title: Non-invasive brain stimulation techniques for chronic pain.
abstract: BACKGROUND
  This is an updated version of the original Cochrane review published in 2010, Issue 9. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS) and reduced impedance non-invasive cortical electrostimulation (RINCE).
  
  
  OBJECTIVE
  To evaluate the efficacy of non-invasive brain stimulation techniques in chronic pain.
  
  
  METHODS
  We searched CENTRAL (2013, Issue 6), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS and clinical trials registers. The original search for the review was run in November 2009 and searched all databases from their inception. To identify studies for inclusion in this update we searched from 2009 to July 2013.
  
  
  METHODS
  Randomised and quasi-randomised studies of rTMS, CES, tDCS or RINCE if they employed a sham stimulation control group, recruited patients over the age of 18 with pain of three months duration or more and measured pain as a primary outcome.
  
  
  METHODS
  Two authors independently extracted and verified data. Where possible we entered data into meta-analyses. We excluded studies judged as being at high risk of bias from the analysis. We used the GRADE system to summarise the quality of evidence for core comparisons.
  
  
  RESULTS
  We included an additional 23 trials (involving 773 participants randomised) in this update, making a total of 56 trials in the review (involving 1710 participants randomised). This update included a total of 30 rTMS studies, 11 CES, 14 tDCS and one study of RINCE(the original review included 19 rTMS, eight CES and six tDCS studies). We judged only three studies as being at low risk of bias across all criteria.Meta-analysis of studies of rTMS (involving 528 participants) demonstrated significant heterogeneity. Pre-specified subgroup analyses suggest that low-frequency stimulation is ineffective (low-quality evidence) and that rTMS applied to the dorsolateral prefrontal cortex is ineffective (very low-quality evidence). We found a short-term effect on pain of active high-frequency stimulation of the motor cortex in single-dose studies (low-quality evidence, standardised mean difference (SMD) 0.39 (95% confidence interval (CI) -0.27 to -0.51 P < 0.01)). This equates to a 12% (95% CI 8% to 15%) reduction in pain, which does not exceed the pre-established criteria for a minimal clinically important difference (≥ 15%). Evidence for multiple-dose studies was heterogenous but did not demonstrate a significant effect (very low-quality evidence).For CES (six studies, 270 participants) no statistically significant difference was found between active stimulation and sham (low-quality evidence).Analysis of tDCS studies (11 studies, 193 people) demonstrated significant heterogeneity and did not find a significant difference between active and sham stimulation (very low-quality evidence). Pre-specified subgroup analysis of tDCS applied to the motor cortex (n = 183) did not demonstrate a statistically significant effect and this lack of effect was consistent for subgroups of single or multiple-dose studies.One small study (n = 91) at unclear risk of bias suggested a positive effect of RINCE over sham stimulation on pain (very low-quality evidence).Non-invasive brain stimulation appears to be frequently associated with minor and transient side effects, though there were two reported incidences of seizure related to active rTMS in the included studies.
  
  
  CONCLUSIONS
  Single doses of high-frequency rTMS of the motor cortex may have small short-term effects on chronic pain. It is likely that multiple sources of bias may exaggerate this observed effect. The effects do not meet the predetermined threshold of minimal clinical significance and multiple-dose studies do not consistently demonstrate effectiveness. The available evidence suggests that low-frequency rTMS, rTMS applied to the pre-frontal cortex, CES and tDCS are not effective in the treatment of chronic pain. While the broad conclusions for rTMS and CES have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation and the conclusion regarding the effectiveness of tDCS has changed. We recommend that previous readers should re-read this update. There is a need for larger, rigorously designed studies, particularly of longer courses of stimulation. It is likely that future evidence may substantially impact upon the presented results.
authors.affiliation: Centre for Research in Rehabilitation, School of Health Sciences and Social Care, Brunel University, Kingston Lane, Uxbridge, Middlesex, UK, UB8 3PH.
authors.forename: Neil E
authors.initials: NE
authors.lastname: O'Connell
authors.forename: Benedict M
authors.initials: BM
authors.lastname: Wand
authors.forename: Louise
authors.initials: L
authors.lastname: Marston
authors.forename: Sally
authors.initials: S
authors.lastname: Spencer
authors.forename: Lorraine H
authors.initials: LH
authors.lastname: Desouza
mesh_terms: D001921:Brain / Q000502:physiology*; D059350:Chronic Pain / Q000628:therapy*; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D059408:Pain Management / Q000379:methods*; D016032:Randomized Controlled Trials as Topic; D050781:Transcranial Magnetic Stimulation / Q000009:adverse effects / Q000379:methods*