Non-invasive brain stimulation techniques for chronic pain

  • Review
  • Intervention

Authors

  • Neil E O'Connell,

    Corresponding author
    1. Brunel University, Department of Clinical Sciences/Health Economics Research Group, Institute of Environment, Health and Societies, Uxbridge, Middlesex, UK
    • Neil E O'Connell, Department of Clinical Sciences/Health Economics Research Group, Institute of Environment, Health and Societies, Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK. neil.oconnell@brunel.ac.uk.

  • Louise Marston,

    1. University College London, Research Department of Primary Care & Population Health, London, UK
  • Sally Spencer,

    1. Edge Hill University, Postgraduate Medical Institute, Ormskirk, Lancashire, UK
  • Lorraine H DeSouza,

    1. Brunel University London, Department of Clinical Sciences/Health Ageing Research Group, Institute of Environment, Health and Societies, Uxbridge, Middlesex, UK
  • Benedict M Wand

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

Abstract

Background

This is an updated version of the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. 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), transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE).

Objectives

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

Search methods

For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017.

Selection criteria

Randomised and quasi-randomised studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of three months' duration or more, and measured pain as an outcome. Outcomes of interest were pain intensity measured using visual analogue scales or numerical rating scales, disability, quality of life and adverse events.

Data collection and analysis

Two review authors independently extracted and verified data. Where possible we entered data into meta-analyses, excluding studies judged as high risk of bias. We used the GRADE system to assess the quality of evidence for core comparisons, and created three 'Summary of findings' tables.

Main results

We included an additional 38 trials (involving 1225 randomised participants) in this update, making a total of 94 trials in the review (involving 2983 randomised participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, two RINCE and two tRNS. One study evaluated both rTMS and tDCS. We judged only four studies as low risk of bias across all key criteria. Using the GRADE criteria we judged the quality of evidence for each outcome, and for all comparisons as low or very low; in large part this was due to issues of blinding and of precision.

rTMS

Meta-analysis of rTMS studies versus sham for pain intensity at short-term follow-up (0 to < 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (standardised mean difference (SMD) -0.22, 95% confidence interval (CI) -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or greater. Pre-specified subgroup analyses did not find a difference between low-frequency stimulation (low-quality evidence) and rTMS applied to the prefrontal cortex compared to sham for reducing pain intensity at short-term follow-up (very low-quality evidence). High-frequency stimulation of the motor cortex in single-dose studies was associated with a small short-term reduction in pain intensity at short-term follow-up (low-quality evidence, pooled n = 249, SMD -0.38 95% CI -0.49 to -0.27). This equates to a 12% (95% CI 9% to 16%) reduction in pain, or a 0.77 (95% CI 0.55 to 0.99) point change on a 0 to 10 pain intensity scale, which does not achieve the minimum clinically important difference threshold of 15% or greater. The results from multiple-dose studies were heterogeneous and there was no evidence of an effect in this subgroup (very low-quality evidence). We did not find evidence that rTMS improved disability. Meta-analysis of studies of rTMS versus sham for quality of life (measured using the Fibromyalgia Impact Questionnaire (FIQ) at short-term follow-up demonstrated a positive effect (MD -10.80 95% CI -15.04 to -6.55, low-quality evidence).

CES

For CES (five studies, 270 participants) we found no evidence of a difference between active stimulation and sham (SMD -0.24, 95% CI -0.48 to 0.01, low-quality evidence) for pain intensity. We found no evidence relating to the effectiveness of CES on disability. One study (36 participants) of CES versus sham for quality of life (measured using the FIQ) at short-term follow-up demonstrated a positive effect (MD -25.05 95% CI -37.82 to -12.28, very low-quality evidence).

tDCS

Analysis of tDCS studies (27 studies, 747 participants) showed heterogeneity and a difference between active and sham stimulation (SMD -0.43 95% CI -0.63 to -0.22, very low-quality evidence) for pain intensity. This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome. This point estimate meets our threshold for a minimum clinically important difference, though the lower confidence interval is substantially below that threshold. We found evidence of small study bias in the tDCS analyses. We did not find evidence that tDCS improved disability. Meta-analysis of studies of tDCS versus sham for quality of life (measured using different scales across studies) at short-term follow-up demonstrated a positive effect (SMD 0.66 95% CI 0.21 to 1.11, low-quality evidence).

Adverse events

All forms of non-invasive brain stimulation and sham stimulation appear to be frequently associated with minor or transient side effects and there were two reported incidences of seizure, both related to the active rTMS intervention in the included studies. However many studies did not adequately report adverse events.

Authors' conclusions

There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and quality of life but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES are effective for reducing pain intensity in chronic pain. The broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation. Future evidence may substantially impact upon the presented results.

Plain language summary

Stimulating the brain without surgery in the management of chronic pain in adults

Bottom line

There is a lack of high-quality evidence to support or refute the effectiveness of non-invasive brain stimulation techniques for chronic pain.

Background

Electrical stimulation of the brain has been used to address a variety of painful conditions. Various devices are available that can electrically stimulate the brain without the need for surgery or any invasive treatment. There are five 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), reduced impedance non-invasive cortical electrostimulation (RINCE) and transcranial random noise stimulation (tRNS) 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. How effective they are is uncertain.

Study characteristics

This review update included 94 randomised controlled studies: 42 of rTMS, 11 of CES, 36 of tDCS two of RINCE, two of tRNS and one study which evaluated both tDCS and rTMS.

Key findings

rTMS applied to the motor cortex may lead to small, short-term reductions in pain but these effects are not likely to be clinically important. tDCS may reduce pain when compared with sham but for rTMS and tDCS our estimates of benefit are likely to be exaggerated by the small number of participants in each of the studies and limitations in the way the studies were conducted. Low- or very low-quality evidence suggests that low-frequency rTMS and rTMS that is applied to prefrontal areas of the brain are not effective. Low-quality evidence does not suggest that CES is an effective treatment for chronic pain. For all forms of stimulation the evidence is not conclusive and there is substantial uncertainty about the possible benefits and harms of the treatment. 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 with real and sham stimulation. Two cases of seizure were reported following real rTMS. Our conclusions for rTMS, CES, tDCS, and RINCE have not changed substantially in this update.

Quality of the evidence

We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. We considered all of the evidence to be of low or very low quality, mainly because of bias in the studies that can lead to unreliable results and the small size of the studies, which makes them imprecise.

Laički sažetak

Metode stimulacije mozga bez kirurškog zahvata za liječenje kronične boli

Zaključak

Nemamo dovoljno visoko-kvalitetnih dokaza koji bi podržali ili osporili učinkovitost metoda za neinvazivnu stimulaciju mozga za liječenje kronične boli.

Dosadašnje spoznaje

Električna stimulacija mozga se koristi za liječenje raznih bolnih stanja. Danas postoje različiti uređaji koji omogućuju električnu stimulaciju mozga bez potrebe za kirurškim zahvatom ili bilo kakvom drugom invazivnom terapijom. Postoji pet glavnih vrste tih terapija: ponavljana transkranijalna magnetska stimulacija (engl. repetitive transcranial magnetic stimulation, rTMS) kod koje se mozak stimulira pomoću zavojnice koja se stavlja 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), neinvazinva kortikalna elektrostimulacija smanjene impedancije (engl. reduced impedance non-invasive cortical electrostimulation, RINCE) i transkranijalna nasumična stimulacija bukom (engl. transcranial random noise stimulation, tRNS) kod koje se elektrode primjenjuju na kožu glave. Ti se uređaji pokušavaju koristiti za ublažavanje boli, pri čemu im je cilj mijenjanje aktivnosti mozga. Međutim, nije jasno kolika je djelotvornost tih terapija.

Obilježja uključenih istraživanja

U ovoj obnovljenoj verziji Cochrane sustavnog pregleda literature uključena su 94 randomizirana kontrolirana istraživanja. Od toga su 42 pokusa analizirala rTMS, 11 CES, 36 tDCS, 2 RINCE, 2 tRNS, a jedan pokus je ispitao i tDCS i rTMS.

Ključni rezultati

Kad se rTMS primijeni na motornu koru mozga (korteks) može dovesti do malog, kratkoročnog smanjenja boli, ali nije vjerojatno da su ti učinci klinički važna. tDCS može smanjiti bol u usporedbi s placebo postupkom, ali za rTMS i tDCS naše procjene pokazuju da je njihov koristan učinak vjerojatno precijenjen zbog malog broja sudionika u svakoj od studija i ograničenja u načinu na koji su ta istraživanja provedena. Dokazi niske- ili vrlo niske kvalitete ukazuju kako rTMS i rTMS niske frekvencije, koje se primjenjuju na prefrontalna područja mozga, nisu učinkovite. Dokazi niske kvalitete pokazuju da CES nije djelotvorna terapija za kroničnu bol. Za sve oblike stimulacije dokazi nisu uvjerljivi i postoji znatna neizvjesnost oko moguće koristi i štetnih učinaka tih terapija. U studijama koje su jasno opisale nuspojave, te su nuspojave bile kratkoročne i sporedne, primjerice glavobolja, mučnina i nadražaj kože, ali takve su nuspojave ispitanici opisali i prilikom stvarne i lažne stimulacije. Dva slučaja napadaja su opisana nakon primjene prave rTMS. Naši zaključci za rTMS, CES, tDCS i RINCE nisu se značajnije promijenili u ovom obnovljenom sustavnom pregledu u odnosu na stariju verziju.

Kvaliteta dokaza

Ocijenjenili smo kvalitetu dokaza iz uključenih istraživanja s pomoću četiri razine: vrlo niske, niske, umjerene ili visoke Vrlo niska kvaliteta dokaza znači da smo jako nesigurni oko rezultata. Visoka kvaliteta dokaza znači da smo vrlo sigurni u rezultate. Ocijenili smo da su svi dokazi u ovom sustavnom pregledu niske ili vrlo niske kvalitete, uglavnom zbog pristranosti koje mogu dovesti do nepouzdanih rezultata i male veličine studija, što ih čini neprecizan.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia PuljakOvaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Ringkasan bahasa mudah

Merangsang otak tanpa pembedahan dalam pengurusan sakit kronik dalam kalangan orang dewasa

Kesimpulannya

Terdapat kekurangan bukti berkualiti tinggi untuk menyokong atau menafikan keberkesanan teknik rangsangan otak tidak invasif untuk sakit kronik.

Latar belakang

Rangsangan elektrik otak telah digunakan untuk menangani pelbagai keadaan yang menyakitkan. Terdapat pelbagai peranti yang boleh merangsang otak secara elektrik tanpa memerlukan pembedahan atau rawatan invasif. Terdapat lima jenis rawatan utama: rangsangan magnetik transkranial berulang (rTMS) di mana otak dirangsang oleh gegelung yang diaplikasi pada kulit kepala, rangsangan elektroterapi kranial (CES) di mana elektrod diletakkan ke telinga atau diaplikasi pada kulit kepala, rangsangan transkranial arus terus (tDCS), elektrostimulasi kortikal terkurang impedans yang tidak invasif (RINCE) dan rangsangan bunyi transkranial rawak (tRNS) di mana elektrod diaplikasi pada kulit kepala. Rawatan tersebut telah digunakan untuk mengurangkan sakit dengan matlamat mengubah aktiviti otak. Keberkesanannya adalah tidak pasti.

Ciri-ciri kajian

Kemas kini ulasan ini termasuk 94 kajian rawak terkawal: 42 rTMS, 11 CES, 36 tDCS, dua RINCE, dua tRNS dan satu kajian yang menilai kedua-dua tDCS dan rTMS.

Keputusan utama

rTMS yang diaplikasi kepada korteks motor boleh membawa kepada pengurangan kecil jangka pendek sakit tetapi kesannya tidak mungkin penting secara klinikal. tDCS boleh mengurangkan sakit berbanding dengan sham tetapi untuk rTMS dan tDCS anggaran manfaat kami mungkin diperbesar-besarkan oleh bilangan peserta yang kecil dalam setiap kajian dan batasan dalam cara kajian dijalankan. Bukti kualiti rendah atau sangat rendah menunjukkan frekuensi rendah rTMS dan rTMS yang diaplikasi pada kawasan prefrontal otak tidak berkesan. Bukti berkualiti rendah tidak menunjukkan CES adalah rawatan yang berkesan untuk sakit kronik. Untuk semua bentuk rangsangan, bukti adalah tidak konklusif dan terdapat ketidakpastian besar mengenai kemungkinan manfaat dan bahaya rawatan. Antara kajian yang melaporkan dengan jelas kesan sampingan, kesan sampingan yang singkat dan kecil seperti sakit kepala, loya dan kerengsaan kulit biasanya dilaporkan dengan rangsangan sebenar dan palsu. Dua kes sawan dilaporkan berikutan rTMS sebenar. Kesimpulan kami untuk rTMS, CES, tDCS, dan RINCE tidak berubah dengan ketara dalam kemas kini ini.

Kualiti bukti

Kami menilai kualiti bukti dari kajian-kajian menggunakan empat peringkat: sangat rendah, rendah, sederhana, atau tinggi. Bukti yang berkualiti sangat rendah bermakna kami sangat tidak pasti tentang hasilnya. Bukti yang berkualiti tinggi bermakna kami sangat yakin dengan hasilnya. Kami menganggap semua bukti mempunyai kualiti rendah atau sangat rendah, terutamanya kerana bias dalam kajian-kajian tersebut yang boleh membawa kepada hasil yang tidak boleh dipercayai dan saiz kecil kajian, yang menjadikannya tidak tepat.

Catatan terjemahan

Diterjemahkan oleh Wong Chun Hoong (International Medical University). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi wong.chunhoong@hotmail.com

Laienverständliche Zusammenfassung

Stimulation des Gehirns ohne Operation zur Behandlung von chronischen Schmerzen bei Erwachsenen

Fazit

Es fehlt an Evidenz von hoher Qualität, die die Wirksamkeit von nicht-invasiven Hirnstimulationsverfahren bei chronischen Schmerzen belegt bzw. widerlegt.

Hintergrund

Elektrische Hirnstimulation wird zur Behandlung verschiedener schmerzhafter Erkrankungen eingesetzt. Verschiedene Geräte für eine elektrische Hirnstimulation stehen zur Verfügung, die keine Operation bzw. invasiven Eingriff erfordern. Es gibt fünf hauptsächliche Behandlungsarten: repetitive transkranielle Magnetstimulation (rTMS), bei der das Hirn mittels einer an der Kopfhaut angelegten Magnetspule stimuliert wird; craniale Elektrostimulation (CES), bei der Elektroden an den Ohren oder der Kopfhaut angelegt werden; transkranielle Gleichstromstimulation (tDCS); nicht-invasive kortikale Elektrostimulation mit reduzierter Impedanz (RINCE) und transkranielle Rauschstromstimulation (tRNS), bei der die Elektroden an der Kopfhaut angelegt werden. Diese Behandlungsmethoden werden genutzt um zu versuchen, eine Schmerzreduktion über veränderte Hirnaktivität zu erreichen. Ihre Wirksamkeit ist unklar.

Studienmerkmale

Diese Aktualisierung eines Reviews schließt 94 randomisierte kontrollierte Studien ein: 42 rTMS-Studien, 11 CES-Studien, 36 tDCS-Studien, 2 RINCE-Studien, 2 tRNS-Studien und eine Studie, die tDCS und rTMS untersuchte.

Hauptergebnisse

rTMS, angewendet auf den Motorcortex, führt möglicherweise zu leichter, kurzzeitiger Schmerzreduktion, allerdings sind diese Wirkungen wahrscheinlich nicht klinisch relevant. tDCS reduziert im Vergleich zur scheinbehandelten Gruppe möglicherweise Schmerzen, allerdings sind unsere Schätzungen für den Nutzen von rTMS und tDCS durch die geringe Teilnehmeranzahl in jeder der Studien und den Einschränkungen in der Studiendurchführung wahrscheinlich überhöht. Es liegt Evidenz von niedriger bzw. sehr niedriger Qualität vor, die nahelegt, dass niederfrequente rTMS bzw. rTMS, die auf präfrontale Hirnareale angewendet wird, nicht wirksam sind. Evidenz von niedriger Qualität spricht nicht dafür, dass CES eine wirksame Behandlung für chronische Schmerzen darstellt. Für alle Formen der Stimulation ist die Evidenzlage nicht eindeutig, und es besteht erhebliche Unsicherheit hinsichtlich des möglichen Nutzens bzw. Schadens der Behandlung. Von den Studien, die ausdrücklich über Nebenwirkungen berichteten, wurden kurzzeitige und geringfügige Nebenwirkungen wie Kopfschmerzen, Übelkeit und Hautirritationen sowohl bei den wirklichen, als auch bei den Scheinstimulationen häufig berichtet. Zwei Fälle von Anfällen nach rTMS-Anwendungen wurden berichtet. Unsere Schlussfolgerungen bezüglich rTMS, CES, tDCS und RINCE haben sich mit dieser Aktualisierung nicht erheblich geändert.

Qualität der Evidenz

Wir bewerten die Qualität der Studien anhand von vierAbstufungen: sehr niedrig, niedrig, moderat oder hoch. Evidenz von sehr niedriger Qualität bedeutet, dass wir hinsichtlich der Ergebnisse sehr unsicher sind. Evidenz von hoher Qualität bedeutet, dass wir großes Vertrauen in die Ergebnissen haben. Wir bewerteten die Qualität der gesamten Evidenz als niedrig bzw. sehr niedrig, hauptsächlich aufgrund von Bias in den Studien, was zu nicht verlässlichen Ergebnissen führen kann, und aufgrund der geringen Größe der Studien, die die Studien unpräzise werden lässt.

Anmerkungen zur Übersetzung

C. Wetzel, freigegeben durch Cochrane Deutschland.

Summary of findings(Explanation)

Summary of findings for the main comparison. Repetitive transcranial magnetic stimulation (rTMS) compared with sham for chronic pain
  1. 1Downgraded once for study limitations due to high or unclear risk of bias and once for inconsistency due to heterogeneity.
    2Downgraded once for study limitations due to high or unclear risk of bias, once for inconsistency due to heterogeneity and once for imprecision due to low participant numbers.
    3Downgraded once for study limitations due to high or unclear risk of bias and once for imprecision due to low participant numbers.

rTMS compared with sham for chronic pain

Patient or population: adults with chronic pain

Settings: laboratory/ clinic

Intervention: active rTMS

Comparison: sham rTMS

OutcomesEffect size

Relative and absolute effect

(average % improvement (reduction) in pain (95% CIs) in relation to post-treatment score from sham group)*

*Where 95%CIs do not cross the line of no effect.

No of participants
(studies)
Quality of the evidence
(GRADE)

Pain intensity (0 to < 1 week postintervention)

measured using visual analogue scales or numerical rating scales

SMD -0.22 (-0.29 to -0.16)This equates to a 7% (95% CI 5% to 9%) reduction in pain intensity, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale.655 (27)⊕⊕⊝⊝ low1

Disability (0 to < 1 week postintervention)

measured using self-reported disability/pain interference scales

SMD -0.29, 95% CI -0.87 to 0.29-119 (5)

⊕⊝⊝⊝

very low2

Quality of life (0 to < 1 week postintervention)

measured using Fibromyalgia Impact Questionnaire

MD -10.80, 95% CI -15.04 to -6.55-105 (4)⊕⊕⊝⊝ low3
CI: confidence interval; MD: mean difference; rTMS: repetitive transcranial magnetic stimulation; SMD: standardised mean difference

GRADE Working Group grades of evidence

High quality: we are very confident that the true effect lies close to that of the estimate of the effect;

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

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

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

Summary of findings 2 Cranial electrotherapy stimulation (CES) compared with sham for chronic pain

Summary of findings 2. Cranial electrotherapy stimulation (CES) compared with sham for chronic pain
  1. 1Downgraded once for study limitations due to high or unclear risk of bias and once for imprecision due to low participant numbers.
    2Downgraded once for study limitations due to high or unclear risk of bias, once for inconsistency (single study) and once for imprecision due to low participant numbers.

CES compared with sham for chronic pain

Patient or population: adults with chronic pain

Settings: laboratory/ clinic

Intervention: active CES

Comparison: sham CES

OutcomesEffect size

Relative effect

(average % improvement (reduction) in pain (95% CIs) in relation to post-treatment score from sham group)*

*Where 95%CIs do not cross the line of no effect.

