trials

23 October 2009

Search 8

 (back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (non-invasive OR non*invasive OR theta burst stimulat* OR iTBS)53 
Current Controlled Trials

3 November 2009

Search 9

(back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (cranial OR magneti* OR direct current OR DC)52 
Current Controlled Trials

3 November 2009

Search 10

(back-ache OR back*ache OR lumbago OR fibromyalg* OR trigem* neuralg* OR herp* neuralg* OR diabet* neuropath* OR reflex dystroph*) AND (brain* OR cortex OR cortical OR transcranial*)63 
Current Controlled Trials

3 November 2009

Search 11

(temp?romandib joint OR central OR post*stroke OR complex OR regional OR spinal cord OR sciatica) AND (cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*)0 
Current Controlled Trials

3 November 2009

Search 12

(temp?romandib joint OR central OR post*stroke OR complex OR regional OR spinal cord OR sciatica) AND (transcranial direct current stimulation OR tDCS)11 
Current Controlled Trials

3 November 2009

Search 13

(central OR post*stroke OR complex OR regional OR spinal cord OR sciatica) AND (iTBS OR cTBS OR transcranial magnetic stimulation OR rTMS)48 
Current Controlled Trials

3 November 2009

Search 14

(central OR post*stroke OR complex OR regional OR spinal cord OR sciatica) AND (electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat*)199 
Current Controlled Trials

3 November 2009

Search 15

(central OR post*stroke OR complex OR regional OR spinal cord OR sciatica) AND (brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR crani* OR electrostim*)1905 
Current Controlled Trials

3 November 2009

Search 16

(temp?romandib joint) AND (brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap* OR electro-therap*)0 
Current Controlled Trials

3 November 2009

Search 17

 (temp?romandib joint) AND (iTBS OR cTBS OR transcranial magnetic stimulation OR rTMS)0 
Current Controlled Trials

3 November 2009

Search 18

(temp?romandib joint) AND (non-invasive OR non*invasive OR theta burst stimulat*)0 
Current Controlled Trials

3 November 2009

Search 19

(chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck) AND (transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*)16 
Current Controlled Trials

3 November 2009

Search 20

(chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck) AND (Ctbs OR transcranial magnetic stimulation OR Rtms)

 

55 
Current Controlled Trials

3 November 2009

Search 21

(chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck) AND (crani* OR electrostim* OR electrotherap* OR electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS)557 
Current Controlled Trials

3 November 2009

Search 22

(chronic* OR back OR musculoskel* OR intractabl* OR neuropath* OR phantom limb OR fantom limb OR neck) AND (brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC)

 

2385 
Current Controlled Trials

3 November 2009

Search 23

(temp*romandibular joint) AND (brain* OR cortex OR cortical OR transcranial* OR cranial OR magneti* OR direct current OR DC OR electric OR crani* OR electrostim* OR electrotherap*)8 
Current Controlled Trials

3 November 2009

Search 24

(temp*romandibular joint) AND (electro-therap* OR non-invasive OR non*invasive OR theta burst stimulat* OR iTBS OR Ctbs OR transcranial magnetic stimulation)1 
Current Controlled Trials

3 November 2009

Search 25

(temp*romandibular joint) AND (rTMS OR transcranial direct current stimulation OR tDCS OR cranial electrostimulation OR cranial electrotherapy OR electrosleep OR electronarco*)0 
   TOTAL RESULTS FOR  CURRENT CONTROLLED TRIALS 5415 14
   TOTAL RESULTS FROM ALL DATABASES   23
   DUPLICATES BETWEEN DATABASES   7
   FINAL TOTAL FROM TRIALS REGISTERS SEARCHES   16

Appendix 6. GRADE judgement summary table

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 (-0.27 to -0.51)

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 pain

Ineffective

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 cortex

Ineffective

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 all

Ineffective

SMD -0.15 (-0.41 to 0.11)

Down one

< 75% studies at low risk of bias

Down one (I2 = 57%, P = 0.02)NoneDown one, N = 184No direct evidenceVery low
Pain: long-term
rTMS all

Ineffective

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 all

Ineffective

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 all

Ineffective

SMD -0.18 (-0.46 to 0.09)

Down one

< 75% studies at low risk of bias

Down one (I2 = 45%, P = 0.05)NoneDown one, n = 183No direct evidenceVery low
tDCS motor cortex

Ineffective

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 = 172No direct evidenceLow
tDCS motor cortex, multiple-dose studies

Ineffective

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 = 119No direct evidenceVery low
Pain: medium-term
tDCS all

Ineffective

SMD -0.42 (-0.63 to 0.24)

Down one

< 75% studies at low risk of bias

None (I2 = 31%, P = 0.21)NoneDown one, n = 77No direct evidenceLow

What's new

DateEventDescription
25 July 2013New citation required and conclusions have changedWe have performed a full update of the searches (January 2013) and a supplemental update of the main databases (July 2013). This involved the inclusion of 21 new trials with 747 participants. We have updated all analyses and made GRADE quality assessments for all core comparisons. The addition of these data has substantially altered our conclusions regarding transcranial direct current stimulation (tDCS), as our analysis no longer suggests that tDCS is effective compared with sham. While the broad conclusions for repetitive transcranial magnetic stimulation (rTMS) and cranial electrotherapy stimulation (CES) have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation. Previous readers should re-read this update.
11 February 2013New search has been performedFor this update we have altered the 'Risk of bias' assessment to reflect new evidence regarding the adequacy of blinding of studies of tDCS and we have included the following new 'Risk of bias' criteria: sample size and study duration. Details of this can be found in the sections: Assessment of risk of bias in included studies and Description of the intervention. We have also applied the GRADE approach to assessing the quality of evidence.

