Stimulating the brain without surgery for the management of chronic pain

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Geneviève Veereman MD, PhD & Chris De Laet MD, PhD

The Cochrane Collaboration performed a meta-analysis to evaluate the efficacy of non-invasive brain stimulation techniques (NIBST) in chronic pain.
The meta-analysis included 56 studies (1710 randomized patients) conducted between 2000 and 2013. Four different methods were evaluated. The quality of the evidence according to GRADE is low to very low and no effect could convincingly be demonstrated. For the last developed technique the reduced impedance non-invasive cortical electrostimulation (RINCE), only one small study was available that showed very low evidence of effectiveness.
At the present time there is no convincing evidence for the efficacy of repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES) or transcranial direct current stimulation (tDCS). Although these techniques have a good safety profile, their usefulness in the clinical setting does not appear justified based on the available data. More novel techniques (such as RINCE) and other approaches should be further explored.

Background

Clinically significant chronic pain, defined as pain lasting for more than three months, is reported to affect up to 20% of the adult population [1]. According to the KCE report on chronic cancer pain management, published in 2013 [2], approximately 8.5% of the Belgian population needs some form of specialised pain treatment.  Another KCE report assessed the additional contribution to pain management of neuromodulation, specifically implanted spinal cord stimulators and implanted intrathecal analgesic delivery pumps [3]. Non-invasive brain stimulation therapy (NIBST) includes a number of additional techniques for pain management. The objective of this KHRFY is to summarize the findings and conclusions of a recent Cochrane review that critically evaluated the efficacy of NIBST compared to sham controls for chronic pain [1].

Meta-analysis performed by the Cochrane Collaboration [1]

Scope

This meta-analysis is an update of a previous Cochrane review [4] and focusses on the use of NIBST for the management of chronic pain due to fibromyalgia, post-stroke pain and complex regional pain syndrome. The non-invasive techniques that were studied, included magnetic brain stimulation (repetitive transcranial magnetic stimulation - rTMS) or direct application of electrical current (transcranial direct current stimulation - tDCS and cranial electrotherapy stimulation - CES). It has been suggested that rTMS would be more effective in the treatment of neuropathic pain arising from damage to the central nervous system rather than in peripheral neuropathic pain [3]. RINCE (reduced impedance non-invasive cortical electrostimulation) is a more recent NIBST technique that applies electrical current via scalp electrodes but utilises specific stimulation frequencies that 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 [1].

Methods

Only randomised or quasi-randomised, parallel or cross-over study designs were considered, using rTMS, CES, tDCS or RINCE with a sham control group and with pain as primary outcome. The eligible population was limited to patients older than 18 years with at least three months of chronic pain. A total of 56 studies, involving 1710 randomized patients, and published between 2000 and 2013 were included in the analysis.

Pain was evaluated using a visual analogue scale or a numerical or verbal rating scale. Outcomes were categorized in short and long-term effects. Data were extracted and meta-analysed and the GRADE methodology was used to assess the body of evidence [5].

Conclusions of the authors

Low frequency stimulation with rTMS and with rTMS specifically applied to the pre-frontal cortex does not appear to be effective (low quality and very low-quality evidence respectively). A short-term effect was found for single-dose high frequency stimulation of the motor cortex (low-quality evidence), but this effect did not exceed the preset threshold for clinically meaningful difference in pain.
Pain after brain stimulation with CES was not significantly different when compared to sham stimulation (low quality evidence). tDCS was also not found to be effective (very low-quality evidence). For RINCE, only one small study was available that showed effectiveness, but with a very low level of evidence.
Due to this uncertainty, any clinical application of NIBST should be conducted within a clinical research framework rather than in routine clinical care.

Other considerations

For none of the stimulation techniques the evidence is conclusive. Non-invasive stimulation techniques require no surgical procedure and are therefore easier to apply than invasive procedures. But although these non-invasive techniques have a good safety profile, their usefulness in the clinical setting does not appear justified based on the available data. More studies of rigorous design and adequate size are required to evaluate accurately all forms of non-invasive brain stimulation for the treatment of chronic pain.

Situation in Belgium

NIBST techniques were not discussed in the 2013 KCE report on the management of cancer pain [2]. In Belgium, these techniques are not currently reimbursed and authors of this summary failed to find reliable information about the frequency of use of these techniques in Belgium. However, NIBST is being offered in some Belgian hospitals and is advertised on their websites.

Conclusion

This extensive meta-analysis on the effect of NIBST on chronic pain fails to show efficacy. The Cochrane reviewers recommend to limit the use of RINCE or other new techniques to clinical trial conditions.

References

1. O'Connell NE, Wand BM, Marston L et al. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2014; 4: CD008208.

2. Eyssen M, Benahmed N, Desomer A. Supportive treatment for cancer – Part 3 : Treatment of pain: most common practices. Good Clinical Practice (GCP). Brussels: Belgian Health Care Knowledge Centre (KCE); 2013. KCE Reports 211 (D/2013/10.273/84)  Available from: https://kce.fgov.be/publication/report/supportive-treatment-for-cancer-–-part-3-treatment-of-pain-most-common-practices

3. Camberlin C, San Miguel L, Smit Y, Post P, Gerkens S, De Laet C. Neuromodulation for the management of chronic pain : implanted spinal cord stimulators and intrathecal analgesic delivery pumps. Health Technology Assessment (HTA). Brussels: Belgian Health Care Knowledge Centre (KCE); 2012. KCE Reports 189 (D/2012/10.273/76)  Available from: https://kce.fgov.be/publication/report/neuromodulation-for-the-management-of-chronic-pain-implanted-spinal-cord-stimulat

4. O'Connell NE, Wand BM, Marston L et al. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2010; CD008208.

5. Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-926.