No of participants
(studies)
Quality of the evidence
(GRADE)

Pain intensity (0 to < 1 week postintervention)

measured using visual analogue scales or numerical rating scales

SMD -0.24 (-0.48 to 0.01)-270 (5)⊕⊕⊝⊝ low1

Disability (0 to < 1 week postintervention)

measured using self-reported disability/pain interference scales

No data availableNo data availableNo data availableNo data available

Quality of life (0 to < 1 week postintervention)

measured using Fibromyalgia Impact Questionnaire

MD -25.05 (-37.82 to -12.28)-36 (1)⊕⊝⊝⊝ very low2
CI: confidence interval; CES: cranial electrotherapy stimulation; MD: mean difference; SMD: standardised mean difference

GRADE Working Group grades of evidence

High quality: we are very confident that the true effect lies close to that of the estimate of the effect;

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

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

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

Summary of findings 3 Transcranial direct current stimulation (tDCS) compared with sham for chronic pain

Summary of findings 3. Transcranial direct current stimulation (tDCS) compared with sham for chronic pain
  1. 1Downgraded once for study limitations due to high or unclear risk of bias, once for inconsistency due to heterogeneity and once for evidence of possible publication bias.
    2Downgraded once for study limitations due to high or unclear risk of bias and once for imprecision due to low participant numbers.

tDCS compared with sham for chronic pain

Patient or population: adults with chronic pain

Settings: laboratory/ clinic

Intervention: active tDCS

Comparison: sham tDCS

OutcomesEffect size

Relative effect

(average % improvement (reduction) in pain (95% CIs) in relation to post-treatment score from sham group)*

*Where 95%CIs do not cross the line of no effect.

No of participants
(studies)
Quality of the evidence
(GRADE)

Pain intensity (0 to < 1 week postintervention)

measured using visual analogue scales or numerical rating scales

SMD -0.43 (-0.63 to -0.22)This equates to a 17% (95% CI 9% to 25%) reduction in pain intensity or a 0.82 (95% CI 0.42 to 1.2) point reduction on a 0 to 10 pain intensity scale.747 (27)⊕⊝⊝⊝ very low1

Disability (0 to < 1 week postintervention)

measured using self-reported disability/pain interference scales

SMD -0.01, (95% CI -0.28 to 0.26)-212 (4)⊕⊕⊝⊝ low2

Quality of life (0 to < 1 week postintervention)

measured using different scales across studies

SMD 0.66, 95% CI 0.21 to 1.11-82 (4)⊕⊕⊝⊝ low2
CI: confidence interval; MD: mean difference; SMD: standardised mean difference; tDCS: transcranial direct current stimulation

GRADE Working Group grades of evidence

High quality: we are very confident that the true effect lies close to that of the estimate of the effect;

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

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

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

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) and updated in 2014 (O'Connell 2014).

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; Van Hecke 2013). 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; Van Hecke 2013). Chronic pain is a heterogeneous phenomenon that results from a wide variety of pathologies including chronic somatic tissue degeneration such as in arthritis, peripheral nerve injury and central nervous system injury, as well as a range of chronic pain syndromes such as fibromyalgia and complex regional pain syndrome. It is likely that different mechanisms of pain production underpin these different types of chronic pain (Ossipov 2006).

Description of the intervention

Electrical brain stimulation techniques have been used to address a variety of pathological pain conditions including fibromyalgia, chronic poststroke pain and complex regional pain syndrome (Cruccu 2017; Fregni 2007; Gilula 2007), and clinical studies of both invasive and non-invasive techniques have produced preliminary data showing reductions in pain (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 2017). 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 a lesion or a disease of the somatosensory 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), transcranial random noise stimulation (tRNS) 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 2012a). 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). 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). tRNS is similar to tDCS but the stimulating current is varied randomly. It has been found to increase cortical excitability (Paulus 2011). 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 2012a).

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). Both RINCE and tRNS are applied in a similar way to tDCS, though the current is delivered differently to enhance, in theory, signal transmission to neural networks. Modulation of activity in brain networks is also proposed as the mechanism of action of CES 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 participant blinding, particularly in cross-over design studies. Lisanby 2001 and Loo 2000 suggest that an ideal sham condition for rTMS should:

  • not stimulate the cortex;

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

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

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

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

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. Published 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 evaluate the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain.

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

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

Types of interventions

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

Types of outcome measures

Primary outcomes

The primary outcome measure was change in pain intensity 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 were 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 (Lefebvre 2011). We have slightly adapted this filter to include the term 'sham' in the title or abstract. The search strategies for this update are presented in Appendix 1 and included a combination of controlled vocabulary (MeSH) and free-text terms. We based all database searches on this strategy but appropriately revised them to suit each database.

Electronic databases

Previous updates searched all databases from their inception to July 2013. To identify studies for inclusion in this update we searched the following electronic databases from July 2013 to September 2016 to identify additional published articles and performed a further search update in October 2017:

  • the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 10);

  • MEDLINE & MEDLINE in Process via OVID to 11 October 2017;

  • Embase via OVID to 11 October 2017;

  • PsycINFO via OVID to 11 October 2017;

  • CINAHL via EBSCO to 11 October 2017;

  • LILACS via Birme to 11 October 2017;

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

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

For this update we searched ClinialTrials.gov (clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en/) to October 2017 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 them 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 the reference lists of included eligible studies. Initially two review authors (NOC and BW) read the titles or abstracts (or both) of identified studies. Where it was clear from the study title or abstract that the study was not relevant or did not meet the selection criteria we excluded it. If it was unclear then we assessed the full paper, as well as all studies that appeared to meet the selection criteria. Disagreement was resolved through discussion between the two review authors. Where resolution was not achieved a third review author (LDS) considered the paper(s) in question.

Data extraction and management

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

  • 'Risk of bias' assessment results

  • Country of origin

  • Study design

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

  • Sample size - active and control groups

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

  • Type of sham

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

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

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

  • Adverse effects

  • Conflict of interest disclosure

Assessment of risk of bias in included studies

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

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

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

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

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

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

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

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 suboptimal (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 first 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 suboptimal 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 10 pain intensity rating scale on the basis of the mean standard deviation from trials using a 0 to 10 point VAS. We considered the likely clinical importance of the pooled effect size using the criteria proposed in the IMMPACT consensus statement (Dworkin 2008). Specifically, we judged a decrease in pain of less than 15% as no important change, of 15% or more as a minimally important change, of 30% or more as a moderately important change and of 50% or more as a substantially important change.

Unit of analysis issues

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

Dealing with missing data

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

Assessment of heterogeneity

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

Assessment of reporting biases

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

Data synthesis

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

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

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

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

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

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

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

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

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

  • Moderate: downgraded randomised trials; or upgraded observational studies

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

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

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

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

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

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

  • imprecision of results (wide confidence intervals);

  • high probability of publication bias.

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

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

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

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

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

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

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

'Summary of findings' table

We included three 'Summary of findings' tables to present the main findings in a transparent and simple tabular format for the three main forms of non-invasive brain stimulation techniques (rTMS, tDCS, CES) compared to sham. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the outcomes pain, disability and quality of life at short-term follow-up (see Summary of findings for the main comparison; Summary of findings 3; Summary of findings 2).

Subgroup analysis and investigation of heterogeneity

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

Sensitivity analysis

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

Results

Description of studies

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

Results of the search

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

Figure 1.

Study flow diagram

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

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

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

Included studies

See Characteristics of included studies.

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, Canada, Colombia, Egypt, Europe (Austria, France, Germany, Italy, Spain, Norway, Russia and the UK), Israel, Japan, South Korea, Thailand, Australia and the USA. Most studies were based in a laboratory or outpatient pain clinic setting.

Type of stimulation, application and use

In total 43 studies investigated rTMS (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Avery 2013; Borckardt 2009; Boyer 2014, Carretero 2009; Dall'Agnol 2014; Defrin 2007; de Oliveira 2014; Fregni 2005; Fregni 2011; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Jetté 2013, Kang 2009; Khedr 2005; Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Malavera 2013; Medeiros 2016; Mhalla 2011; Nardone 2017; Nurmikko 2016; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011; Tekin 2014; Tzabazis 2013; Umezaki 2016; Yagci 2014; Yilmaz 2014). 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), 36 studies investigated tDCS (Ahn 2017; Antal 2010; Ayache 2016; Bae 2014; Boggio 2009; Brietzke 2016; Chang 2017; Donnell 2015; Fagerlund 2015; Fenton 2009; Fregni 2006a; Fregni 2006b; Hagenacker 2014; Harvey 2017; Hazime 2017; Jales Junior 2015; Jensen 2013; Khedr 2017; Kim 2013; Lagueux 2017; Luedtke 2015; Mendonca 2011; Mendonca 2016; Mori 2010; Ngernyam 2015; Oliveira 2015; Portilla 2013; Riberto 2011; Sakrajai 2014; Soler 2010; Souto 2014; Thibaut 2017; Valle 2009; Villamar 2013; Volz 2016; Wrigley 2014), two studies investigated RINCE (Deering 2017; Hargrove 2012a) two studies investigated tRNS (Curatolo 2017; Palm 2016) and one both rTMS and tDCS (Attal 2016).

Study designs

There was a mixture of parallel and cross-over study designs. For rTMS there were 22 parallel studies (Ahmed 2011; Avery 2013; Boyer 2014; Carretero 2009; Dall'Agnol 2014; Defrin 2007; de Oliveira 2014; Fregni 2011; Khedr 2005; Lee 2012; Malavera 2013; Medeiros 2016; Mhalla 2011; Nardone 2017 Passard 2007; Picarelli 2010; Short 2011; Tekin 2014; Tzabazis 2013; Umezaki 2016; Yagci 2014; Yilmaz 2014), and 20 cross-over studies (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Borckardt 2009; Fregni 2005; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Jetté 2013; Kang 2009; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Nurmikko 2016; 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 26 parallel studies (Ahn 2017; Bae 2014; Brietzke 2016; Chang 2017; Donnell 2015; Fagerlund 2015; Fregni 2006a; Fregni 2006b; Harvey 2017; Hazime 2017; Jales Junior 2015; Khedr 2017; Lagueux 2017; Kim 2013; Luedtke 2015; Mendonca 2011; Mendonca 2016; Mori 2010; Oliveira 2015; Riberto 2011; Sakrajai 2014; Soler 2010; Souto 2014; Thibaut 2017; Valle 2009; Volz 2016), and 10 cross-over studies (Antal 2010; Ayache 2016; Boggio 2009; Fenton 2009; Hagenacker 2014; Jensen 2013; Ngernyam 2015; 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). One study of tRNS (Palm 2016) used a cross-over design and one a parallel design (Curatolo 2017) and both RINCE studies used a parallel design (Deering 2017; Hargrove 2012a). The one study of both rTMS and tDCS employed a parallel design (Attal 2016).

Study participants

The included studies were published between 2000 and 2017. 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 135 participants, the two RINCE studies recruited 91 and 46 participants and the two studies of tRNS included 16 and 20 participants.

Studies included a variety of chronic pain conditions. Ten rTMS studies included participants with neuropathic pain of mixed origin; of these, seven included a mix of participants with central, peripheral and facial neuropathic pain (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Hirayama 2006; Hosomi 2013, Lefaucheur 2004; Lefaucheur 2008), three included a mix of participants with central and peripheral neuropathic pain (Lefaucheur 2006; Nurmikko 2016; Saitoh 2007), of which two studies included one or more participants with phantom limb pain (Nurmikko 2016; Saitoh 2007). One study included a mix of participants with central neuropathic pain and phantom limb pain (Irlbacher 2006). One study included a mix of participants with central and facial neuropathic pain (Lefaucheur 2001a), six rTMS studies included only participants with central neuropathic pain (Defrin 2007; de Oliveira 2014; Jetté 2013; Kang 2009; Nardone 2017, Yilmaz 2014 ), one included only participants with peripheral neuropathic pain (Borckardt 2009), and one study included participants with burning mouth syndrome (Umezaki 2016). Sixteen studies included non-neuropathic chronic pain including fibromyalgia (Boyer 2014; Carretero 2009; Lee 2012; Mhalla 2011; Passard 2007; Short 2011; Tekin 2014; Tzabazis 2013; Yagci 2014), chronic widespread pain (Avery 2013), chronic pancreatitis pain (Fregni 2005; Fregni 2011), chronic myofascial pain (Dall'Agnol 2014; Medeiros 2016) and complex regional pain syndrome type I (CRPSI) (Picarelli 2010; Pleger 2004). Two studies included only phantom limb pain (Ahmed 2011; Malavera 2013). 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 (21) 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; Nardone 2017; Nurmikko 2016; Onesti 2013; Picarelli 2010; Rollnik 2002; Saitoh 2007; Yagci 2014; Yilmaz 2014). This inclusion criterion was varyingly described as intractable, resistant to medical intervention or resistant to 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), two studies included participants with neuropathic pain secondary to multiple sclerosis (Ayache 2016; Mori 2010), five included participants with central neuropathic pain following spinal cord injury (Fregni 2006a; Ngernyam 2015; Soler 2010; Thibaut 2017; Wrigley 2014), one with central poststroke pain (Bae 2014), one with neuropathic or non-neuropathic pain following spinal cord injury (Jensen 2013), one with trigeminal neuralgia (Hagenacker 2014) and one with painful diabetic polyneuropathy (Kim 2013). Twenty studies included non-neuropathic pain, specifically chronic pelvic pain (Fenton 2009), osteoarthritis (OA) of the knee (Ahn 2017; Chang 2017), fibromyalgia (Fagerlund 2015; Fregni 2006b; Jales Junior 2015; Khedr 2017; Mendonca 2011; Mendonca 2016; Riberto 2011; Villamar 2013), temporomandibular joint pain (Donnell 2015; Oliveira 2015), hepatitis C-related chronic pain (Brietzke 2016), human T-lymphotropic virus 1 (HTLV-1) and viral hepatitis-related chronic back or leg pain (Souto 2014), chronic nonspecific low back pain (Hazime 2017; Luedtke 2015), inflammatory bowel disease-related pain (Volz 2016) or a mixed pain group (Antal 2010; Harvey 2017). One study included participants with neuropathic pain following burn injury (Portilla 2013) and one included participants with CRPS1 (Lagueux 2017). Four studies of tDCS specified recruiting participants with pain that was refractory to medical management (Antal 2010; Boggio 2009; Fenton 2009; Fregni 2006a). The studies relating to RINCE included participants with fibromyalgia (Deering 2017; Hargrove 2012a). The studies of tRNS included participants with multiple sclerosis-related neuropathic pain (Palm 2016) and fibromyalgia (Curatolo 2017). The study of both tDCS and rTMS included participants with lumbar radicular pain (Attal 2016).

Most studies included both male and female participants except Fenton 2009 (chronic pelvic pain), Dall'Agnol 2014, Medeiros 2016 (chronic myofascial pain), Donnell 2015 (temporomandibular disorder), Curatolo 2017; Fregni 2006b; Jales Junior 2015; Lee 2012; Mhalla 2011; Riberto 2011; Valle 2009; Yagci 2014 (fibromyalgia) which recruited women only and Yilmaz 2014 (post-spinal cord injury pain), which recruited only men. Three studies did not present data on gender distribution (Capel 2003; Fregni 2005; Katsnelson 2004).

Outcomes
Primary outcomes

All included studies assessed pain using self-reported pain visual analogue scales (VAS) or numerical rating scales (NRS). 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. Thirty-seven studies reported medium-term outcome data (1 to 6 weeks post-treatment) (Ahmed 2011; Ahn 2017 André-Obadia 2008; Antal 2010; Ayache 2016; Bae 2014; Borckardt 2009; Carretero 2009; Defrin 2007; de Oliveira 2014; Fagerlund 2015; Fenton 2009; Fregni 2006a; Fregni 2006b; Fregni 2011; Gabis 2009; Kang 2009; Khedr 2005; Khedr 2017; Kim 2013; Lee 2012; Lefaucheur 2001a; Luedtke 2015; Mendonca 2016; Mori 2010; Nardone 2017; Nurmikko 2016; Passard 2007; Picarelli 2010; Short 2011; Soler 2010; Thibaut 2017; Tzabazis 2013; Valle 2009; Volz 2016; Wrigley 2014; Yagci 2014). Eight studies collected outcome data at long-term (> 6 weeks post-treatment) follow-up (Avery 2013; Hazime 2017; Kang 2009; Luedtke 2015; Mendonca 2016; Passard 2007; Thibaut 2017; Yagci 2014).

Secondary outcomes

We considered secondary outcomes that distinctly measured self-reported disability (that capture the extent of disability or functional limitation experienced, usually in relation to the pain) or quality of life (a multidimensional construct that includes domains related to physical, emotional and social functioning).

Sixteen studies used measures of disability (Ahn 2017; Attal 2016; Avery 2013; Chang 2017; Cork 2004; Hazime 2017; Kang 2009; Lagueux 2017; Luedtke 2015; Mhalla 2011; Passard 2007; Short 2011; Soler 2010; Tan 2000; Tan 2006; Umezaki 2016), and 27 studies collected measures of quality of life (Avery 2013; Boyer 2014; Curatolo 2017; de Oliveira 2014; Fregni 2006b; Jales Junior 2015; Lagueux 2017; Lee 2012; Lichtbroun 2001; Mendonca 2016; Mhalla 2011; Mori 2010; Oliveira 2015; Passard 2007; Picarelli 2010; Riberto 2011;Sakrajai 2014; Short 2011; Tan 2011; Taylor 2013; Tekin 2014; Thibaut 2017; Tzabazis 2013; Valle 2009; Villamar 2013; Volz 2016; Yagci 2014).

Twenty-four studies did not report any information regarding adverse events (Ahmed 2011; André-Obadia 2011; Bae 2014; Borckardt 2009; Brietzke 2016; Cork 2004; Curatolo 2017; Defrin 2007; Gabis 2009; Harvey 2017; Jales Junior 2015; Jensen 2013; Kang 2009; Katsnelson 2004; Khedr 2005; Lefaucheur 2006; Lefaucheur 2008; Lichtbroun 2001; Pleger 2004; Riberto 2011; Tan 2000; Tan 2006; Tekin 2014; Yilmaz 2014). Reporting of adverse events in the remaining studies varied substantially in terms of detail.

Studies of rTMS

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

Table 1. Repetitive transcranial magnetic stimulation (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

    *Inconsistency between stimulation parameters and reported total number of pulses in study report. See Included studies section for mored detail.