History

Protocol first published: Issue 1, 2010
Review first published: Issue 9, 2010

DateEventDescription
13 September 2010Amended We amended the 'Risk of bias' tables so that the criteri on "allocation concealment" is not assessed for studies with cross-over designs and the criteri on "free from carry-over effects?" is not assessed for studies with parallel designs. These changes are now reflected in Figure 1, where those criteria now appear as empty boxes for the appropriate studies. This is in line with the original review protocol and the changes are necessary due to a copy-editing error rather than any change to the review methods.
Figure 1.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Contributions of authors

NOC: Conceived and designed the review protocol, co-implemented the search strategy alongside the Cochrane PaPaS Group Trials Search Co-ordinator, applied eligibility criteria, assessed studies, extracted and analysed data, and led the write-up of the review.

BM: Closely informed the protocol design and acted as the second review author, applied eligibility criteria, assessed studies, extracted data and assisted with the write-up of the review.

LM: Provided statistical advice and support throughout the review and contributed to the design of the protocol.

LDS: Was involved in the conception and design of the review and acted as a third review author for conflicts in applying eligibility criteria and assessing included studies.

SS: Informed the design of the protocol and has supported the implementation and reporting of the review throughout.

All authors read and commented upon the systematic review and commented on and approved the final manuscript.

Declarations of interest

None known.

Differences between protocol and review

The database Scopus was not searched as the other searches had covered the full scope of this database.

As described in detail in Unit of analysis issues, on advice from a Cochrane statistician we meta-analysed parallel and cross-over studies using the generic inverse variance method rather than combining them without this statistical adjustment as was specified in the protocol. Subsequently the planned sensitivity analysis investigating the influence of study design was not deemed necessary.

The following decision was taken on encountering multiple outcomes within the same time period: for short-term outcomes where more than one data point was available, we used the first post-stimulation measure; 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 was closest to the mid-point of this time period. We decided to pool data from studies with a low or unclear risk of bias as we felt that the analysis specified in the protocol (including only those studies with an overall low risk of bias) was too stringent and would not allow any statistical assessment of the data.

We did not use overall risk of bias in sensitivity analyses as we found that it lacked sensitivity. Instead we considered individual criteria in the 'Risk of bias' assessment for sensitivity analyses. However, we excluded studies with a 'high' risk of bias for any criterion from the meta-analysis.

For this update we have altered the 'Risk of bias' assessment to reflect new evidence regarding the adequacy of blinding of studies of tDCS. Details of this can be found in Assessment of risk of bias in included studies and Description of the intervention.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ahmed 2011

MethodsParallel, quasi-randomised controlled trial
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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

Notes

Adverse events: not reported

Conflict of interest: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

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

When taken: daily for 2 weeks following each stimulation

Secondary: none relevant

Notes

Adverse 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 risk

Comment: 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 risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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

Notes

Funding: government funding

Conflicts of interest: none declared

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "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 risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "... 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Quote: "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 risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Comment: 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 risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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)
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Comment: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Current 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 risk

Comment: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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

Notes

Adverse 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Comment: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Comment: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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

Notes

Adverse 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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
Participants

Country 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)

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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
Participants

Country 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

Interventions

Stimulation 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

Outcomes

Primary: 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 risk

Quote: "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

  1. a

    AE: adverse event

    BIRS: Gracely Box Intensity Scale (BIRS)

    BOCF: baseline observation carried forward

    BPI: Brief Pain Inventory

    CES: cranial electrotherapy stimulation

    CNP: central neuropathic pain

    COI: conflict of interest

    CRPS: complex regional pain syndrome

    DLPFC: dorsolateral pre-frontal cortex

    F: female

    FIQ: Fibromyalgia Impact Questionnaire

    HD-tDCS: High definition tDCS

    ITI: inter-train interval

    ITT: intention-to-treat

    L: left

    LANSS: Leeds Assessment of Neuropathic Symptoms and Signs pain scale

    M: male

    MCS: motor cortex stimulation (MCS)

    NIH: National Institutes of Health

    NRS: numerical rating scale

    PLP: phantom limb pain

    R: right

    RCT: randomised controlled trial

    RMT: resting motor threshold

    rTMS: repetitive transcranial magnetic stimulation

    SCI: spinal cord injury

    SD: standard deviation

    TCES: transcranial electrical stimulation

    tDCS: transcranial direct current stimulation

    TENS: transcutaneous electrical nerve stimulation

    TMS: transcranial magnetic stimulation

    VAS: visual analogue scale

MethodsCross-over RCT
Participants

Country 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

Interventions

Stimulation 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)

Outcomes

Primary: 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 risk

Comment: 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
  1. a

    NIBS: non-invasive brain stimulation
    RCT: randomised controlled trial
    tDCS: transcranial direct current stimulation

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

  1. a

    DLPFC: dorsolateral pre-frontal cortex
    FIQ: Fibromyalgia Impact Questionnaire
    RCT: randomised controlled trial
    tDCS: transcranial direct current stimulation
    VAS: visual analogue scale

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