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
Attal 2016M1 contralateral to painful sideAnteroposterior induced current108030102030003, x1 daily
André-Obadia 2006M1 contralateral to painful sidePosteroanterior20, 190

20 Hz: 20

1 Hz: 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
Borckardt 2009Left PFCNot specified101004010 sec2040003 over a 5-day period
Boyer 2014Left M1anteroposterior1090201050200014, 10 sessions in 2 weeks followed by maintenance phase of 1 session at weeks 4, 6, 8, and 10
Carretero 2009Right DLPFCNot specified11102060 sec451200Up to 20 on consecutive working days
Dall'Agnol 2014Left M145° angle from sagittal line1080161026160010, timescale not specified
Defrin 2007M1 midlineNot specified511550010 sec30? 500*10, x 1 daily
de Oliveira 2014Left DLPFC/premotornot specified10120255 sec25125010, x 1 daily (working days) for 2 weeks
Fregni 2005Left and right SIINot specified1 or 2090Not specifiedNot specifiedNot specified16001
Fregni 2011Right SIINot specified170% maximum stimulator output intensity (not RMT)1Not specifiedNot specified160010, x 1 daily (weekdays only)
Hirayama 2006M1, S1, PMA, SMANot specified5901010 sec505001
Hosomi 2013M1 corresponding to painful regionNot specified5901010 sec5050010, x 1 daily (weekdays only)
Irlbacher 2006M1 contralateral to painful sideNot specified5, 195Not specifiedNot specifiedNot specified5001
Jetté 2013M1 hand or leg area with neuro navigation45º postero-lateral10904052520001, per stimulation condition
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 (weekdays 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
Malavera 2013M1 contralateral to painful side45° angle from sagittal line109020654120010, x 1 daily (weekdays only)
Medeiros 2016Left M145° angle from sagittal line1080not reportednot reportednot reported160010, x 1 daily
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
Nardone 2017Left PFCPosteroanterior10120255 sec25125010, x5 per week for 2 weeks
Nurmikko 2016

M1 hotspot contralateral to pain

M1 in reorganised area contralateral to pain

Posteroanterior10902010 sec6020005, x 3-5 times per week
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
Short 2011Left DLPFCParasagittal10120805 sec10 sec400010, x 1 daily (working days) for 2 weeks
Tekin 2014M1 midline45° angle from sagittal line1010030512150010, x 1 daily (not clear if only work days)
Tzabazis 2013Targeted to ACC4-coil configuration1 Hz (10 Hz data excluded as not randomised)110Not reportedNot reportedNot reported180020, x 1 daily (working days)
Umezaki 2016Left DLPFCNot specified1010010510300010, x1 daily (working days)
Yagci 2014Left M1Not specified190206045120010, x1 daily (working days)
Yilmaz 2014M1 midlineHandle pointing posteriorly101030525150010, x1 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; Attal 2016; Boyer 2014; Dall'Agnol 2014; Defrin 2007; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Jetté 2013; Kang 2009; Khedr 2005; Lee 2012, Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Malavera 2013; Medeiros 2016; Mhalla 2011; Nurmikko 2016; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Tekin 2014;). Of these, one study specified stimulation of the right hemisphere (Kang 2009), five studies specified the left hemisphere (Boyer 2014; Dall'Agnol 2014; Medeiros 2016; Mhalla 2011; Yagci 2014), and four studies specified stimulation over the midline (Defrin 2007; Pleger 2004; Tekin 2014; Yilmaz 2014). 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). Seven studies stimulated the dorsolateral prefrontal cortex (DLPFC) or prefrontal cortex (PFC), with five studies stimulating the left hemisphere (Borckardt 2009; de Oliveira 2014; Nardone 2017; Short 2011; Umezaki 2016), 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

Twelve 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; Yagci 2014). 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. Thirty-nine studies investigated high-frequency (≥ 5 Hz) rTMS (Ahmed 2011; André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Attal 2016; Avery 2013; Borckardt 2009; Boyer 2014; Dall'Agnol 2014; Defrin 2007; de Oliveira 2014; Fregni 2005; Hirayama 2006; Hosomi 2013; Irlbacher 2006; Jetté 2013; Kang 2009; Khedr 2005; Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Malavera 2013; Medeiros 2016; Mhalla 2011; Nardone 2017; Nurmikko 2016; Onesti 2013; Passard 2007; Picarelli 2010; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011; Tekin 2014; Umezaki 2016; Yilmaz 2014). 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. 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. Thirteen studies specified a posteroanterior or parasagittal orientation of the stimulating coil (André-Obadia 2006; Attal 2016; Boyer 2014; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Nardone 2017; Nurmikko 2016; Passard 2007; Picarelli 2010; Short 2011; Yilmaz 2014), seven studies specified a coil orientation 45º to the midline (Ahmed 2011; Dall'Agnol 2014; Jetté 2013; Kang 2009; Malavera 2013; Medeiros 2016; Tekin 2014), 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 13 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; Yagci 2014; Yilmaz 2014), 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). One study (Nurmikko 2016) applied active stimulation at the same parameters as for the active stimulation condition, but applied to the occipital fissure, which is a site at which stimulation is not hypothesised to induce analgesia. The remaining studies utilised sham coils. Of these, 13 studies specified that the sham coil made similar or identical sounds to those elicited during active stimulation (André-Obadia 2011; Borckardt 2009; Boyer 2014; Defrin 2007; de Oliveira 2014; Irlbacher 2006; Malavera 2013; Mhalla 2011; Nardone 2017; Passard 2007; Picarelli 2010; Tekin 2014; Tzabazis 2013), and eight specified that the sham coil made similar sounds, looked the same and elicited similar scalp sensations as the real coil (Attal 2016; Avery 2013; Fregni 2011; Hosomi 2013; Jetté 2013; Onesti 2013; Short 2011; Umezaki 2016). Eight studies did not specify whether the sham coil controlled for the auditory characteristics of active stimulation (Dall'Agnol 2014; Fregni 2005; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Medeiros 2016).

Studies of CES

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

Table 2. Cranial electrotherapy stimulation (CES) studies - characteristics of stimulation
StudyElectrode placementFrequency (Hz)Pulse width (ms)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 participant'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 participant blinding. Similarly, Katsnelson 2004 utilised a visually indistinguishable sham device that delivered brief pulses of current of less than 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. Transcranial direct current stimulation (tDCS) studies - characteristics of stimulation
  1. DLPFC: dorsolateral prefrontal cortex; HD-tDCS: high definition tDCS; M1: primary motor cortex

StudyLocation of stimulation (Anode)Electrode pad sizeIntensity (mA)Anodal or cathodal?Stimulus duration (min)Treatment sessions per group
Ahn 2017M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily
Antal 2010M1 left hand area35 cm21 mAAnodal205, x 1 daily
Ayache 2016Left DLPFC25 cm22mAAnodal203, x 1 daily
Bae 2014M1 contralateral to painful side35 cm22 mAAnodal20x 3 per week for 3 weeks
Boggio 2009M1 contralateral to painful side35 cm22 mAAnodal301
Brietzke 2016Left M125-35 cm22 mAAnodal205, x 1 daily
Chang 2017M1 contralateral to painful side35 cm21 mAAnodal2016, x 2 weekly for 8 weeks
Donnell 2015M1 contralateral to painful sideHD-tDCS2 mAAnodal205, x 1 daily
Fagerlund 2015M1, side not specified35 cm22mAAnodal205, x 1 daily
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
Hagenacker 2014M1 contralateral to painful side40 cm21mAAnodal20Daily, self-administered for 14 days
Harvey 2017M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily
Hazime 2017M1 contralateral to painful side35 cm22 mAAnodal2012, x 3 per week for 4 weeks
Jales Junior 2015Left M115 cm21mAAnodal20x 1 weekly for 10 weeks
Jensen 2013M1 left35cm22 mAAnodal201
Khedr 2017M1 contralateral to painful side24 cm22 mAAnodal2010, x 1 daily, 5 days per week for 2 weeks
Kim 2013

M1, side not specified

DLPFC

25 cm22mAAnodal205, x 1 daily
Lagueux 2017M1 contralateral to painful side35 cm22 mAAnodal2014, x 5 weekly for 2 weeks, x 1 weekly for 4 weeks
Luedtke 2015M1 left side not specified35 cm22 mAAnodal205, x 1 daily
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
Mendonca 2016Left M135 cm22 mAAnodal205, x 1 daily
Mori 2010M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily
Ngernyam 2015M1 contralateral to painful side35 cm22 mAAnodal201
Oliveira 2015M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily, then x 2 weekly for 3 weeks, up to 10 sessions
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
Sakrajai 2014M1 contralateral to painful side35 cm21 mAAnodal205, x 1 daily
Soler 2010M1 contralateral to painful side or dominant hand35 cm22 mAAnodal2010, x 1 daily (weekdays only)
Souto 2014Left M125 cm22 mAAnodal205, x 1 daily
Thibaut 2017M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily
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
Volz 2016M1 contralateral to painful side35 cm22 mAAnodal205, x 1 daily
Stimulation parameters and electrode location

Four studies of tDCS stimulated the dorsolateral prefrontal cortex in one treatment group (Ayache 2016; Fregni 2006b; Kim 2013; Valle 2009). Thirty-four studies stimulated the motor cortex (Ahn 2017; Antal 2010; Bae 2014; Boggio 2009; Brietzke 2016; Chang 2017; Donnell 2015; Fagerlund 2015; Fenton 2009; Fregni 2006a; Fregni 2006b; Hagenacker 2014; Harvey 2017; Hazime 2017; Jales Junior 2015; Jensen 2013; Khedr 2017; Kim 2013; Lagueux 2017; Luedtke 2015; Mendonca 2016; Mori 2010; Ngernyam 2015; Oliveira 2015; Portilla 2013; Riberto 2011; Sakrajai 2014; Soler 2010; Souto 2014; Thibaut 2017; Valle 2009; Villamar 2013; Volz 2016; Wrigley 2014). Of these, 23 stimulated the cortex contralateral to the side of worst pain (Ahn 2017; Bae 2014; Boggio 2009; Chang 2017; Donnell 2015; Fregni 2006a; Fregni 2006b; Hagenacker 2014; Harvey 2017; Hazime 2017; Khedr 2017; Lagueux 2017; Mori 2010; Ngernyam 2015; Oliveira 2015; Portilla 2013; Riberto 2011; Sakrajai 2014; Soler 2010; Thibaut 2017; Villamar 2013; Volz 2016; 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). Seven studies stimulated the left hemisphere for all participants (Antal 2010; Brietzke 2016; Jales Junior 2015; Mendonca 2016; Souto 2014; 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 study applied anodal or cathodal stimulation to the left motor cortex or to the right supraorbital area (Mendonca 2011).

Eighteen studies delivered a current intensity of 2 mA for 20 minutes once a day for five days (Ahn 2017; Antal 2010; Brietzke 2016; Donnell 2015; Fagerlund 2015; Fregni 2006a; Fregni 2006b; Harvey 2017; Kim 2013; Luedtke 2015; Mendonca 2016; Mori 2010; Sakrajai 2014; Souto 2014; Thibaut 2017; Valle 2009; Volz 2016; Wrigley 2014). Across the remaining studies, dose, in terms of the number and frequency of stimulation sessions, varied considerably, from a single 20-minute session to up to 10 weeks of stimulation with either one or multiple sessions of stimulation in a week. In one study (Hagenacker 2014) tDCS was self-administered by participants, daily for 14 days. Six studies (Antal 2010; Chang 2017; Fenton 2009; Hagenacker 2014; Jales Junior 2015; Sakrajai 2014) delivered stimulation at a current intensity of 1 mA.

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

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

Studies awaiting classification

In this update we have 18 studies registered as awaiting classification. Of these 16 have been published as conference abstracts but we have not been able to obtain a full study report. We were unable to source the original study report for the remaining two. For further details see Characteristics of studies awaiting classification.

Ongoing studies

In this update we have identified 48 ongoing studies. These studies all investigate the effect of either tDCS or rTMS for chronic pain. For further details see Characteristics of ongoing studies.

Risk of bias in included studies

Risk of bias varied across studies for all of the assessment criteria. For summaries of 'Risk of bias' assessment across studies see Figure 2 and Figure 3.

Figure 2.

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

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Sequence generation

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

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

Allocation concealment

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

Blinding

Blinding of participants

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 angled or angled 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 angling 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 suboptimal sham control conditions and we therefore assessed them as having an 'unclear' risk of bias.

One study with a sham of this type presented a formal assessment of blinding that demonstrated blinding success (Malavera 2013) and was rated at low risk. Seven rTMS studies included in this update utilised sham coils that are visually indistinguishable, emit the same noise during stimulation and elicit similar scalp sensations (Avery 2013; Dall'Agnol 2014; Fregni 2011; Jetté 2013; Onesti 2013; Short 2011; Umezaki 2016). One study (Nurmikko 2016) applied active stimulation to a site of the brain not hypothesised to elicit analgesia as its sham condition. While there may be a risk of this stimulation having an effect we considered that this sham could be expected to be indistinguishable from real stimulation. 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 (Ahn 2017; Attal 2016; Ayache 2016; Bae 2014; Boggio 2009; Brietzke 2016; Donnell 2015; Fagerlund 2015; Fregni 2006a; Fregni 2006b; Harvey 2017; Hazime 2017; Jensen 2013; Khedr 2017; Kim 2013; Mendonca 2011; Mendonca 2016; Mori 2010; Ngernyam 2015; Oliveira 2015; Portilla 2013; Riberto 2011; Soler 2010; Souto 2014; Thibaut 2017; Valle 2009; Villamar 2013; Volz 2016; Wrigley 2014) unless there was evidence of blinding success (Lagueux 2017; Luedtke 2015). We judged one study Hagenacker 2014 at unclear risk of bias as the method of blinding was not described.

We assessed all studies of CES and RINCE and the single study of tRNS as having a low risk of bias for this criterion.

Overall, we judged 27 studies at low risk of bias, and 57 studies at unclear risk of bias.

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. This is particularly the case when a VAS is used to measure pain intensity as this requires the assessor to measure the distance from the zero anchor point to the mark made by the participant. As such, where blinding of assessors was not clearly stated we made a judgement of 'unclear' for this criterion. We rated studies of tDCS that applied stimulation intensity of 2 mA and where no formal assessment of blinding success was presented as at unclear risk of bias, since there is evidence that assessor blinding may be compromised at the stimulation intensities used (O'Connell 2012).

We judged 48 studies to be at unclear risk of bias (Ahn 2017; André-Obadia 2011; Attal 2016; Ayache 2016; Bae 2014; Boggio 2009; Borckardt 2009; Brietzke 2016; Curatolo 2017; Deering 2017; Fregni 2006a; Fregni 2006b; Hagenacker 2014; Harvey 2017; Hazime 2017; Hirayama 2006; Irlbacher 2006; Jensen 2013; Khedr 2017; Kim 2013; Lagueux 2017;Lee 2012; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Mendonca 2011; Mendonca 2016; Mori 2010; Ngernyam 2015; Oliveira 2015; Onesti 2013; Picarelli 2010; Pleger 2004; Portilla 2013; Riberto 2011; Rollnik 2002; Saitoh 2007; Sakrajai 2014; Soler 2010; Souto 2014; Tan 2000; Thibaut 2017; Tzabazis 2013; Valle 2009; Villamar 2013; Volz 2016; Wrigley 2014), two studies (Donnell 2015; Umezaki 2016) at high risk of bias, as they clearly reported that assessors were not blinded, and we rated the remaining studies at low risk of bias.

Incomplete outcome data

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

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

Selective reporting

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

Carry-over effects in cross-over trials

We judged seven studies (Attal 2016; Ayache 2016; Fenton 2009; Hagenacker 2014; Jetté 2013; Palm 2016; Portilla 2013) as unclear on this criterion as no formal investigation of carry-over effects was discussed in the study report. 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 difference (P > 0.1) and we judged this study as having a low risk of bias for carry-over effects. We rated 25 cross-over studies at low risk of bias and the remaining 52 studies were not assessed due to their parallel design.

A number of studies were judged at unclear risk of bias as information regarding between group baseline comparability was not presented.

Study size

We rated four studies at unclear risk of bias (Hosomi 2013; Lefaucheur 2004; Luedtke 2015; Tan 2011), with all remaining studies rated at high risk of bias on this criterion.

Study duration

We rated 14 studies at low risk of bias on this criterion (Ahmed 2011; Avery 2013; Dall'Agnol 2014; Gabis 2009; Hazime 2017; Luedtke 2015; Mendonca 2016; Mhalla 2011; Passard 2007; Picarelli 2010; Thibaut 2017; Valle 2009; Yagci 2014; Yilmaz 2014), 34 studies at unclear risk of bias (Ahn 2017; André-Obadia 2008; André-Obadia 2011; Antal 2010; Bae 2014; Borckardt 2009; Carretero 2009; Deering 2017; Defrin 2007; de Oliveira 2014; Donnell 2015; Fagerlund 2015; Fenton 2009; Fregni 2006a; Fregni 2006b; Fregni 2011; Hosomi 2013; Kang 2009; Khedr 2005; Khedr 2017; Kim 2013; Lagueux 2017; Lee 2012; Malavera 2013; Mori 2010; Nardone 2017; Nurmikko 2016; Oliveira 2015; Onesti 2013; Sakrajai 2014; Soler 2010; Tzabazis 2013; Umezaki 2016; Wrigley 2014), and the remaining studies at high risk of bias (André-Obadia 2006; Attal 2016; Ayache 2016; Boggio 2009; Boyer 2014; Brietzke 2016; Capel 2003; Chang 2017; Cork 2004; Curatolo 2017; Fregni 2005; Gabis 2003; Hagenacker 2014; Hargrove 2012a; Harvey 2017; Hirayama 2006; Irlbacher 2006; Jales Junior 2015; Jensen 2013; Jetté 2013; Katsnelson 2004; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Lichtbroun 2001; Medeiros 2016; Mendonca 2011; Ngernyam 2015; Palm 2016; Pleger 2004; Portilla 2013; Riberto 2011; Rintala 2010; Rollnik 2002; Saitoh 2007; Short 2011; Souto 2014; Tan 2000; Tan 2006; Tan 2011; Taylor 2013; Tekin 2014; Villamar 2013; Volz 2016).

Other potential sources of bias

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

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

Effects of interventions

See: Summary of findings for the main comparison Repetitive transcranial magnetic stimulation (rTMS) compared with sham for chronic pain; Summary of findings 2 Cranial electrotherapy stimulation (CES) compared with sham for chronic pain; Summary of findings 3 Transcranial direct current stimulation (tDCS) compared with sham for chronic pain

For a summary of all core findings, see Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3.

Primary outcome: pain intensity

Repetitive transcranial magnetic stimulation (rTMS): short-term (0 to < 1 week postintervention)

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 (27 studies, n = 655), including cross-over and parallel designs, using the generic inverse variance method (André-Obadia 2006; André-Obadia 2008; André-Obadia 2011; Avery 2013; Borckardt 2009; Carretero 2009; Defrin 2007; de Oliveira 2014; Hirayama 2006; Hosomi 2013; Jetté 2013; Kang 2009; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Lefaucheur 2006; Lefaucheur 2008; Medeiros 2016; Mhalla 2011; Nardone 2017; Passard 2007; Pleger 2004; Rollnik 2002; Saitoh 2007; Short 2011; Tekin 2014; Yagci 2014). We excluded the studies by Ahmed 2011; Boyer 2014; Dall'Agnol 2014; Khedr 2005; Irlbacher 2006; Lee 2012; Nurmikko 2016 and Umezaki 2016 as we classified them as having a high risk of bias on at least one criterion. We were unable to include data from six studies (Fregni 2005; Fregni 2011; Onesti 2013; Picarelli 2010; Tzabazis 2013; Umezaki 2016, combined n = 107) as the necessary data were not available in the study report or upon request by the submission date of this update. We could not include the data from Yilmaz 2014 as outcomes were only reported as a median (interquartile range). 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 included in the meta-analysis. For parallel studies we calculated the standard error of the mean (SEM) from the 95% confidence intervals (CIs) 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.

The pooled SMD for this comparison was -0.22 (95% CI -0.29 to -0.16, P < 0.001). We back-transformed the SMD to a mean difference using the mean standard deviation of the post-treatment sham group scores of the studies included in this analysis (1.86). We then used this to estimate the real percentage change on a 0 to 10 pain intensity scale of active stimulation compared with the mean poststimulation score from the sham groups of the included studies (5.94). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or more. Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once on the basis of inconsistency due to heterogeneity (see Summary of findings for the main comparison). We observed substantial heterogeneity (I2 = 70%, P < 0.001) and investigated this using pre-planned subgroup analyses. Categorising studies by high (≥ 5 Hz) or low (< 5 Hz) frequency, rTMS demonstrated a difference between subgroups (P < 0.001) and reduced heterogeneity in the low-frequency group (n = 106, I2 = 0%). In this group there was no evidence of an effect of low-frequency rTMS for pain intensity (SMD 0.13, 95% CI -0.03 to 0.28, P = 0.11). While high-frequency stimulation demonstrated an effect (n = 560, SMD -0.30, 95% CI -0.37 to -0.23, P < 0.001), we observed substantial heterogeneity in this analysis (P < 0.001, I2 = 68%). 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 = 357, I2 = 80%, P < 0.001) or single-dose studies (n = 319, I2 = 57%, P < 0.001) (Analysis 1.2).

There were insufficient data to support the 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), there was little impact on heterogeneity (I2 = 69%, P < 0.001). In the subgroup of non-neuropathic pain studies overall heterogeneity remained high (I2 = 77%, P < 0.001) (Analysis 1.4). Responder data were available from one study not judged at high risk of bias (Malavera 2013 n = 54, Analysis 1.14; Analysis 1.25). This demonstrated an effect in favour of active stimulation for 30% reduction in pain (risk ratio (RR) 2.11, 95% CI 1.17 to 3.80, P = 0.01).

rTMS motor cortex

Restricting the analysis to studies of high-frequency stimulation of the motor cortex (Analysis 1.5) (21 studies, n = 505) the pooled SMD was -0.37 (-0.51 to 0.22, P < 0.001) though heterogeneity was high (I2 = 67%, P < 0.001). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once on the basis of inconsistency due to heterogeneity (see Summary of findings for the main comparison).

Further restricting the analysis to single-dose studies of high-frequency stimulation of the motor cortex (n = 249) reduced heterogeneity (I2 = 23%, P = 0.19) (Analysis 1.5). The pooled SMD was -0.38 (95% CI -0.49 to -0.27, P < 0.001). We back-transformed the SMD to a mean difference using the mean standard deviation of the post-treatment sham group scores of the studies included in this analysis (2.04). We then used this to estimate the real percentage change on a 0 to 10 pain intensity scale of active stimulation compared with the mean poststimulation score from the sham groups of the included studies (6.2). This equated to a reduction of 0.77 (95% CI 0.55 to 0.99) points, or a percentage change of 12% (95% CI 9% to 16%) 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). A 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 difference between sham and active stimulation although the SMD reduced to -0.29 (95% CI -0.49 to -0.13). This equates to a percentage change of 9% (95% CI 4% to 14%) in comparison with sham stimulation. For multiple-dose studies of high-frequency motor cortex stimulation heterogeneity was high (n = 256, I2 = 82%, P < 0.001), and the pooled effect was not significant (SMD -0.34, 95% CI -0.73 to 0.05, P = 0.09).

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 and Rollnik 2002), there was little effect on the pooled estimate (SMD -0.41, 95% CI -0.52 to -0.29) or heterogeneity (I2 = 23%, P = 0.20). When we applied the same process to multiple-dose studies of high-frequency motor cortex stimulation (excluding data from Medeiros 2016; Mhalla 2011; Passard 2007; Tekin 2014 and Yagci 2014 we found no pooled effect (SMD 0.12, 95% CI -0.16 to 0.40) and heterogeneity remained high.

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). We applied the same process 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 for this subgroup.

To assess the impact of excluding the studies at high risk of bias 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 68% to 72%. Inclusion of high risk of bias studies to the multiple-dose studies of high-frequency motor cortex stimulation subgroup increased heterogeneity (I2 = 85%, P < 0.001), though the analysis demonstrated an effect (SMD -0.53, 95% CI -0.91 to -0.15, P = 0.006) (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 -0.35, 95% CI -0.46 to -0.24) with no impact on heterogeneity.

Small study effects

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 prefrontal cortex (PFC) included six studies (n = 103) (Avery 2013; Borckardt 2009; Carretero 2009; de Oliveira 2014; Nardone 2017; Short 2011) (Analysis 1.12). We excluded the study by Lee 2012 due to its high risk of bias. There was no clear pooled effect (P = 0.11) with substantial heterogeneity (I2 = 79%, P < 0.001). Restricting the analysis to high-frequency studies (Avery 2013; Borckardt 2009; Nardone 2017; Short 2011), the results were unchanged (P = 0.12, I2 = 83%, P < 0.001).

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 = 0.08) with high heterogeneity (I2 = 75%, P < 0.001).

rTMS: medium-term (≥ 1 to < 6 weeks postintervention)

Eleven studies provided data on medium-term pain outcomes (Avery 2013; Carretero 2009; de Oliveira 2014; Hosomi 2013; Lefaucheur 2001a; Kang 2009; Malavera 2013; Nardone 2017; Passard 2007; Short 2011; Yagci 2014). We excluded the studies by Ahmed 2011; Khedr 2005; Lee 2012 and Nurmikko 2016 as we classified them as having a high risk of bias. The analysis included 293 participants (Analysis 1.16). Overall heterogeneity was high (I2 = 77%, P < 0.001) and no clear evidence of effect was observed (SMD -0.28, 95% CI -0.61 to 0.05, P = 0.09). Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once on the basis of inconsistency due to heterogeneity and once for imprecision due to low participant numbers. Restricting the analysis to studies of prefrontal cortex stimulation (Avery 2013; Carretero 2009; de Oliveira 2014; Nardone 2017; Short 2011) demonstrated no clear effect (SMD -1.08, 95% CI -2.49 to 0.32, P = 0.13, I2 = 88%, P < 0.001, Analysis 1.19 ). Studies of motor cortex stimulation also demonstrated no effect (SMD -0.22, 95% CI -0.46 to 0.02, P = 0.08) although heterogeneity was high (I2 = 59%, P < 0.02) and remained high when only high-frequency stimulation studies were included (SMD -0.23 (-0.49 to 0.03, P = 0.08, I2 = 66%, P = 0.01) (Analysis 1.18). We performed sensitivity analysis to assess the impact of excluding the studies by Ahmed 2011; Khedr 2005; Lee 2012 and Nurmikko 2016 on the basis of risk of bias (Analysis 1.17). Including these studies did not substantially alter heterogeneity (I2 = 80%, P < 0.01) though the effect reached significance overall (SMD -0.50, 95% CI -0.80 to -0.20, P = 0.001).

rTMS: long-term (≥ 6 weeks postintervention)

Four studies provided data for long-term pain relief (Avery 2013; Kang 2009; Passard 2007; Yilmaz 2014) (Analysis 1.20). The analysis included 75 participants. There was no heterogeneity (I2 = 0%, P = 0.99). The analysis demonstrated no effect (SMD -0.14, 95% CI -0.44 to 0.17, P = 0.39). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers. Sensitivity analysis to assess the impact of excluding the study of Ahmed 2011 due to its high risk of bias continued to demonstrate no evidence of effect, though heterogeneity was introduced (Analysis 1.21, I2 = 57%, P = 0.05).

Cranial electrotherapy stimulation (CES): short-term (0 to < 1 week postintervention)

Six studies provided data for this analysis (Gabis 2003; Gabis 2009;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 differed 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 demonstrated superiority of active stimulation over sham and the results of the meta-analysis do not demonstrate a clear effect (SMD -0.24, 95% CI -0.48 to 0.01, P = 0.06). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers (see Summary of findings 2). 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).

CES: medium-term (≥ 1 to 6 weeks postintervention) and long-term (≥ 6 weeks postintervention)

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

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

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

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

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

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

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

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

Small study effects

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

Figure 4.

Funnel plot of comparison 3. Transcranial direct current stimulation (tDCS), outcome 3.1. Pain: short-term follow-up

Figure 5.

Funnel plot of comparison 3. Transcranial direct current stimulation (tDCS), outcome 3.5. Pain: short-term follow-up, subgroup analysis: motor cortex studies only

tDCS: medium-term (1 to < 6 weeks post-treatment)

Fourteen studies provided adequate data for this analysis (Ahn 2017; Ayache 2016 ; Bae 2014; Fagerlund 2015; Fenton 2009; Khedr 2017; Lagueux 2017; Luedtke 2015; Mendonca 2016; Mori 2010; Sakrajai 2014; Soler 2010, Volz 2016; Wrigley 2014, pooled n = 443) (Analysis 3.11). There was heterogeneity (I2 = 60%, P = 0.003) and the pooled results demonstrated an effect of tDCS (SMD -0.43, 95% CI -0.72 to -0.13, P = 0.004). Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency and once for evidence of publication bias.

Small study effects

We investigated small study effects using Egger's test. Funnel plot asymmetry was apparent and Egger's test indicated small study effects (P = 0.013).

tDCS: long-term (> 6 weeks post-treatment)

Three studies provide data for this analysis (Hazime 2017; Luedtke 2015; Mendonca 2016, pooled n = 137). There was no heterogeneity (I2 = 36%, P = 0.21) and no effect of tDCS was observed (SMD -0.01, 95% CI -0.43 to 0.41, P = 0.97) (Analysis 3.15). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers.

Reduced impedance non-invasive cortical electrostimulation (RINCE): short-term (0 to < 1 week postintervention)

The one study not at high risk of bias that investigated RINCE demonstrated a positive effect on pain intensity (n = 77, mean difference (0 to 10 pain scale) -1.41, 95% CI -2.48 to -0.34, P < 0.01) (Analysis 4.1; Hargrove 2012a). Using GRADE we rated the quality of evidence as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency (single study) and once for imprecision due to low participant numbers. Sensitivity analysis including the study at high risk of bias (Deering 2017) did not increase heterogeneity (pooled n = 115, SMD -0.59, 95% CI -0.99 to -0.18, P = 0.004).

Transcranial random noise stimulation (tRNS): short-term (0 to < 1 week postintervention)

One study at high risk of bias Palm 2016 offered data for tRNS. This study did not report a difference between active and sham stimulation (Analysis 5.1). Using GRADE we rated the quality of evidence as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency (single study) and once for imprecision due to low participant numbers. Curatolo 2017 did not report outcome data in a numeric format at any postintervention time point but the authors reported a statistically significant difference in favour of tRNS. It was not possible to extract an estimate of effect size from this high-risk-of-bias study.

tRNS: medium-term (≥1 to 6 weeks postintervention) and long-term (≥ 6 weeks postintervention)

No data were available for medium- or long-term pain outcomes for tRNS.

Secondary outcome: disability

rTMS: short-term (0 to < 1 week postintervention) disability

Five studies provided data on disability at short-term follow-up (Avery 2013; Kang 2009; Mhalla 2011; Passard 2007; Short 2011). Pooling of these studies (Analysis 1.22; n = 119) demonstrated no effect (SMD -0.29, 95% CI -0.87 to 0.29, P = 0.33) with substantial heterogeneity (I2 = 71%, P = 0.007). All of these studies delivered multiple doses of high-frequency stimulation. Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once on the basis of inconsistency due to heterogeneity and once for imprecision due to low participant numbers (see Summary of findings for the main comparison). 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. Sensitivity analysis including studies at high risk of bias (Umezaki 2016, n = 20) increased heterogeneity but did not substantially change the outcome (pooled n = 139, SMD -0.36, 95% CI -0.72 to 0.12, P = 0.16, I2 = 59%, P = 0.02).

rTMS:medium-term (1 to < 6 weeks postintervention) disability

Four studies provided data on disability at medium-term follow-up (Avery 2013; Kang 2009; Mhalla 2011; Passard 2007). Pooling of these studies (Analysis 1.24; n = 99) demonstrated no effect (SMD -0.37, 95% CI -1.07 to 0.33, P = 0.3) with heterogeneity (I2 = 78%, P = 0.004). Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once on the basis of inconsistency due to heterogeneity and once for imprecision due to low participant numbers (see Summary of findings for the main comparison).

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 = 0.001). Sensitivity analysis including studies at high risk of bias (Umezaki 2016, n = 20) increased heterogeneity but did not substantially change the outcome (pooled n = 119, SMD -0.42, 95% CI -1.01 to 0.17, P = 0.17, I2 = 72%, P < 0.001).

rTMS: long-term (≥ 6 weeks postintervention) disability

Three studies provided data on disability at long-term follow-up (Avery 2013; Kang 2009; Passard 2007). Pooling of these studies demonstrated no effect (pooled n = 63, SMD -0.23, 95% CI -0.62 to 0.16, P = 0.24) without heterogeneity (I2 = 15%, P = 0.31) (Analysis 1.26). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers. Sensitivity analysis including studies at high risk of bias (Umezaki 2016, n = 20) did not substantially change the outcome (pooled n = 83, SMD -0.41, 95% CI -0.87 to 0.05, P = 0.08, I2 = 39%, P = 0.18).

tDCS: short-term (0 to < 1 week postintervention) disability

Four studies (Ahn 2017; Chang 2017; Luedtke 2015; Soler 2010) provided data on disability in the short term. While Ayache 2016 reported disability, this was a cross-over study and we were unable to source a representative correlation coefficient for this outcome in order to calculate the standard error (SMD) for cross-over studies. No effect was seen (pooled n = 212, SMD -0.01, 95% -0.28 to 0.26, P = 0.84) and there was no heterogeneity (I2 = 0%, P = 0.59, Analysis 3.16). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers (see Summary of findings 3).

tDCS: medium-term (1 to < 6 weeks post-treatment) disability

One study (Luedtke 2015) provided data on disability in the medium term. This study demonstrated no effect of tDCS (RMDQ mean difference 0.00 (95% CI -0.38 to 0.38).

Secondary outcome: quality of life

rTMS: short-term (0 to < 1 week postintervention) quality of life

Four studies provided data on quality of life at short-term follow-up (Mhalla 2011; Passard 2007; Short 2011; Yagci 2014). 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 (FIQ) so we were able to use the mean difference as the measure of effect. Pooling data from these studies (Analysis 1.28; n = 105) demonstrated an effect in favour of active stimulation (mean difference (MD) -10.80, 95% CI -15.04 to -6.55, P < 0.001) with no heterogeneity (I2 = 0%, P = 0.96). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers (see Summary of findings for the main comparison). Tekin 2014 measured quality of life using the World Health Organization Quality of Life (WH-QoL) scale but only reported data from individual subdomains. They reported a statistically significant difference in favour of active stimulation for the physical subdomain but not the psychological, social, environmental or national domains.

rTMS: medium-term (1 to < 6 weeks postintervention) quality of life

The same four studies provided data on quality of life at medium-term follow-up (Mhalla 2011; Passard 2007; Short 2011; Yagci 2014). All studies used the FIQ so we were able to use the mean difference as the measure of effect. Pooling data from these studies (Analysis 1.29; n = 105) demonstrated an effect (MD -11.49, 95% CI -16.73 to -6.25, P < 0.001) with no heterogeneity (I2 = 0%, P = 0.82). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers. Sensitivity analysis including studies at high risk of bias (Boyer 2014) did not meaningfully alter the result (pooled n = 143, MD -8.93, 95% CI -13.49 to -4.37, P < 0.001, I2 = 15%, P = 0.32).

rTMS: long-term (≥ 6 weeks postintervention) quality of life

Data were available from two studies (Passard 2007, Yagci 2014, pooled n = 51) for quality of life at long-term follow-up. The analysis demonstrated an effect in favour of active stimulation (FIQ total score: MD -6.78, 95% CI -13.43 to -0.14, I2 = 0%, P = 0.56) (Analysis 1.31). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers. Sensitivity analysis including studies at high risk of bias (Boyer 2014) did not meaningfully alter the result (pooled n = 89, MD -8.58, 95% CI -13.84 to -3.33, P < 0.001, I2 = 0%, P = 0.58).

CES: short-term (0 to < 1 week postintervention) quality of life

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 FIQ. However, one study demonstrated a baseline imbalance of the SF-12 that exceeded in size any pre-poststimulation 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 (MD -25.05,95%CI -37.82, -12.28, Analysis 2.2). Using GRADE we rated the quality of evidence for this comparison as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency (single study) and once for imprecision due to low participant numbers (see Summary of findings 2).

tDCS: short-term (0 to < 1 week postintervention) quality of life

Four studies provided adequate data for this analysis (Jales Junior 2015; Mori 2010; Riberto 2011; Volz 2016; pooled n = 82). Of these, Jales Junior 2015 used the FIQ, Mori 2010 used the Multiple Sclerosis Quality of Life 54 scale (MS-QoL-54), Riberto 2011 used the SF-36 (total score) and Volz 2016 used the Inflammatory Bowel Disease Questionnaire Quality of Life scale. The pooled effect was in favour of active stimulation (SMD 0.66, 95% CI 0.21 to 1.11, P = 0.004) with no heterogeneity (I2 = 0%, P = 0.62) (Analysis 3.18). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers. Lagueux 2017, Mendonca 2016 and Oliveira 2015 reported quality of life using the or SF-36 and WH-QoL scales but did not report composite scores that we could enter into the meta-analysis. All three studies reported no statistically significant differences across the different quality-of-life domains. We excluded Thibaut 2017 from the analysis due to high risk of bias. They measured quality of life using the Patient Health Questionnaire (PHQ-9) but reported no significant difference between groups.

tDCS: medium-term (1 to < 6 weeks post-treatment) quality of life

At medium-term follow-up Fagerlund 2015; Mori 2010 and Volz 2016 (pooled n = 87) provided data and demonstrated no clear effect of tDCS on quality of life (SMD 0.34, 95% CI -0.09 to 0.76, P = 0.12, I2 = 0%, P = 0.54, Analysis 3.19). Using GRADE we rated the quality of evidence for this comparison as low, downgraded once on the basis of study limitations due to risk of bias and once for imprecision due to low participant numbers.

RINCE: short-term (0 to < 1 week postintervention) quality of life

One study of RINCE therapy (Hargrove 2012a, n = 77) demonstrated no effect on quality of life (FIQ, MD -6.50, 95% CI -15.21 to 2.21, Analysis 4.3). Using GRADE we rated the quality of evidence as very low, downgraded once on the basis of study limitations due to risk of bias, once for inconsistency (single study) and once for imprecision due to low participant numbers. Sensitivity analysis including studies at risk of bias (the addition of Deering 2017, n = 38) did not alter the outcome (SMD -0.45, 95% CI -0.91 to 0.02, P = 0.06, I2 = 10%, P = 0.33).

Secondary outcome: adverse events

rTMS
Minor

Thirty-one of 42 studies of rTMS reported on adverse events. Of these, 10 studies reported none (André-Obadia 2006; André-Obadia 2008; Boyer 2014; Fregni 2005; Hirayama 2006; Lefaucheur 2001a; Lefaucheur 2001b; Lefaucheur 2004; Onesti 2013; Saitoh 2007). Attal 2016 reported similar proportions of side effects between stimulation conditions with no serious events. 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. 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. Dall'Agnol 2014 reported that they did not observe moderate or severe adverse effects but did not report any details on the incidence of mild effects. de Oliveira 2014 reported mild headaches in three participants (27.3%) receiving active rTMS and in one participant receiving sham rTMS. 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. Hosomi 2013 reported no difference between real and sham rTMS for minor adverse events. Jetté 2013 reported that seven participants receiving rTMS reported mild discomfort related to scalp pressure and facial twitching. Malavera 2013 reported no serious adverse effects but reports of headache, neck pain and sleepiness without differences between groups, while Medeiros 2016 simply reported that they did not observe serious or moderate side effects from the treatment, with no further detail. Mhalla 2011 reported that nine participants (five following active stimulation and four following sham stimulation) reported transient headache, and one participant reported transient dizziness after active stimulation. Nardone 2017 reported that two participants undergoing active rTMS reported uncomfortable twitching of facial muscles during stimulation but that rTMS was tolerated well. Nurmikko 2016 reported that rTMS was well tolerated. Minor adverse effects observed during active stimulation included headache (25%), sleepiness (38%), transient increase in pain (31%) and dizziness (15%). 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). 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. Rollnik 2002 reported that one participant experienced headache, but it is unclear in the report whether this was following active or sham stimulation. Short 2011 reported that there were few side effects.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 versus 11% following sham) were more common with active stimulation. Umezaki 2016 reported headaches in seven (58%) participants in the active stimulation and five (62%) in the sham stimulation group that were mild and resolved in one to two days. Yagci 2014 reported that three (23%) participants in the active group and one (8%) in the sham group reported adverse events. They only described those in the active group, which were two cases of transient headache and one of "daily tinnitus".

Major

Both Lee 2012 and Picarelli 2010 reported one incidence of seizure following high-frequency active stimulation. The seizures occurred after the 6th and 7th session of active stimulation respectively. Nurmikko 2016 reported that one participant experienced a permanent reduction of hearing during an active stimulation phase. Investigations ruled out cochlear damage leading the study authors to conclude that an association with rTMS was unlikely.

CES

Four out of 11 studies of CES reported the incidence of adverse events (Capel 2003; Gabis 2003; Rintala 2010; Tan 2011). In these studies no serious adverse events were reported. Rintala 2010 reported that in the active stimulation group participants reported incidences of pulsing, tingling and tickling in the ears (three participants), tender ears (one participant) and a pins and needles feeling near the 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

Thirty out of 36 studies of tDCS reported the incidence of adverse events with varying degrees of detail. Of these, five studies reported none (Fregni 2006a; Hagenacker 2014; Mendonca 2011; Mori 2010; Portilla 2013). Attal 2016 reported similar proportions of side effects between stimulation conditions with no serious events. Most studies reported similar rates of mild and transient effects. Ahn 2017 reported six incidents of pain at the stimulation site; two in the sham group and four in the active group. One participant in the active group reported change in visual perception. Thirteen participants reported tingling, itching or burning sensations at the stimulation site. The severity of these symptoms was rated as low. Tingling was more common during active 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. Ayache 2016 reported that headache occurred in three participants after active stimulation and one after sham but that otherwise rates were similar between active and sham stimulation and there was no difference in discomfort rates. Boggio 2009 reported that one participant experienced headache with active stimulation. Chang 2017 reported two adverse reactions to tDCS, one participant reported a headache after active stimulation and one participant reported a single incident of painful sensation under the electrode that resolved on cessation of stimulation. Donnell 2015 reported only mild adverse events with higher rates of skin redness in the active group (16.6% in active group versus 3.3% in the sham group) but similar rates for all others. Fagerlund 2015 found no difference in adverse events between active and sham stimulation except for acute mood change, which was higher in the sham group. However trouble concentrating was higher after active stimulation (18% of total sessions after active stimulation versus 5% of sessions after sham), as was scalp pain (18% of sessions versus 9%) and headache (18% of sessions versus 12%).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. Hazime 2017 reported the incidence of a variety of adverse effects but did not separate them into active and sham stimulation groups. These included headache, neck pain, scalp pain, back pain, tingling, itching, redness, burning sensations, sleepiness, trouble concentrating and largely reported as mild or moderate in severity. Khedr 2017 reported that all participants tolerated stimulation well with three cases of itching and redness seen in the active stimulation group. Kim 2013 reported that all participants tolerated tDCS well without "significant adverse events". Headache was reported in three participants, all in an active stimulation group, and skin itching was reported by three participants, one in each active stimulation group and one in the sham group. Lagueux 2017 reported that three participants in the active stimulation group and two in the sham group reported minor transient headaches. One participant reported skin redness and itching after active stimulation. Two participants in the active group and one in the sham group reported feelings of tiredness. Four participants in the active stimulation group are reported to have declared "being indisposed" by a stinging/ burning sensation under the electrodes. Luedtke 2015 briefly reported that the stimulation was tolerated well with minimal transitory side effects but gave no further detail. Mendonca 2016 reported just that all adverse events were mild and did not differ between groups, with no further detail. Ngernyam 2015 reported that all participants tolerated stimulation well, seven (of 20) in the active group experienced erythematous skin rash at the cathode placement site. Oliveira 2015 also did not formally report all events but reported that one of the participants suffered burns due to an electrode being placed on a skin site with acne, the skin healed but left a small scar. Similarly Sakrajai 2014 reported no adverse events in either group except transient skin redness in 13% of the active group. Soler 2010 recorded three reports of headache, all following active stimulation. Souto 2014 recorded adverse events in nine out of 10 participants in the sham group and all 10 participants in the active group. Thibaut 2017 reported that all participants tolerated stimulation well and that the majority reported mild to moderate itching and tingling during both active and sham stimulations. These were all mild and transient. 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 were equally distributed between active and sham stimulation. Volz 2016 reported no differences in side effects between stimulation groups except that skin redness was more common in the active group. Wrigley 2014 reported only "mild to moderate" side effects with no difference between active and sham over the 24-hour poststimulation 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. Bae 2014; Brietzke 2016; Harvey 2017; Jales Junior 2015; Jensen 2013 and Riberto 2011 did not consider adverse events in their study reports.

tRNS

Curatolo 2017 did not report on adverse events. Palm 2016 reported similar rates of adverse events between the active and sham groups with no suggestion of higher rates of any in the active group. Phosphenes were reported by one participant after sham treatment but none after active treatment. Six participants reported insomnia after sham treatment compared to five after tRNS, nausea occurred in four participants after sham treatment and in two after tRNS. Severe headache was reported by one participant after sham treatment but no participants reported severe headache after active stimulation.

RINCE

Hargrove 2012a reported a low incidence of side effects from RINCE 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). Deering 2017 reported an average of two adverse events per participant, of which 47% were reported to be mild and 50% moderate in severity. Thirty-seven per cent of adverse events were reported to be related to study treatments. The authors reported that compared to sham, RINCE may be associated with small increases in the risk of mild to moderate headaches, nausea, dizziness/vertigo, and localised skin reactions, possibly due to the electrode gel. All events were short lived and resolved without further intervention.

The study by Attal 2016 delivered both rTMS and tDCS. They reported that the proportion of participants displaying side effects was low and similar between active rTMS or tDCS and sham stimulations. Three (out of 35) participants withdrew from the study because of side effects, after the second day of stimulation in the second treatment block.

Discussion

Summary of main results

This update has included a substantial number of new studies. Despite this our findings have not altered substantially from the previous version of this review.

Repetitive transcranial magnetic stimulation (rTMS) for chronic pain

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

Cranial electrotherapy stimulation (CES) for chronic pain

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

Transcranial direct current stimulation (tDCS) for chronic pain

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

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

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

Transcranial random noise stimulation (tRNS) for chronic pain

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

Secondary outcome measures

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

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

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

Overall completeness and applicability of evidence

For rTMS we were unable to include pain intensity data from six full published studies (Fregni 2005; Fregni 2011, Onesti 2013; Picarelli 2010; Tzabazis 2013; Umezaki 2016, combined n = 107). In addition, we identified 11 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 is 438, assuming that some reports refer to the same study.

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 three studies of tDCS (Donnell 2015; Mendonca 2011; Valle 2009), and these data were not made available upon request to the study authors. These data would have contributed a further 95 participants to our analysis and may have altered our conclusions. In addition, we identified five studies of tDCS (Acler 2012; Albu 2011; Knotkova 2011; Moreno-Duarte 2013a; Mylius 2013) published in abstract format that appear clearly relevant for which we have not been able to acquire full study reports.

For both rTMS and tDCS there are a number of ongoing studies identified through the trials registry searches. Of note, eight trials were registered prior to 2012, seven of which are of tDCS and have not yet been published to our knowledge. Given our finding of small study effects in tDCS studies this gives cause for concern regarding the risk of potential publication bias and this is reflected in our GRADE judgements. 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, meaning that our confidence in the effect estimate is limited or we have very little confidence in the effect estimate and the true effect is likely to be substantially different from the estimated effect. In large part this is due to issues of blinding and of precision. The majority of studies of rTMS were at unclear risk of bias. The predominant reason for this was the use of suboptimal 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. Furthermore, 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. The combined evidence from studies of high-frequency rTMS to the motor cortex that delivered multiple doses, so better reflecting the likely clinical delivery of rTMS (excluding studies judged as being at high risk of bias), demonstrate no effect, but with substantial heterogeneity.

There are multiple sources of potential heterogeneity within the rTMS literature, relating to stimulation parameters, dose and population. We have explored, through pre-planned subgroup analyses the influence of cortical target, stimulation frequency and dose at the crude level of single versus multiple dose. However we did not plan to formally explore the influence of all of the potential sources of variation in terms of stimulation parameters. As an example it is possible that some studies delivered suboptimal stimulation in terms of the numbers of pulses delivered, which ranged in our review from 120 to more than 2000 per treatment session. In addition, for studies of motor cortex stimulation there was variation in the somatotopic target of stimulation and this may be an important factor. While some studies used imaging-based neuro-navigation techniques to more precisely locate targeted brain regions most did not. There were not adequate data to meaningfully explore the influence of using neuro-navigation on outcomes. There is evidence that approaches to identifying prefrontal targets that do not use neuronavigation are inaccurate (Ahdab 2010; Herwig 2001). Should neuro-navigation be found to be crucial to effectiveness it would have implications for the costs and availability of this intervention.

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 first version of this review that 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 (Ezquerro 2014; Horvath 2014; O'Connell 2012; Wallace 2016). Meta-epidemiological evidence demonstrates that incomplete blinding in controlled trials that measure subjective outcomes may exaggerate the observed effect sizes (Savovic 2012; 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. It is noteworthy that the largest study of tDCS (Luedtke 2015), also judged at low risk of bias for all criteria except study size, demonstrated no effect of tDCS versus sham.

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 small study bias and the related issue of publication bias, wherein there is a propensity for small negative studies to not reach full publication. There is evidence that this might lead to an overly positive picture for some interventions (Dechartres 2013; 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 Cochrane Reviews of amitriptyline for neuropathic pain and fibromyalgia (Moore 2015a; Moore 2015b), smaller studies were associated with substantially lower numbers needed to treat for an additional beneficial outcome (NNTBs) 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. In this update we found evidence of small study effects affecting the tDCS evidence, but not for rTMS or CES. However, it is accepted that existing approaches to detecting publication bias are unsatisfactory and lack sensitivity. It should therefore 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. Funnel plot asymmetry may be explained by reasons other than publication bias, such as methodological quality, or simple chance (Sterne 2011), but for tDCS there is an association between study size and effect size, with smaller studies demonstrating larger 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 reduced this heterogeneity in some instances.

Many of the 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 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 0-10 pain intensity 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 pharmacological treatments has been found to display a bimodal distribution (Moore 2013). More plainly, some participants demonstrate a substantial improvement with pain therapies while many demonstrate little or no change, with few individual participants demonstrating a change 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 analyses 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 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 only a small number of participants. We are not aware of any direct evidence that participant outcomes are commonly bimodally distributed following these interventions and a recent analysis of data from trials of various non-surgical interventions for spinal pain did not find evidence for bimodal distribution of outcomes (O'Connell 2017). It is also worth noting that when the effect estimates were back-transformed to a 0 to 10 pain intensity scale they were also below theminimal clinically important difference threshold for the between-group difference of 1 point recently recommended by the OMERACT-12 group (Busse 2015).

Agreements and disagreements with other studies or reviews

The European Academy of Neurology published guidelines on the use of neurostimulation therapy for chronic neuropathic pain in 2017 (Cruccu 2017). Based on a narrative synthesis of the evidence gave "weak recommendations" for the use of rTMS in neuropathic pain and fibromyalgia and "inconclusive recommendations" in CRPS. They offered "inconclusive recommendations" regarding tDCS for fibromyalgia and "weak recommendations" for the use of tDCS for peripheral neuropathic pain. The 'weak' descriptor term used to describe the positive recommendations was based on the low quality of the supporting evidence. Another recent guideline specific to the use of rTMS (Lefaucheur 2014) concluded that there was "level A evidence", which represents "definite efficacy" for the analgesic effect of high frequency rTMS applied to the motor cortex contralateral to the side of pain. In light of our findings we suggest that this assessment of the evidence may not adequately reflect the numerous limitations of the evidence base.

Leung 2009 performed a meta-analysis of individual participant 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 noxious input (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 study authors also performed an analysis of the influence of the neuroanatomical origins of noxious input 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 noxious input, 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 higher following active stimulation compared with sham (risk ratio 2.64, 95% 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 in the main analysis published since that review (André-Obadia 2008; Defrin 2007; Hosomi 2013; Jetté 2013; Kang 2009; Lefaucheur 2006; Lefaucheur 2008; Medeiros 2016; Mhalla 2011; Passard 2007; Saitoh 2007; Tekin 2014; Yagci 2014). 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, 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 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 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 of 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 dropout. The results of their meta-analysis are broadly consistent with those presented here in that the authors 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. 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 postspinal 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 did not suggest a 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.

A recent review of rTMS for chronic pain (Galhardoni 2015) concluded that rTMS has potential utility. This review reported that rTMS was frequently associated with greater that 30% pain relief when compared with a control treatment, though no meta-analysis was reported and no formal assessment of study quality or risk of bias was presented. Our results suggest that, compared with sham, rTMS is associated with somewhat smaller effects and that the effect estimate may be exaggerated by various biases in the literature.

While many reviews have concluded positively regarding the effectiveness and early promise of non-invasive brain stimulation techniques this is frequently based on markers of statistical significance and arguably does not adequately consider the influence of the various biases at play in the literature.

Authors' conclusions

Implications for practice

For people with chronic pain

There is a lack of high-quality evidence to support or refute the effectiveness of non-invasive brain stimulation techniques for chronic pain. Due to the small size of included studies and limitations in the way that many studies were conducted, future studies may have a substantial impact upon the estimates of effects presented.

For clinicians

Low- or very low-quality evidence suggests that low-frequency repetitive transcranial magnetic stimulation (rTMS), or rTMS applied to the prefrontal cortex, may not be effective for the treatment of chronic pain. Subgroup analysis suggests that single doses of high-frequency rTMS of the motor cortex may 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 to the motor cortex is heterogeneous but does not demonstrate an effect (very low-quality evidence). Very low-quality evidence suggests that transcranial direct current stimulation (tDCS) may have short-term effects on chronic pain but these observed effects may be exaggerated by the dominance of small studies and other sources of bias. Low-quality evidence suggests that cranial electrotherapy stimulation (CES) is not effective. Due to this uncertainty, clinical application of non-invasive brain stimulation techniques would be most appropriate within a clinical research setting rather than in routine clinical care and it is not currently clear if any form of non-invasive brain stimulation is a useful clinical tool.

For policy makers and funders of the intervention

There is a lack of high-quality evidence to support or refute the effectiveness of non-invasive brain stimulation techniques when compared to sham stimulation for people with chronic pain. The short-term effects observed for rTMS and tDCS on pain may be exaggerated by the dominance of small studies and limitations in study methods. There is not currently a strong evidence base for routinely offering these options for the treatment of chronic pain.

Implications for research

General

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. It is noteworthy that in the seven years since our original review the number of included studies has risen substantially but our conclusions have not changed. Contrasting the large number of trials included in this review with the persisting lack of certainty over its effectiveness speaks to a problem of research waste.

After our first review of this evidence was completed in 2010 we recommended that there was a need to examine the more promising findings within the existing data through more robust, large, rigorous, adequately blinded trials that deliver a reasonable dose and investigate effects over a meaningful timescale (O'Connell 2011). Until a body of this type of research is generated there will continue to be uncertainty over the clinical utility of any form of non-invasive brain stimulation for chronic pain. This recommendation is relevant to all other types of non-invasive brain stimulation. The ongoing studies, identified from searching trials registers, predominantly consist of more, relatively small trials and it is unlikely that the results will meaningfully change the findings of this review. A recent consensus statement (Klein 2015) has produced guidelines for future rTMS research on clinical pain with the goal of improving quality and these recommendations should be taken under consideration.

The proliferation of small heterogeneous trials presents a challenge to evidence synthesis. A robust, large scale trial of rTMS or tDCS might fail to reduce uncertainty if included in the same analysis as the existing trials. For future reviews of this evidence base, that seek to answer the question of clinical effectiveness, there may be a case for excluding single-dose trials on the basis of inadequate dose and trials below a threshold size on the basis of imprecision. There is also a case for not updating the current review until trials of adequate size have been added to the evidence base, since an update characterised by the inclusion of more, small heterogeneous trials will sufficiently reduce uncertainty.

Design

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 valid sham controls. Future studies should have a strong theoretical basis underpinning the choice of stimulation location and parameters and ensure that stimulation delivered to high technical standards. Future studies of tDCS should give consideration to the integrity of participant blinding, particularly when utilising stimulation intensities that exceed 1 mA. The field should seek to generate consensus on optimal stimulation parameters and procedures.

Outcome measurement

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). All studies of non-invasive brain stimulation techniques should measure, record and clearly report adverse events from both active and sham stimulation.

Acknowledgements

For this update

We would like to extend particular thanks to Cochrane Pain, Palliative and Supportive Care for their assistance throughout the review, in particular Anna Erskine (nee Hobson) and Joanne Abbott. We would also like to thank the following authors for generously providing additional data for this review upon request: Dr Paradee Auvichayapa, Dr Abrahão Fontes Baptista, Dr Jeffrey Hargrove, Dr Catherine Mercier. We would like to thank Professor Turo Nurmikko and Janet Wale for their valuable peer review comments.

For 2014 update

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 Erskine (née 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 Andrea Antal, Professor Mark Jensen, Dr Francesco Mori, Dr Marcelo Riberto, Prof Youichi Saitoh and Ann Gillian Taylor.

For 2010 version of review

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 also like to thank the following authors for generously providing additional data for this review upon request: Dr Nathalie André-Obadia, Dr Didier Bouhassira, Dr Ruth Defrin, Dr Bradford Fenton, Dr Felipe Fregni, Dr Linda Gabis/Dr Ranann Raz, Dr Eman Khedr, Prof. Jean-Pascale Lefaucheur, Dr Burkhard Pleger, Prof. Jens Rollnik, Prof Youichi Saitoh.

Cochrane Review Group funding acknowledgement: this project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pain, Palliative and Supportive Care (PaPaS). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

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-up27 Std. Mean Difference (Fixed, 95% CI)-0.22 [-0.29, -0.16]
1.1 Low-frequency ≤ 1 Hz7 Std. Mean Difference (Fixed, 95% CI)0.13 [-0.03, 0.28]
1.2 High-frequency ≥ 5 Hz25 Std. Mean Difference (Fixed, 95% CI)-0.30 [-0.37, -0.23]
2 Pain: short-term follow-up, subgroup analysis: multiple-dose vs single-dose studies27 Std. Mean Difference (Random, 95% CI)-0.26 [-0.40, -0.13]
2.1 Single-dose studies13 Std. Mean Difference (Random, 95% CI)-0.23 [-0.36, -0.10]
2.2 Multiple-dose studies14 Std. Mean Difference (Random, 95% CI)-0.40 [-0.76, -0.05]
3 Pain: short-term follow-up, subgroup analysis, neuropathic pain participants only17 Std. Mean Difference (Fixed, 95% CI)-0.20 [-0.28, -0.13]
3.1 Low-frequency ≤ 1 Hz5 Std. Mean Difference (Fixed, 95% CI)0.15 [-0.02, 0.32]
3.2 High-frequency ≥ 5 Hz17 Std. Mean Difference (Fixed, 95% CI)-0.28 [-0.36, -0.20]
4 Pain: short-term follow-up, subgroup analysis, non-neuropathic pain participants only8 Std. Mean Difference (Fixed, 95% CI)-0.39 [-0.61, -0.17]
4.1 Low-frequency ≤ 1 Hz1 Std. Mean Difference (Fixed, 95% CI)0.16 [-0.29, 0.61]
4.2 High-frequency ≥ 5 Hz7 Std. Mean Difference (Fixed, 95% CI)-0.56 [-0.81, -0.31]
5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded21 Std. Mean Difference (Random, 95% CI)-0.37 [-0.51, -0.22]
5.1 Single-dose studies13 Std. Mean Difference (Random, 95% CI)-0.38 [-0.49, -0.27]
5.2 Multiple-dose studies8 Std. Mean Difference (Random, 95% CI)-0.34 [-0.73, 0.05]
6 Sensitivity analysis - imputed correlation coefficient increased. Pain: short-term follow-up29 Std. Mean Difference (Random, 95% CI)-0.27 [-0.40, -0.14]
6.1 Low-frequency ≤ 1 Hz7 Std. Mean Difference (Random, 95% CI)0.15 [0.01, 0.29]
6.2 High-frequency ≥ 5 Hz28 Std. Mean Difference (Random, 95% CI)-0.35 [-0.49, -0.22]
7 Sensitivity analysis - imputed correlation coefficient decreased. Pain: short-term follow-up28 Std. Mean Difference (Random, 95% CI)-0.26 [-0.40, -0.13]
7.1 Low-frequency ≤ 1 Hz7 Std. Mean Difference (Random, 95% CI)0.13 [-0.06, 0.33]
7.2 High-frequency ≥ 5 Hz26 Std. Mean Difference (Random, 95% CI)-0.34 [-0.49, -0.19]
8 Sensitivity analysis - imputed correlation increased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded20 Std. Mean Difference (Random, 95% CI)-0.37 [-0.50, -0.24]
8.1 Single-dose studies13 Std. Mean Difference (Random, 95% CI)-0.39 [-0.50, -0.28]
8.2 Multiple-dose studies7 Std. Mean Difference (Random, 95% CI)-0.33 [-0.71, 0.04]
9 Sensitivity analysis - imputed correlation decreased. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded20 Std. Mean Difference (Random, 95% CI)-0.37 [-0.52, -0.22]
9.1 Single-dose studies13 Std. Mean Difference (Random, 95% CI)-0.37 [-0.47, -0.26]
9.2 Multiple-dose studies7 Std. Mean Difference (Random, 95% CI)-0.36 [-0.81, 0.09]
10 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up31 Std. Mean Difference (Fixed, 95% CI)-0.27 [-0.34, -0.20]
10.1 Low-frequency ≤ 1 Hz10 Std. Mean Difference (Fixed, 95% CI)0.07 [-0.07, 0.22]
10.2 High-frequency ≥ 5 Hz28 Std. Mean Difference (Fixed, 95% CI)-0.36 [-0.44, -0.29]
11 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: motor cortex studies only, low-frequency studies excluded24 Std. Mean Difference (Random, 95% CI)-0.41 [-0.55, -0.26]
11.1 Single-dose studies15 Std. Mean Difference (Random, 95% CI)-0.35 [-0.46, -0.24]
11.2 Multiple-dose studies10 Std. Mean Difference (Random, 95% CI)-0.53 [-0.91, -0.15]
12 Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only6 Std. Mean Difference (Random, 95% CI)-0.67 [-1.48, 0.15]
12.1 Low frequency ≤ 1 Hz1 Std. Mean Difference (Random, 95% CI)0.16 [-0.29, 0.61]
12.2 High frequency ≥ 5 Hz5 Std. Mean Difference (Random, 95% CI)-0.92 [-1.95, 0.12]
13 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up, subgroup analysis: prefrontal cortex studies only7 Std. Mean Difference (Random, 95% CI)-0.64 [-1.36, 0.08]
13.1 Multiple-dose studies7 Std. Mean Difference (Random, 95% CI)-0.64 [-1.36, 0.08]
14 Pain: short term responder analysis 30% pain reduction289Risk Ratio (M-H, Random, 95% CI)2.11 [1.17, 3.80]
15 Sensitivity analysis- inclusion of high risk of bias studies. Disability: medium-term follow-up5 Std. Mean Difference (Random, 95% CI)-0.42 [-1.01, 0.17]
16 Pain: medium-term follow-up11 Std. Mean Difference (Random, 95% CI)-0.28 [-0.61, 0.05]
16.1 Low-frequency ≤ 1 Hz2 Std. Mean Difference (Random, 95% CI)0.14 [-0.41, 0.69]
16.2 High-frequency ≥ 5 Hz9 Std. Mean Difference (Random, 95% CI)-0.36 [-0.73, 0.00]
17 Sensitivity analysis - inclusion of high risk of bias studies. Pain: medium-term follow-up15 Std. Mean Difference (Random, 95% CI)-0.50 [-0.80, -0.20]
17.1 Low-frequency ≤ 1 Hz3 Std. Mean Difference (Random, 95% CI)0.02 [-0.52, 0.56]
17.2 High-frequency ≥ 5 Hz13 Std. Mean Difference (Random, 95% CI)-0.57 [-0.90, -0.25]
18 Pain: medium-term follow-up, subgroup analysis: motor cortex studies only6 Std. Mean Difference (Random, 95% CI)-0.22 [-0.46, 0.02]
18.1 Low frequency ≤ 1Hz1 Std. Mean Difference (Random, 95% CI)-0.08 [-0.86, 0.70]
18.2 High-frequency ≥ 5 Hz5 Std. Mean Difference (Random, 95% CI)-0.23 [-0.49, 0.03]
19 Pain: medium-term follow-up, subgroup analysis: prefrontal cortex studies only5 Std. Mean Difference (Random, 95% CI)-1.08 [-2.49, 0.32]
19.1 Low frequency ≤ 1 Hz1 Std. Mean Difference (Random, 95% CI)0.36 [-0.41, 1.13]
19.2 High-frequency ≥ 5 Hz4 Std. Mean Difference (Random, 95% CI)-1.74 [-3.66, 0.19]
20 Pain: long-term follow-up4 Std. Mean Difference (Random, 95% CI)-0.14 [-0.44, 0.17]
21 Sensitivity analysis - inclusion of high risk of bias studies. Pain: long-term follow-up5 Std. Mean Difference (Random, 95% CI)-0.40 [-0.89, 0.10]
22 Disability: short-term follow-up5 Std. Mean Difference (Random, 95% CI)-0.29 [-0.87, 0.29]
23 Sensitivity analysis- inclusion of high risk of bias studies. Disability: short-term follow-up7 Std. Mean Difference (Random, 95% CI)-0.30 [-0.72, 0.12]
24 Disability: medium-term follow-up4 Std. Mean Difference (Random, 95% CI)-0.37 [-1.07, 0.33]
25 Pain: short term responder analysis 50% pain reduction154Risk Ratio (M-H, Random, 95% CI)1.89 [1.03, 3.47]
26 Disability: long-term follow-up3 Std. Mean Difference (Random, 95% CI)-0.23 [-0.62, 0.16]
27 Sensitivity analysis - inclusion of high risk of bias studies. Disability: long-term follow-up4 Std. Mean Difference (Random, 95% CI)-0.41 [-0.87, 0.05]
28 Quality of life: short-term follow-up (Fibromyalgia Impact Questionnaire)4105Mean Difference (IV, Random, 95% CI)-10.80 [-15.04, -6.55]
29 Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire)4105Mean Difference (IV, Fixed, 95% CI)-11.49 [-16.73, -6.25]
30 Sensitivity analysis - inclusion of high risk of bias studies. Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire)5143Mean Difference (IV, Fixed, 95% CI)-8.93 [-13.49, -4.37]
31 Quality of life: long-term follow-up251Mean Difference (IV, Fixed, 95% CI)-6.78 [-13.43, -0.14]
32 Sensitivity analysis - inclusion of high risk of bias studies. Quality of life: long-term follow-up389Mean Difference (IV, Fixed, 95% CI)-8.58 [-13.84, -3.33]
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: short term responder analysis 30% pain reduction.

Analysis 1.15.

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

Analysis 1.16.

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

Analysis 1.18.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 18 Pain: medium-term follow-up, subgroup analysis: motor cortex studies only.

Analysis 1.19.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 19 Pain: medium-term follow-up, subgroup analysis: prefrontal cortex studies only.

Analysis 1.20.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 20 Pain: long-term follow-up.

Analysis 1.21.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 21 Sensitivity analysis - inclusion of high risk of bias studies. Pain: long-term follow-up.

Analysis 1.22.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 22 Disability: short-term follow-up.

Analysis 1.23.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 23 Sensitivity analysis- inclusion of high risk of bias studies. Disability: short-term follow-up.

Analysis 1.24.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 24 Disability: medium-term follow-up.

Analysis 1.25.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 25 Pain: short term responder analysis 50% pain reduction.

Analysis 1.26.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 26 Disability: long-term follow-up.

Analysis 1.27.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 27 Sensitivity analysis - inclusion of high risk of bias studies. Disability: long-term follow-up.

Analysis 1.28.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 28 Quality of life: short-term follow-up (Fibromyalgia Impact Questionnaire).

Analysis 1.29.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 29 Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire).

Analysis 1.30.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 30 Sensitivity analysis - inclusion of high risk of bias studies. Quality of life: medium-term follow-up (Fibromyalgia Impact Questionnaire).

Analysis 1.31.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 31 Quality of life: long-term follow-up.

Analysis 1.32.

Comparison 1 Repetitive transcranial magnetic stimulation (rTMS), Outcome 32 Sensitivity analysis - inclusion of high risk of bias studies. 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 Quality of life: short term follow up1 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 Quality of life: short term follow up.

Comparison 3. Transcranial direct current stimulation (tDCS)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain: short-term follow-up26 Std. Mean Difference (Random, 95% CI)-0.43 [-0.63, -0.22]
1.1 Single-dose studies4 Std. Mean Difference (Random, 95% CI)-0.18 [-0.38, 0.02]
1.2 Multiple-dose studies22 Std. Mean Difference (Random, 95% CI)-0.51 [-0.77, -0.25]
2 Pain: short-term sensitivity analysis: correlation increased26 Std. Mean Difference (Random, 95% CI)-0.43 [-0.62, -0.23]
3 Pain: short-term sensitivity analysis: correlation decreased26 Std. Mean Difference (Random, 95% CI)-0.44 [-0.64, -0.23]
4 Pain: short term sensitivity analysis, inclusion of high risk of bias studies31 Std. Mean Difference (Random, 95% CI)-0.48 [-0.67, -0.29]
4.1 Single-dose studies4 Std. Mean Difference (Random, 95% CI)-0.18 [-0.38, 0.02]
4.2 Multiple-dose studies27 Std. Mean Difference (Random, 95% CI)-0.56 [-0.79, -0.32]
5 Pain: short-term follow-up, subgroup analysis: motor cortex studies only25 Std. Mean Difference (Random, 95% CI)-0.47 [-0.67, -0.28]
5.1 Single-dose studies4 Std. Mean Difference (Random, 95% CI)-0.18 [-0.38, 0.02]
5.2 Multiple-dose studies21 Std. Mean Difference (Random, 95% CI)-0.58 [-0.84, -0.33]
6 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation increased26 Std. Mean Difference (Random, 95% CI)-0.45 [-0.64, -0.26]
6.1 Single-dose studies4 Std. Mean Difference (Random, 95% CI)-0.18 [-0.37, 0.01]
6.2 Multiple-dose studies22 Std. Mean Difference (Random, 95% CI)-0.55 [-0.81, -0.30]
7 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation decreased26 Std. Mean Difference (Random, 95% CI)-0.40 [-0.58, -0.22]
7.1 Single-dose studies4 Std. Mean Difference (Random, 95% CI)-0.18 [-0.38, 0.03]
7.2 Multiple-dose studies22 Std. Mean Difference (Random, 95% CI)-0.49 [-0.72, -0.26]
8 Pain: short-term follow-up, subgroup analysis, neuropathic and non neuropathic pain25 Std. Mean Difference (Random, 95% CI)-0.37 [-0.56, -0.19]
8.1 Neuropathic9 Std. Mean Difference (Random, 95% CI)-0.26 [-0.53, 0.01]
8.2 Non neuropathic16 Std. Mean Difference (Random, 95% CI)-0.42 [-0.67, -0.17]
9 Pain: short term follow-up responder analysis 30% pain reduction2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10 Pain: short term follow-up responder analysis 50% pain reduction2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11 Pain: medium-term follow-up14 Std. Mean Difference (Random, 95% CI)-0.43 [-0.72, -0.13]
12 Pain: medium term follow-up responder analysis 30% pain reduction1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13 Pain: medium term follow-up responder analysis 50% pain reduction2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14 Sensitivity analysis - inclusion of high risk of bias studies. Pain: medium-term follow-up16 Std. Mean Difference (Random, 95% CI)-0.45 [-0.72, -0.18]
15 Pain: long-term follow-up3 Std. Mean Difference (Random, 95% CI)-0.01 [-0.43, 0.41]
16 Disability: short-term follow-up4212Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.28, 0.26]
17 Disability: medium-term follow-up1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
18 Quality of life: short-term follow-up482Std. Mean Difference (IV, Random, 95% CI)0.66 [0.21, 1.11]
19 Quality of life: medium-term follow-up387Std. Mean Difference (IV, Random, 95% CI)0.34 [-0.09, 0.76]
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 sensitivity analysis: correlation increased.

Analysis 3.3.

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

Analysis 3.4.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 4 Pain: short term sensitivity analysis, inclusion of high risk of bias studies.

Analysis 3.5.

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

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 increased.

Analysis 3.7.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 7 Pain: short-term follow-up, subgroup analysis: motor cortex studies only, sensitivity analysis: correlation decreased.

Analysis 3.8.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 8 Pain: short-term follow-up, subgroup analysis, neuropathic and non neuropathic pain.

Analysis 3.9.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 9 Pain: short term follow-up responder analysis 30% pain reduction.

Analysis 3.10.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 10 Pain: short term follow-up responder analysis 50% pain reduction.

Analysis 3.11.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 11 Pain: medium-term follow-up.

Analysis 3.12.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 12 Pain: medium term follow-up responder analysis 30% pain reduction.

Analysis 3.13.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 13 Pain: medium term follow-up responder analysis 50% pain reduction.

Analysis 3.14.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 14 Sensitivity analysis - inclusion of high risk of bias studies. Pain: medium-term follow-up.

Analysis 3.15.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 15 Pain: long-term follow-up.

Analysis 3.16.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 16 Disability: short-term follow-up.

Analysis 3.17.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 17 Disability: medium-term follow-up.

Analysis 3.18.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 18 Quality of life: short-term follow-up.

Analysis 3.19.

Comparison 3 Transcranial direct current stimulation (tDCS), Outcome 19 Quality of life: medium-term follow-up.

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 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up2115Std. Mean Difference (IV, Random, 95% CI)-0.59 [-0.99, -0.18]
3 Quality of Life: short term follow-up1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4 Sensitivity analysis - inclusion of high risk of bias studies. Quality of life: short term follow-up2115Std. Mean Difference (IV, Random, 95% CI)-0.45 [-0.91, 0.02]
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 Sensitivity analysis - inclusion of high risk of bias studies. Pain: short-term follow-up.

Analysis 4.3.

Comparison 4 Reduced impedance non-invasive cortical electrostimulation (RINCE), Outcome 3 Quality of Life: short term follow-up.

Analysis 4.4.

Comparison 4 Reduced impedance non-invasive cortical electrostimulation (RINCE), Outcome 4 Sensitivity analysis - inclusion of high risk of bias studies. Quality of life: short term follow-up.

Comparison 5. Transcranial random noise stimulation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain1 Std. Mean Difference (Fixed, 95% CI)-0.19 [-0.64, 0.26]
Analysis 5.1.

Comparison 5 Transcranial random noise stimulation, Outcome 1 Pain.

Appendices

Appendix 1. Main database search strategies for current update

CENTRAL (CRSO)

#1 MESH DESCRIPTOR pain EXPLODE ALL TREES 32731

#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*)):TI,AB,KY 15073

#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*))):TI,AB,KY 6757

#4 #1 OR #2 OR #3 45871

#5 MESH DESCRIPTOR Transcranial Magnetic Stimulation 974

#6 MESH DESCRIPTOR Electronarcosis 33

#7 (((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*)):TI,AB,KY 4072

#8 (((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*))):TI,AB,KY 64

#9 (((non-invasive or non*invasive) adj4 stimulat*)):TI,AB,KY 337

#10 ((theta burst stimulat* or iTBS or cTBS)):TI,AB,KY 150

#11 ((transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy)):TI,AB,KY 2912

#12 ((electrosleep or electronarco*)):TI,AB,KY 47

#13 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 4355

#14 #4 AND #13 310

#15 31/07/2013 TO 30/09/2016:DL 264060

#16 #14 AND #15 176

MEDLINE (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/ (1006798)

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. (158849)

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. (52041)

4 or/1-3 (1044575)

5 Transcranial Magnetic Stimulation/ or Electronarcosis/ (18453)

6 ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).tw. (50617)

7 ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).tw. (237)

8 ((non-invasive or non*invasive) adj4 stimulat*).tw. (2843)

9 (theta burst stimulat* or iTBS or cTBS).tw. (1549)

10 (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).tw. (17745)

11 (electrosleep or electronarco*).tw. (383)

12 or/5-11 (57298)

13 random$.tw. (1121981)

14 factorial$.tw. (28563)

15 crossover$.tw. (58949)

16 cross over$.tw. (26241)

17 cross-over$.tw. (26241)

18 placebo$.tw. (244121)

19 (doubl$ adj blind$).tw. (172110)

20 (singl$ adj blind$).tw. (18218)

21 assign$.tw. (295873)

22 allocat$.tw. (107828)

23 volunteer$.tw. (211373)

24 Crossover Procedure/ (48595)

25 double-blind procedure.tw. (236)

26 Randomized Controlled Trial/ (419274)

27 Single Blind Procedure/ (23071)

28 or/13-27 (1749640)

29 (animal/ or nonhuman/) not human/ (5110486)

30 28 not 29 (1554658)

31 4 and 12 and 30 (1112)

32 (201307* or 201308* or 201309* or 201310* or 201311* or 201312* or 2014* or 2015* or 2016*).dd. (5443542)

33 31 and 32 (527)

34 limit 33 to embase (487)

PsycINFO (OVID)

1 exp Pain/ (48364)

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. (25922)

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. (4998)

4 or/1-3 (56650)

5 Transcranial Magnetic Stimulation/ or Electronarcosis/ (5956)

6 ((brain* or cortex or cortical or transcranial* or cranial or magneti*) adj4 stimulat*).tw. (17936)

7 ((transcrani* or crani* or brain*) adj4 (electrostim* or electro-stim* or electrotherap* or electro-therap*)).tw. (89)

8 ((non-invasive or non*invasive) adj4 stimulat*).tw. (983)

9 (theta burst stimulat* or iTBS or cTBS).tw. (791)

10 (transcranial magnetic stimulation or rTMS or transcranial direct current stimulation or tDCS or cranial electrostimulation or cranial electrotherapy).tw. (7884)

11 (electrosleep or electronarco*).tw. (139)

12 or/5-11 (18853)

13 clinical trials/ (9724)

14 (randomis* or randomiz*).tw. (62274)

15 (random$ adj3 (allocat$ or assign$)).tw. (35100)

16 ((clinic$ or control$) adj trial$).tw. (52603)

17 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. (22429)

18 (crossover$ or "cross over$").tw. (8346)

19 random sampling/ (699)

20 Experiment Controls/ (856)

21 Placebo/ (4606)

22 placebo$.tw. (35030)

23 exp program evaluation/ (18184)

24 treatment effectiveness evaluation/ (20144)

25 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw. (70971)

26 or/13-25 (221762)

27 4 and 12 and 26 (180)

28 limit 27 to yr="2013 -Current" (82)

CINAHL (EBSCO)

S26 S25 Limiters - Published Date from: 20130701-20160914

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

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]

Appendix 2. Trials register search results for current update

RegisterDate of searchSearch termsNumber of records
Clinical trials.gov20 September 2016

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

91
Clinical trials.gov20 September 2016

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

1
Clinical trials.gov20 September 2016

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
Clinical trials.gov20 September 2016

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
WHO ICTRP20 September 2016

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

60
WHO ICTRP20 September 2016

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

 
WHO ICTRP20/9/16

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
WHO ICTRP20 September 2016

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

 
RegisterDate of searchSearch termsNumber of records
Clinical trials.gov18 Octoberr 2017

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

6
Clinical trials.gov18 Octoberr 2017

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

3
Clinical trials.gov18 Octoberr 2017

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

3
Clinical trials.gov18 Octoberr 2017

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
WHO ICTRP18 Octoberr 2017

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

36
WHO ICTRP18 Octoberr 2017

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
WHO ICTRP18 Octoberr 2017

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
WHO ICTRP18 Octoberr 2017

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

Appendix 3. Search results summary table for current update

Database searchedDate last searchedNumber of results
CENTRAL (CRSO) 31/07/2013 TO 30/09/201611/10/17243
MEDLINE (OVID) July 2013 to Aug week 5 201611/10/17217
Embase (OVID) July 2013 to 2016 week 3711/10/17595
PsycINFO (OVID) 2013 to July week 4 201611/10/17117
CINAHL (EBSCO) July 2013 to Sept 201611/10/1742
LILACS (Birme) 2013 to Sept 201611/10/1742
Total1256

Appendix 4. Main database search strategies for 2014 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 5. Trials register search results for 2014 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 6. Search results summary table for 2014 update

Database searchedDate searchedNumber 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
Total39
After de-duplication35
After title abstract screening0
After expert checking2

Appendix 7. 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,ab25127
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,ab4111
41 OR 2 OR 375018
5ELECTRONARCOSIS/1
6ELECTRIC STIMULATION/3829
7((brain* OR cortex OR cortical OR transcranial* OR cranial OR "magneti*) AND stimulat*).ti,ab545
8((transcrani* OR crani* OR brain*) AND (electrostim* OR electro-stim* OR electrotherap* OR electro-therap*)).ti,ab26
9(("non-invasive brain" OR "non*invasive brain") AND stimulat*).ti,ab12
10("theta burst stimulat*" OR iTBS OR cTBS).ti,ab16
11("transcranial magnetic stimulation" OR rTMS OR "transcranial direct current stimulation" OR tDCS OR "cranial electrostimulation" OR "cranial electrotherapy").ti,ab437
12(electrosleep OR electronarco*).ti,ab1
135 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 124387
144 AND 13836
15exp CLINICAL TRIALS/79642
16(clinical AND trial*).af148411
17((singl* OR doubl* OR trebl* OR tripl*) AND (blind* OR mask*)).ti,ab11736
18(Randomi?ed AND control* AND trial*).af65515
19RANDOM ASSIGNMENT/22506
20(Random* AND allocat*).ti,ab3666
21placebo*.af34556
22PLACEBOS/5386
23QUANTITATIVE STUDIES/5131
2415 OR 16 OR17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23176918
2514 AND 24226

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 8. 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 3662
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.GOV627
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*)770
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 TRIALS541514
  TOTAL RESULTS FROM ALL DATABASES 23
  DUPLICATES BETWEEN DATABASES 7
  FINAL TOTAL FROM TRIALS REGISTERS SEARCHES 16

What's new

DateEventDescription
12 April 2018AmendedReview to be published with Gold Open Access.
12 April 2018New citation required but conclusions have not changedReview to be published with Gold Open Access.

History

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

DateEventDescription
7 November 2017New citation required but conclusions have not changedWe have updated all analyses and GRADE quality assessments for all core comparisons. The addition of data has not substantially altered our conclusions that there remains substantial uncertainty regarding the effectiveness of non invasive brain stimulation techniques for chronic pain.
11 October 2017New search has been performedWe have performed a full update of the searches (October 2017). This involved the inclusion of 38 new trials with an additional 1225 participants.
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.
13 September 2010AmendedWe amended the 'Risk of bias' tables so that the criterion "allocation concealment" is not assessed for studies with cross-over designs and the criterion "free from carry-over effects?" is not assessed for studies with parallel designs. These changes are now reflected in Figure 2, 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.

Contributions of authors

For this update

NOC: co-implemented the search strategy alongside the Cochrane PaPaS Group Information Specialist, applied eligibility criteria, assessed studies, extracted and analysed data, and led the write-up of the review.

BW: 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.

LDS: acted as a third review author for conflicts in applying eligibility criteria and assessing included studies.

SS: aupported the implementation and reporting of the review throughout.

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

For previous versions of this review

NOC: conceived and designed the review protocol, co-implemented the search strategy alongside the Cochrane PaPaS Group Information Specialist, applied eligibility criteria, assessed studies, extracted and analysed data, and led the write-up of the review.

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

Declarations of interest

NOC: none known

LM: none known

SS: none known

LHD: none known

BW: none known

Sources of support

Internal sources

  • Brunel University London, UK.

    Salary for authors NOC, LDS

  • Edge Hill University, UK.

    Salary for author SS

  • University College London, UK.

    Salary for author LM

  • University of Notre Dame Australia, Australia.

    Salary for author BMW

External sources

  • No sources of support supplied

Differences between protocol and review

For this update

For this update we searched ClinialTrials.gov and the World Health Organization International Clinical Trials Registry Platform, as these searches offer superior coverage to those outlined in our original protocol, and because the meta-register of controlled trials is no longer operational. We assessed the quality of the body of evidence using GRADE and added three 'Summary of findings' tables.

For the 2014 update

We did not search the database Scopus in the 2014 update or this update as the other searches had covered the full scope of this database.

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

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

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

For the 2010 update

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. However on advice from a Cochrane statistician we performed a sensitivity analysis to assess the impact of our approach to imputation of standard errors for cross-over studies.

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.

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 except study size and study duration.

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-RCT
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) years, sham group 53.3 (13.3) years

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, number of trains 10; duration of trains 10 s; ITI 50 s; total number of 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: poststimulation session 1 and 5 and at 1 month and 2 months post-treatment

Secondary: none relevant

Notes

AEs: not reported

COI: not reported

Sources of support: 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
Adequate blinding of participants?Unclear riskComment: sham credibility assessment - suboptimal. Coil angled away from scalp. Did not control for sensory characteristics of active stimulation and was visually distinguishable
Adequate blinding of assessors?Low riskQuote: "The second author evaluated these measures blindly, without knowing the type of TMS"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: levels of dropout not reported
Selective reporting (reporting bias)Low riskComment: primary outcomes presented in full
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationLow risk> 8 weeks' follow-up
Other biasLow riskComment: no other bias detected

Ahn 2017

MethodsParallel RCT
Participants

Country of study: USA

Setting: laboratory

Condition: OA knee

Prior management details: not reported

n = 41 randomised, 40 analysed

Age, mean (SD): active group 60.6 (9.8) years, sham group 59.3 (8.6) years

Duration of symptoms: not reported

Gender distribution: 19 M, 21 F

Interventions

Stimulation type: tDCS

Stimulation parameters: tDCS 2mA intensity, 20 min

Stimulation location: M1 contralateral to painful side

Number of treatments: x 1 daily for 5 days

Control type: sham tDCS

Outcomes

Primary: pain NRS anchors 0 = no pain, 10 = worst pain imaginable

When taken: 1 d postintervention, 3 weeks postintervention

Secondary: WOMAC function score

AEs

Notes

Funding source: supported in part by the Claude D. Pepper Older American's Independence Center (P30 AG028740), the Universityof Florida Center for Cognitive Aging and Memory, and NIA

Grants K07AG04637 and K01AG050707, and R01AG054077. This Work was also partially supported by VA HSR&D Houston Center for Innovations in Quality, Effectiveness and Safety (CIN# 13-413), Michael E. DeBakey VA Medical Center, Houston, TX.

COI: study authors declared no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “randomly assigned with a ratio of 1 to 1 to either the active tDCS (n ¼ 20) or sham tDCS group (n ¼ 20) using a covariate adaptive randomization procedure so that the two groups had approximately equal distribution regarding age, gender and race.”
Allocation concealment (selection bias)Low riskQuote “Allocation concealment was ensured as the randomization codes were released only after all the interventions and assessments were completed.”
Adequate blinding of participants?Unclear riskComment: evidence that participant blinding can be inadequate at intensity of 2 mA. No assessment of blinding success. No formal assessment of blinding success
Adequate blinding of assessors?Unclear riskComment: evidence that assessor blinding can be inadequate at intensity of 2 mA. No assessment of blinding success. No formal assessment of blinding success
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only one participant withdrew.
Selective reporting (reporting bias)Low riskComment: outcomes reported adequately
Study SizeHigh riskComment: n = 20
Study durationUnclear riskComment: 3-week follow-up
Other biasUnclear riskComment: statistically significant between-group difference in pain NRS scores at baseline

André-Obadia 2006

MethodsCross-over RCT; 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: 31-66 years; 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; number of trains 20; duration of trains 4 s; ITI 84 s; total number of pulses 1600

Condition 2: frequency 1 Hz; coil orientation lateromedial; number of trains 1; duration of trains 26 min, total number of pulses 1600

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

Stimulation location: M1 contralateral to painful side

Number of treatments: 1 for each condition

Outcomes

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

When taken: immediately poststimulation then daily for 1 week

Secondary: none

Notes

Data requested from study authors and received

Sources of support: Supported in part by a Grant from the Fondation pour la Recherche Médicale (FRM), France

COI: no declaration made

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."
Adequate blinding of participants?Unclear riskComment: sham credibility assessment 'suboptimal'. Coil angled away from scalp and not in contact in sham condition. Did not control for sensory characteristics of active stimulation and was visually distinguishable
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."
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
Free from carry-over effects?Low riskComment: a 2-week washout 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
Other biasLow riskComment: no significant other bias detected

André-Obadia 2008

MethodsCross-over RCT; 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: 31-72 years, 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; number of trains 20; duration of trains 4 s; ITI 84 s; total number of pulses 1600

Condition 2: frequency 20 Hz, coil orientation lateromedial; number of trains 20; duration of trains 4 s; ITI 84 s; total number of pulses 1600

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

Stimulation location: M1 contralateral to painful side

Number of treatments: 1 for each condition

Outcomes

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

When taken: daily for 2 weeks poststimulation

Secondary: none

Notes

Data requested from study authors

Sources of support: supported in part by a Grant from the Fondation pour la Recherche Médicale (FRM), France

COI: study authors declared no COI

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)"
Adequate blinding of participants?Unclear riskComments: sham credibility assessment - suboptimal. Coil angled away from scalp and not in contact in sham condition. Did not control for sensory characteristics of active stimulation and was visually distinguishable
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."
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 study authors on request
Free from carry-over effects?Low riskComment: a 2-week washout 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
Other biasLow riskComment: no significant other bias detected

André-Obadia 2011

MethodsCross-over RCT
Participants

Country of study: France

Setting: laboratory-based

Condition: chronic neuropathic pain (mixed)

Prior management details: resistant to conventional pharmacological treatment

n = 45

Age: 31-72 years (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, number of trains 20; duration of trains 4 s; ITI 84 s; total number of 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

AEs: not reported

Funding source: charity-funded

COI: 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"

Adequate blinding of participants?Unclear risk

Comment: the study 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

Adequate blinding of assessors?Unclear riskComment: no mention of blinded assessors
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: no mention of dropout/withdrawal
Selective reporting (reporting bias)Low riskComment: primary outcomes reported for all groups and further data made available upon request to authors
Free from carry-over effects?Low riskComment: 2-week washout period observed
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks' follow-up
Other biasLow riskComment: no other biases detected

Antal 2010

MethodsCross-over RCT
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 28-70 years, sham-only group 50-70 years, cross-over group 41-70 years

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

Gender distribution: 6 M, 17 F

Interventions

Stimulation type: tDCS

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

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

Number of treatments: x 5, daily

Control type: sham tDCS

Outcomes

Primary: pain VAS 0-10; 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

COI: 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
Adequate blinding of participants?Low riskComment: see above
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"

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: the high level of dropout 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 were 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
Free from carry-over effects?Low riskComment: participants 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
Other biasLow riskComment: no other sources of bias detected

Attal 2016

MethodsParallel RCT
Participants

Country of study: France

Setting: hospital pain units

Condition: lumbar radicular pain

Prior management details: stable pharmacological treatment for pain and sleep disorders for at least 1 month prior to study

n = 36

Age, mean (SD): active group 53.4 (8) years, sham group 51.5 (13) years

Duration of symptoms: not reported

Gender distribution: 17 F 18 M

Interventions

Stimulation type: rTMS and tDCS (order randomised in active group)

Stimulation parameters: rTMS frequency 10 Hz; coil orientation anteroposterior induced current; 80% RMT; number of trains 30; duration of trains 10 s; ITI 20 s; total number of pulses 3000

tDCS: 2 mA intensity, 30 min

Stimulation location: M1 contralateral to painful side

Number of treatments: 3 stimulation visits on 3 consecutive days for each stimulation type. 3 week washout period.

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

Outcomes

Primary: pain NRS anchors 0 = no pain, 10 = maximal pain imaginable

When taken: postintervention

Secondary: BPI interference scale

AEs

Notes

Funding source: The study received financial support from the Institut National de la Sante´ et de la Recherche Médicale (INSERM)

COI: the authors declared no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “The 2 successive randomisations were prepared by a study nurse not involved in the running of the study or in data analysis, using validated software and a centralised randomisation schedule.”
Allocation concealment (selection bias)Low riskQuote: “The treatment allocation code was kept in a sealed envelope until the completion of the study.”
Adequate blinding of participants?Unclear riskComment: rTMS sham described as controlling for sensory, auditory and visual cues. tDCS 2 mA intensity - evidence that blinding can be inadequate at intensity of 2 mA. No formal assessment of blinding success
Adequate blinding of assessors?Unclear risktDCS 2 mA intensity - evidence that blinding can be inadequate at intensity of 2 mA. No formal assessment of blinding success
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: ITT analysis used and low dropout
Selective reporting (reporting bias)High riskComment: point estimates for pain scores not provided - only a responder analysis was presented
Free from carry-over effects?Unclear riskComment: the order of active stimulation types was randomised but it is not clear that there were not baseline differences between pre-rTMS and pre tDCS from the presented data
Study SizeHigh riskn = 36
Study durationHigh riskComment: 5 days post intervention was the longest follow up
Other biasLow riskComment: no other bias detected

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) years, sham 52.09 (10.02) years

Duration of symptoms (months mean (SD)): active group 11 (4.26), sham group 15.64 (6.93)

Gender distribution: all F

Interventions

Stimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation not specified; 120% RMT; number of trains 75; duration of trains 4 s; ITI 26 s; total number of pulses 3000

Stimulation location: L 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 0-10 anchors not reported

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

Secondary: pain interference BPI

QoL SF-36

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

Notes

Government-funded study, manufacturer loaned stimulators

COI: funded by the National Institute for Arthritis, Musculoskeletal and Skin Diseases, R21 ART053963 and the Bipolar Illness Fund

Neuronetics, Inc. loaned the TMS machine to the study

Dr. Avery was a consultant for Neuronetics, Inc. for one day, is a member of the Data and Safety Monitoring Board for Cerval Neuortech, Inc., was on the speakers bureau for Eli Lilly and Takeda, was a consultant for Takeda and received a grant from the National Institute of Mental Health. Dr. Roy-Byrne is editor for Journal Watch, Depression and Anxiety, and UpToDate and has stock in Valant Medical Systems. None of the other authors has potential COI.

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)Unclear risk

Quote: "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"

Comment: not entirely clear whether the personnel overseeing randomisation was separate from that performing the screening assessment.

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

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
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 dropouts from the TMS group, 1 was excluded (reasons given)

Selective reporting (reporting bias)Low riskComment: all outcomes presented in full in study report
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationLow riskComment: > 8 weeks' follow-up
Other biasLow riskNo other bias detected

Ayache 2016

MethodsCross-over RCT
Participants

Country of study: France

Setting: laboratory

Condition: MS-related neuropathic pain

Prior management details: concomitant medication intake stable throughout protocol

n = 16

Age, mean (SD) 48.9 (10) years

Duration of symptoms: mean (SD) 11.8 (9.4) months

Gender distribution: 13 F, 3 M

Interventions

Stimulation type: tDCS

Stimulation parameters: intensity 2 mA, 25 cm2 electrodes, duration 20 min

Stimulation location: anode - L DLPFC, cathode right supraorbital

Number of treatments: x 3, daily

Control type: sham tDCS

Outcomes

Primary: pain VAS 0 -10; VAS anchors not reported

When taken:

Postintervention, 7 days postintervention

Secondary: AEs

Notes

COI:

"AC gave expert testimony for CSL Behring, Novartis, received grants from Biogen, Novartis, CSLBehring, GENeuro, Octapharma, and gave lectures for Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships "that could be construed as potential conflict of interest"

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote “The randomization schedule was generated by U.P. prior to the beginning of the study using a dedicated software (“true”random number generation without any restriction, stored in a computer until the patient was assigned to the intervention).”
Adequate blinding of participants?Unclear riskComment: there is evidence that participant blinding of tDCS may be inadequate at 2 mA intensity, particularly in cross-over designs. Results of guessing mode of stimulation not reported
Adequate blinding of assessors?Unclear risk

Quote: "Only the performing physician (S.S.A) was aware of the stimulation mode (real or sham tDCS). The evaluators (U.P and M.A.C) and the patients were blind to it.”

Comment: there is evidence that assessor blinding of tDCS may be inadequate at 2 mA intensity

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no attrition reported
Selective reporting (reporting bias)Low riskComment: results reported in full
Free from carry-over effects?Unclear riskComment: baseline scores for each period not reported. No formal analysis for carry-over effects presented
Study SizeHigh riskComment: n = 16
Study durationHigh riskComment: longest follow-up 7 days after stimulation
Other biasLow riskNo other bias detected

Bae 2014

MethodsParallel RCT
Participants

Country of study: South Korea

Setting: laboratory

Condition: CPSP

Prior management details: not reported

n = 14

Age, mean (SD): active group 51.1 (3.1) years, sham group 52.3 (2.8) years

Duration of symptoms, mean (SD): active group 14.5 (3.2) months, sham group 14.7 (2.7)

Gender distribution: 7 M, 7 F

Interventions

Stimulation type: tDCS

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

Stimulation location: anode - M1 contralateral to painful side, cathode right supraorbital

Number of treatments: x 3 per week for 3 weeks

Control type: sham tDCS

Outcomes

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

When taken: "immediacy", 1 week, 3 weeks (unclear if from end of intervention)

Secondary: None relevant

Notes

COI: study authors declared no COI

Sources of support: none declared

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: method of randomisation not reported
Allocation concealment (selection bias)Unclear riskComment: no mention of allocation concealment procedures
Adequate blinding of participants?Unclear riskComment: blinding not reported. Evidence that blinding can be inadequate at intensity of 2 mA
Adequate blinding of assessors?Unclear riskComment: blinding not reported. Evidence that blinding can be inadequate at intensity of 2 mA
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: unable to clearly verify if there was any attrition
Selective reporting (reporting bias)Low riskComment: adequate reporting of outcomes
Study SizeHigh riskComment: total n = 14
Study durationUnclear riskComment: 3-week follow-up
Other biasLow riskComment: no other bias detected

Boggio 2009

MethodsCross-over RCT; 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: 40-82 years; mean 63.3 (SD 5.6)

Duration of symptoms: 1-20 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 min

Condition 1: active tDCS/active TENS

Condition 2: active tDCS/sham TENS

Condition 3: sham tDCS/sham TENS

Stimulation location: M1 contralateral to painful side

Number of treatments: 1 for each condition

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

Outcomes

Primary: VAS 0-10 anchors "no pain" to "worst possible pain"

When taken: pre and post each stimulation

Secondary: none

Notes

Sources of support: not declared

COI: not declared

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)."
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)
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)

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 were 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
Free from carry-over effects?Low risk

Comment: a 48-h washout 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
Other biasLow riskComment: no significant other bias detected

Borckardt 2009

MethodsCross-over RCT; 2 conditions
Participants

Country of study: USA

Setting: laboratory

Condition: peripheral neuropathic pain

Prior management details: not specified

n = 4

Age: 33-58 years; mean 46 (SD 11)

Duration of symptoms: 5-12 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; number of trains 40; duration of trains 10 s; ITI 20 s; total number of pulses 4000

Stimulation location: L PFC

Number of treatments: 3 over a 5-d period

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

Outcomes

Primary: average daily pain 0-10 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 poststimulation

Secondary: none

Notes

AEs: not reported

Sources of support: no separate statement provided

COI: "Dr. Borckardt receives research funding from the National Institute for Neurological Disorders and Stroke at NIH, Cyberonics Inc, the Neurosciences Institute at MUSC, and is a consultant for Neuropace; however, he has no equity ownership in any device or pharmaceutical company. Dr. George receives research funding from the National Institute for Mental Health, NIDA, and NIAAA at NIH, Jazz Pharmaceuticals, GlaxoSmithKline, and Cyberonics Inc. He is a consultant for Aspect Biomedical, Argolyn, Aventis, Abbott, Bristol-Meyers Squibb, Cephos, Cyberonics, and Neuropace; however, he has no equity ownership in any device or pharmaceutical company. Dr. Nahas receives research funding from the National Institute for Mental Health at NIH and Cyberonics Ind, and is a consultant for Neuropace. Dr. Kozel receives research funding from the National Institute for Mental Health at NIH and the U.S. Department of Defense. MUSC has filed six patents or invention disclosures in one or more of the authors’ names regarding brain imaging and stimulation."

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

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 - suboptimal. Sham coil controlled for auditory cues and was visually indistinguishable from active stimulation but did not control for sensory characteristics of active stimulation

Adequate blinding of assessors?Unclear riskComment: not specified
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no dropout
Selective reporting (reporting bias)Low riskComment: all results reported clearly and in full
Free from carry-over effects?Low riskComment: a 3-week washout period was observed. Presented average pain values were very similar pre- each condition
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

Boyer 2014

MethodsParallel RCT
Participants

Country of study: France

Setting: specialised pain treatment centre

Condition: fibromyalgia

Prior management details: stable treatment for more than 1 month before enrolment

n = 38

Age, mean (SD): active group 49.1(10.6) years, sham group 47.7 (10.4) years

Duration of symptoms, mean (SD): active group 3.7 (4.5) years, sham group 3.6 (3.8)

Gender distribution: 37 F, 1 M

Interventions

Stimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation anteroposterior; 90% RMT; number of trains 20; duration of trains 10 s; ITI 50 s; total number of pulses 2000

Stimulation location: L M1

Number of treatments: 14 sessions. 10 sessions in 2 weeks followed by maintenance phase of 1 session at weeks 4, 6, 8 and 10

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

Outcomes

Primary: pain VAS 0 = no pain, 10 = maximal pain imaginable

When taken: 2 weeks, 11 weeks

Secondary: FIQ

AEs

Notes

Funding source: Supported by Inserm (Centre d’Investigation Clinique, CIC, Hôpital de la Conception, Marseille) and AP-HM (AORC 2008/01)

COI: the study authors report no disclosures relevant to the manuscript

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “Individuals were randomized by a computer-generated list…”
Allocation concealment (selection bias)Low riskQuote: “...which was maintained centrally so no investigators knew the treatment allocation of any patient.”
Adequate blinding of participants?Unclear risk

Quote: “Sham stimulation was conducted with a sham coil of identical size, color, and shape, emitting a sound similar to that emitted by the active coil. Stimulations were administered by the same technologist.”

Comments: sham credibility assessment - suboptimal. Sham coil controlled for auditory cues and was visually indistinguishable from active stimulation but did not control for sensory characteristics of active stimulation

Adequate blinding of assessors?Low riskQuote: “Patients and clinical raters were blinded to treatment”
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote “All patients completed the induction phase, but 9 (23.7%) were excluded during the maintenance phase (3 in the active rTMS group and 6 in the sham rTMS group)“

Comment: dropout high, ITT analysis used but no information with regards imputation approach taken (or not)

Selective reporting (reporting bias)Low riskComment: all results reported clearly and in full
Study SizeHigh riskComment: n = 38
Study durationHigh riskComment: no follow-up after end of maintenance phase
Other biasLow riskComment: no other bias detected

Brietzke 2016

MethodsParallel RCT
Participants

Country of study: Brazil

Setting: laboratory

Condition: hepatitis C-related chronic pain

Prior management details: not reported

n = 28

Age, mean (SD): active group 53.86 (5.76) years, sham group 56.57 (8.52) years

Duration of symptoms: not reported

Gender distribution: 21 M, 7 F

Interventions

Stimulation type: tDCS

Stimulation parameters: intensity 2 mA, 25-35 cm2 electrodes, duration 20 min

Stimulation location: anode - M1 L, cathode right supraorbital

Number of treatments: daily, x 5

Control type: sham tDCS

Outcomes

Primary: pain VAS; anchors 0 = no pain, 10 = worst possible pain

When taken: end of intervention

Secondary: none relevant

Notes

Funding from Brazilian funding agencies:

(i) Committee for the Development of Higher Education Personnel
(ii) National Council for Scientific and Technological Development-CNPq
(iii) Postgraduate Program in Medical Sciences of Medical School of the Federal University of
Rio Grande do Sul.

(iv) Postgraduate Research Group at the Hospital de Clínicas de Porto Alegre

(v) Laboratory of Neuromodulation & Center for Clinical Research Learning
(vi) Foundation for Support of Research at Rio Grande do Sul

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

Quote: “Randomized numbers in a 1:1 ratio were generated using appropriate software (www.randomization.com) to assign each

Participant to either active or sham-placebo group.”

Allocation concealment (selection bias)Low riskQuote: “Envelopes were prepared for randomization process and sealed. After subject’s agreement to participate in the trial, one investigator who was not involved with either stimulation or assessments opened the envelope. The allocation concealment was reached since no investigator (stimulators nor accessors) was aware of treatment allocations and had no control over the order of patients randomized.”
Adequate blinding of participants?Unclear riskComment: evidence that blinding can be inadequate at intensity of 2 mA
Adequate blinding of assessors?Unclear risk

Quote: “Two independent blinded examiners were trained to apply the pain scales and to conduct the psychological tests.

Comment: evidence that assessor blinding can be inadequate at intensity of 2 mA. No assessment of blinding success

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: 3 participants dropped out (> 10%) reasons not given. ITT analysis with LOCF
Selective reporting (reporting bias)Low riskComment: outcome data adequately reported
Study SizeHigh riskComment n = 28
Study durationHigh riskComment: no follow-up after immediate postintervention period.
Other biasLow riskNo other bias detected

Capel 2003

MethodsPartial cross-over RCT. NB: we only considered first-phase results therefore we considered the trial as having a parallel design
Participants

Country of study: UK

Setting: residential educational centre

Condition: post-SCI pain (unclear whether this was 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 ms; intensity 1 2 μA; 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: 0-10 VAS 'level of pain', anchors not specified

When taken: daily during the treatment period

Secondary: none

Notes

COI: no declaration made

Sources of support: Laing Foundation (charity) "financial assistance"

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
Adequate blinding of participants?Low riskQuote: "neither the administrators nor the recipients of the treatment could distinguish between the devices."
Adequate blinding of assessors?Low riskQuote: "neither the administrators nor the recipients of the treatment could distinguish between the devices."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: 3 participants withdrew (not voluntarily) and while the data were not clearly accounted for in the data analysis this constituted 10% of the overall cohort and was 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 were not provided for any time point
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationHigh riskComment: < 2 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

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) years, sham group 54.9 (SD 4.9) years

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; number of trains 20; duration of trains 60 s; ITI 45 s; number of pulses 1200

Stimulation location: R DLPFC

Number of treatments: up to 20 on consecutive working days

Control type: coil angled 45º from the scalp

Outcomes

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

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

Secondary: none

Notes

COI: no declaration made

Sources of support: IUNICS Institute, Research Institute of Health Sciences

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
Adequate blinding of participants?Unclear riskComments: sham credibility assessment - suboptimal. Coil angled 45º away from scalp. Did not control for sensory characteristics of active stimulation and was visually distinguishable
Adequate blinding of assessors?Low riskQuote: "patients and raters (but not the treating physician) were blind to the procedure"
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
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

Chang 2017

MethodsParallel RCT
Participants

Country of study: Australia

Setting: laboratory

Condition: knee OA

Prior management details: not reported

n = 30

Age, mean (SD): active group 59.8 (9.1) years, sham group 64.1 (11.1) years

Duration of symptoms mean (SD) years: active group: 7.2 (5.3), sham group 9.0 (7.3)

Gender distribution: 10 M, 19 F

Interventions

Stimulation type: tDCS

Stimulation parameters:

tDCS: 1 mA intensity, 20 min

Stimulation location: M1 contralateral to painful side

Number of treatments: x 2 weekly for 8 weeks prior to a 30-min supervised strengthening exercise session. 16 sessions

Control type: sham tDCS

Outcomes

Primary: pain NRS anchors 0 = no pain, 10 = worst pain imaginable

When taken: postintervention

Secondary: WOMAC function

AEs

Notes

Funding source: Trial funded by Arthritis Australia (The Zimmer Australia Grant). W-JC (1094434), PWH (1002190), KLB (1058440), MBL (1059116) and SMS (1105040) receive salary support from the National Health and Medical Research Council of Australia, RSH from the Australian Research Council (FT#130100175) and VB from a Western Sydney University Postgraduate Research Award.

COI: study authors declared no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: method of randomisation not described
Allocation concealment (selection bias)Low riskQuote: “The randomisation schedule was concealed in consecutively numbered, sealed opaque envelopes. An investigator not involved in recruitment and assessment prepared and provided the envelopes to the treating physiotherapists who revealed group allocation.”
Adequate blinding of participants?Low riskComment: blinding likely maintained at 1 mA intensity
Adequate blinding of assessors?Low riskQuote: "A single investigator (W-JC), blinded to the group allocation of the participants, performed participant recruitment, screening, and testing."
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: 2 (13% dropout from active group), 3 (20%) from control group. ITT analysis with no imputation of missing values.
Selective reporting (reporting bias)Low riskComment: outcomes reported adequately
Study SizeHigh riskComment: n = 30
Study durationHigh riskComment: postintervention follow-up only (within 1 week)
Other biasLow riskComment: no other bias detected

Cork 2004

MethodsCross-over RCT (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: 22-75 years; mean 53

Duration of symptoms: 1-21 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 -5 pain NRS, 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

Notes

AEs: not reported

COI: no declaration made

Sources of support: "Supported by a grant from the Department of Anesthesiology, LSU Health Sciences Center. No financial support was received from the makers of the Alpha-Stim™; however, Electromedical Products International, Inc. did loan the authors the Alpha-Stim™ units necessary to do the study."

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
Adequate blinding of participants?Low riskQuote: "All staff, the physicians, and the patient were blind to the treatment conditions."
Adequate blinding of assessors?Low riskQuote: "All staff, the physicians, and the patient were blind to the treatment conditions."
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: dropout rate not reported
Selective reporting (reporting bias)High riskComment: pain score numerical values not provided clearly with measures of variance for any time point
Study SizeHigh riskComment: < 50 participants per treatment arm (considered as a parallel trial - 1st phase only)
Study durationHigh riskComment: < 2 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

Curatolo 2017

MethodsParallel RCT
Participants

Country of study: Italy

Setting: laboratory

Condition: fibromyalgia

Prior management details: not reported

n = 20

Age, mean (SD): active group 41.4 (10.25) years, sham group 44.2 (9.81) years

Duration of symptoms, mean (SD) years: active group 4.3 (2.62), sham group 5 (5.04)

Gender distribution: all F

Interventions

Stimulation type: tRNS

Stimulation parameters:

tDCS: 1.5 mA intensity, 20 min (randomly oscillating in frequency range 101-640 Hz for 10 min, offset set to 0 ma sham - stimulation turned on for 30 s only)

Stimulation location: M1 (side not reported)

Number of treatments: x 1 daily, 5 days a week for 2 weeks (x 10 sessions)

Control type: sham tRNS

Outcomes

Primary: pain NRS anchors not reported

When taken: postintervention

Secondary: FIQ

AEs not reported

Notes

Funding source: not reported

COI: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: method of randomisation not described
Allocation concealment (selection bias)Unclear riskComment: allocation concealment not described
Adequate blinding of participants?Unclear riskComment: method of blinding not reported
Adequate blinding of assessors?Unclear riskComment: method of blinding not reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no dropout reported
Selective reporting (reporting bias)High riskComment: no numeric reporting of primary outcomes
Study SizeHigh riskComment: n = 20
Study durationHigh riskComment: postintervention follow-up only
Other biasLow riskComment: no other bias detected

Dall'Agnol 2014

MethodsParallel RCT
Participants

Country of study: Brazil

Setting: not specified

Condition: chronic myofascial pain in the upper body

Prior management details: not reported

n = 24

Age, mean (SD): active group 45.83 ( 9.63) years, sham group 44.83 (14.09) years

Duration of symptoms: not reported

Gender distribution: all F

Interventions

Stimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation 45º from midline, 80% RMT, number of trains 16; duration of trains 10 s; ITI 26 s; total number of pulses 1600

Stimulation location: L M1

Number of treatments: 10 sessions, timescale not specified

Control type: sham coil - same sound and appearance and sensation

Outcomes

Primary: pain NRS anchors 0 = no pain, 10 = worst possible pain

When taken: postintervention

Secondary: AEs

Notes

Funding source: grants and material support from the following Brazilian agencies: Brazilian Innovation Agency (FINEP), process number 1245/13; Committee for the Development of Higher Education Personnel—PNPD/CAPES, process number 023-11, and material support; National Council for Scientific and Technological Development—CNPq (grants WC-301256/2013-6 and ILST- 302345/2011-6 ); Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul (material support); Postgraduate Research Group at the Hospital de Clınicas de Porto Alegre (grant number 120343 and material support); and Foundation for Support of Research at Rio Grande do Sul (FAPERGS).

COI: study authors declared that there was no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “A computer random number generator assigned patients to 1 of 2 groups: rTMS or placebo-sham using a block randomization strategy.”
Allocation concealment (selection bias)Low riskQuote: “Before the recruitment phase, opaque envelopes containing the protocol materials were prepared. Each opaque envelope was sealed and numbered sequentially, containing 1 intervention allocation.”
Adequate blinding of participants?Low risk

Quote “we used an inactive rTMS coil (MagPro X100; MagVenture Company, Lucernemarken, Denmark) as a sham method by placing it in the identical area as the active coil. Thus, sham patients underwent similar rTMS experience (including rTMS sound) as those receiving active stimulation.....The patient recorded identical experiences (including sound effects and somatic sensations caused by contraction of the muscles of the scalp) as during active stimulation”

Comment: assessment indicates that blinding was successful.

Adequate blinding of assessors?Low riskQuote “Two independent evaluators who were blinded to the group assignments(W.C. and another) were trained to apply the pain scales and conduct psychophysical and psychological tests.”
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 dropout
Selective reporting (reporting bias)High riskComment: point estimates for outcomes only reported at one time point
Study SizeHigh riskn = 24
Study durationLow risk12-week follow-up postintervention
Other biasLow riskComment: no other bias detected

de Oliveira 2014

MethodsParallel RCT
Participants

Country of study: Brazil

Setting: neurology dept

Condition: CPSP

Prior management details: stable medication for 30 d preceding baseline

n = 23

Age, mean (SD): active group 55 (9.67) years, sham group SD 57.8 (11.86) years

Duration of symptoms, mean (SD): active group 64.18 (49.27) months, sham group 50.1 (28.04)

Gender distribution:active group 45% M, sham group 50% M

Interventions

Stimulation type: rTMS

Stimulation parameters: frequency 10 Hz; coil orientation not specified, 120% RMT, number of trains 25; duration of trains 5 s; ITI 25s; total number of pulses 1250

Stimulation location: L premotor/DLPFC

Number of treatments: 10 sessions daily for 2 weeks

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

Outcomes

Primary: pain NRS anchors not reported

When taken: end of intervention, 1, 2 and 4 weeks postintervention

Secondary: AEs, QoL (SF-36)

Notes

Funding source: study was supported by the Pain Center of the Department of Neurology and by the Transcranial Magnetic Stimulation Laboratory of the Psychiatry Institute, University of Sao Pau

COI: the study authors declared no COI

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

Quote “Participants were randomly assigned into 2 groups, active stimulation (a-rTMS) and sham stimulation

(s-rTMS), according to a list automatically generated by an internet-based tool (www.random.org)”

Allocation concealment (selection bias)Unclear riskComment: allocation concealment not reported
Adequate blinding of participants?Unclear risk

Quote “Sham stimulation was carried out with a sham coil of identical size color and shape emitting a sound similar to that emitted by the active coil (MC-P-B70).”

Comment: sham credibility assessment - suboptimal. Sham coil controlled for auditory cues and was visually indistinguishable from active stimulation but did not control for sensory characteristics of active stimulation

Adequate blinding of assessors?Low riskQuote: “Pain intensity (VAS) was assessed daily, right before and immediately after each rTMS session, from D1 to D10 by an investigator (M.M.) blinded to the type of rTMS patients were receiving. All clinical assessments were performed by a physician and a neuropsychologist (T.L., M.L.M) who were blinded to the type of treatment and had no other role in the study.”
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: 1 dropout per group
Selective reporting (reporting bias)Low riskComment: outcomes reported adequately
Study SizeHigh riskn = 21
Study durationUnclear riskComment: 4-week follow-up
Other biasLow riskComment: no other bias detected

Deering 2017

MethodsParallel RCT
Participants

Country of study: USA

Setting: "single clinical location"

Condition: fibromyalgia

Prior management details: FDA-approved fibromyalgia drugs and centrally active analgesics or stimulants "prohibited".

n = 46

Age mean (SD) active 12-week programme group 55.7 (8.7) active 8-week programme group 46.6 (10.3), sham group 47.9 (11.2)

Duration of symptoms: not reported

Gender distribution: reported for completers only 35 F, 3 M

Interventions

Stimulation type: RINCE

Stimulation parameters: not reported

Stimulation location: parietal region (international 10/20 site PZ),"positioned to create a conduction pathway that includes the primary somatosensory and motor cortex".

Number of treatments:

Active 12-week group: 24 treatments of 12 weeks

Active 8-week group: 16 treatments over 8 weeks followed by 8 sham sessions in 4 weeks

Sham group: 24 sham sesssions over 12 weeks

Control type: nonactivated identical stimulation unit

Outcomes

Primary: pain VAS; 0 = no pain, 10 = worst pain imaginable

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

Secondary: total FIQ score

AEs

Notes

Sources of support: all funding for this study was provided by Cerephex Corporation who manufacture the device.

COI: no formal declaration. 5 study authors affiliated to funder - who manufacture the RINCE technology

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: method of random sequence generation unclear
Allocation concealment (selection bias)Unclear riskComment: allocation concealment not clearly established
Adequate blinding of participants?Unclear riskQuote: “patients cannot feel the RINCE signal and are therefore blinded to receiving treatment or not….no element of hardware or software gave any indication of group assignment”
Adequate blinding of assessors?Unclear riskQuote: “The investigators were blinded to these codes and no element of hardware or software gave any indication of group assignment, thus maintaining a double blinded sham controlled condition.”
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: 7/14 participants not analysed in the sham group due to “exposure to unexpected signal source”. These participants not included in sham analysis. Details on how this was confirmed or what the exposure was are not clear.
Selective reporting (reporting bias)High riskComment: point estimates with measures of variance not provided for all groups at all time points
Study SizeHigh riskn = 46, divided into 3 groups
Study durationUnclear riskComment: 4-week follow-up period
Other biasUnclear riskComment: full baseline data not tested and only data with 8 excluded sham participants removed were presented

Defrin 2007

MethodsParallel RCT
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: 44-60 years; 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; number of trains 500; duration of trains 10 s; ITI 30 s; total number of pulses 500 reported, likely to have been 25,000 judging by these parameters

Stimulation location: M1 - 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 0-10 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

Notes

AEs: not reported

Sources of support: supported by the National Association of the insurance companies.

COI: study authors declared no COI

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
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 - suboptimal. Sham coil controlled for auditory cues and was visually indistinguishable from active stimulation, but did 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

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."
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: only 1 participant withdrew for "logistic reasons". Unlikely to have strongly influenced the findings
Selective reporting (reporting bias)Low riskComment: while group means/SD were not presented in the study report, the study authors provided the requested data
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks' follow-up
Other biasUnclear riskComment: baseline differences observed in pain intensity levels (higher in active group)

Donnell 2015

MethodsParallel RCT
Participants

Country of study: USA

Setting: laboratory

Condition: chronic temperomandibular disorder

Prior management details: pain not adequately controlled by previous therapies for more than 1 year

n = 24

Age range, mean (SD): active group 34.8 (13.7) years, sham group 35.6 (16.7) years

Duration of symptoms: not reported

Gender distribution: all F

Interventions

Stimulation type: HD-tDCS

Stimulation parameters: intensity 2 mA, 4 electrodes arranged at the corners of a 4 x 4 cm square centred over M1

Stimulation location: anode - M1 contralateral to painful side

Number of treatments: daily, x 5

Control type: sham tDCS

Outcomes

Primary: pain VAS; anchors not reported - responder analysis only reported

When taken: 1-month follow-up

Secondary: AEs

Notes

Sources of funding: this project was funded by grants from the American Academy of Orofacial Pain and the University of Michigan Rackham Graduate School.

Potential undisclosed COI: 1 study author (Biksom) worked for stimulation device manufacturer Soterix

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote “participants were randomized to the treatment or placebo group using the Taves covariate adaptive randomization method.”
Allocation concealment (selection bias)Unclear riskComment: no mention of allocation concealment procedures
Adequate blinding of participants?Unclear riskComment: 2 mA intensity. Evidence that blinding can be inadequate at intensity of 2 mA
Adequate blinding of assessors?High riskComment: study described as single blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no participant dropout
Selective reporting (reporting bias)High riskComment: pain outcomes not presented for all follow-up time points
Study SizeHigh riskn = 24
Study durationUnclear risk1-month follow-up postintervention
Other biasLow riskComment: no other bias detected

Fagerlund 2015

MethodsParallel RCT
Participants

Country of study: Norway

Setting: university hospital

Condition: fibromyalgia

Prior management details: prescription medication stable for 3 months prior to inclusion

n = 50

Age, mean (SD): active group 49/04 (8.63) years, sham group 48.17 (10.56) years

Duration of symptoms, mean (SD) sham group 17.73 (7.54) years, sham group 18.50 (11.48)

Gender distribution: 47 F, 3 M

Interventions

Stimulation type: tDCS

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

Stimulation location: anode - M1 side not reported, cathode supraorbital contralateral to anode

Number of treatments: daily, x 5

Control type: sham tDCS

Outcomes

Primary: pain VAS, anchors not reported

When taken: postintervention, mean 30 days postintervention

Secondary: FIQ, SF-36, AEs

Notes

Sources of funding: study was funded by a grant from the Norwegian Extra Foundation for Health and Rehabilitation through the Norwegian Fibromyalgia Association

Study authors declared no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: “The codes were associated with the active or sham tDCS condition and randomized using the online Web service www.randomize.org. The ratio of active and sham codes was 1:1.”
Allocation concealment (selection bias)Unclear riskComment: not clearly stated that the sequence generation was separated and concealed
Adequate blinding of participants?Unclear riskComment: evidence that blinding can be inadequate at intensity of 2 mA. Not formal assessment of blinding success
Adequate blinding of assessors?Low riskComment: outcomes collected through text message with little potential for assessors to influence process
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: high noncompletion rate for some outcomes and there is not full clarity on how many participants were analysed
Selective reporting (reporting bias)Low riskComment: full reporting of key outcomes
Study SizeHigh riskn = 50
Study durationUnclear riskComment: follow-up 30 days postintervention
Other biasLow riskComment: no other bias detected

Fenton 2009

MethodsCross-over RCT
Participants

Country of study: USA

Setting: unclear

Condition: chronic pelvic pain

Prior management details: refractory to treatment

n = 7

Age: mean 38 years

Duration of symptoms: mean 80 months

Gender distribution: all F

Interventions

Stimulation type: tDCS

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

Stimulation location: M1 dominant hemisphere

Number of treatments: 2

Control type: sham tDCS (switched off after 30 s 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

Sources of support: no declaration made

COI: no declaration made

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
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."
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."
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no dropout reported
Selective reporting (reporting bias)Low riskComment: variance measures not presented for group means poststimulation but data provided by study author on request
Free from carry-over effects?Unclear riskComments: pre-stimulation data not presented and no formal investigation for carry-over effects discussed
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: < 2 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

Fregni 2005

MethodsCross-over RCT
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 or 20 Hz; coil orientation not specified; 90% RMT; number of trains not specified; duration of trains not specified; ITI not specified; total number of pulses 1600

Stimulation location: L and R 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

COI: no declaration made

Sources of support: National Pancreas Foundation/ NIH

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."
Adequate blinding of participants?Unclear riskComment: sham credibility assessment "unclear". Type of sham coil not specified
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."
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: no dropout reported
Selective reporting (reporting bias)High riskComment: pain NRS values not provided clearly with measures of variance for any time point for the sham condition
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
Other biasLow riskComment: no significant other bias detected

Fregni 2006a

MethodsParallel RCT
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) years

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 min

Stimulation location: M1 (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 s stimulation)

Outcomes

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

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

Secondary: none

Notes

COI: no declaration made

Sources of support: support from Harvard Medical School Scholars in Clinical Science programme

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
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)
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)
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 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
Study SizeHigh riskComment: < 50 participants per treatment arm
Study durationUnclear riskComment: ≥ 2 weeks but < 8 weeks' follow-up
Other biasLow riskComment: no significant other bias detected

Fregni 2006b

MethodsParallel RCT; 3 conditions
Participants

Country of study: Brazil

Setting: laboratory

Condition: fibromyalgia

Prior management details: unclear

n = 32

Age: 53.4 (SD 8.9) years

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: 32 F

Interventions

Stimulation type: tDCS

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

Stimulation location: condition 1: DLPFC; condition 2: M1; condition 3: sham M1. 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 s stimulation)

Outcomes

Primary: pain VAS 0-10 cm, anchors not specified

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

Secondary: QoL: FIQ

Notes

COI: no declaration made

Sources of support: support from Harvard Medical School Scholars in Clinical Science programme/ NIH

Risk of bias
Bias<