Recommendations  for  future  research

Based on the results of the RCT reported in this thesis and on the systematic review of the currently available literature on tDCS for pain reductions, tDCS is not effective for the treatment of clinical pain and does not consistently reduce experimentally induced pain. It is highly unlikely that altered stimulation paradigms, such as longer duration, higher intensities or a different stimulation target will increase its effectiveness. Future research on tDCS should therefore focus on different clinical conditions such as stroke, Parkinson’s disease or dementia. Research in these areas is in its preliminary phase with few small scale trials indicating clinical improvements of the conditions. However, without a low risk of bias and adequately powered RCT, there is only a low level of evidence for its effectiveness.

Regarding chronic pain research, future research should further attempt to identify interventions that might improve the outcomes of CBT. These should continue to target pain processing within the central nervous system and effects of the intervention on pain processing within the brain should be monitored. A range of interventions has been proposed such as graded motor imagery, including left/right recognition and mirror therapy as well as sensory perception interventions.

Chapter Summary

This was the first adequately powered and low risk of bias trial to investigate the effectiveness of anodal tDCS over M1 for the reduction of pain and disability in a population of NSCLBP patients. Trial results indicated that tDCS compared to sham stimulation was ineffective to change both primary outcome measures and did not influence the outcome of a CBT. Participants perceived a range of side effects but these were of mild to moderate intensity. Blinding of participants and researchers was evaluated following a recent discussion on the reliability of sham stimulation.

Participants and researchers were effectively blinded in the current trial.

Neurophysiological hypotheses as to why tDCS did not effectively reduce pain in NSCLBP patients were based on the multidimensional nature of the pain experience.

While the literature reported a measurable response to tDCS in brain regions underneath the electrodes, it was not sufficient to alter the perception of pain or to change perceived disability. Trial results did not support the use of tDCS for the reduction of pain and disability in NSCLBP.

9.  CHAPTER      

CONCLUSIONS  

This PhD aimed to evaluate the effectiveness of tDCS on pain and disability in patients with NSCLBP. It provided an overview of the published literature (overview of reviews and a systematic review of clinical trials) on the effectiveness of tDCS for the reduction of pain. Findings from the systematic review informed the design and methods for a RCT investigating the effectiveness of tDCS for pain and disability in a NSCLBP population. The trial was preceded by a feasibility study that evaluated practical aspects of trial procedures and the acceptability of tDCS as an intervention for NSCLBP. The results of the main trial were presented. The systematic review was updated. Trial results and limitations were discussed within the context of the updated systematic review, representing current evidence. Possible explanations for the non-significant effect of tDCS were explored from a neurophysiological perspective.

The initial systematic review (Chapter 3) revealed a high scientific interest in tDCS as a pain reducing intervention, as indicated by the large number of trials being published each year. Preliminary evidence was provided for a pain reducing effect for a variety of chronic pain disorders that raised hope for a new and effective tool in the management of chronic pain. However, the systematic review and meta-analysis of published trials revealed an unclear or high risk of bias in most trials due to methodological issues such as non-randomised sequence generation or unconcealed allocation to intervention groups. The external validity of reviewed trials

experimental pain in healthy participants showed that trials could not be combined in a meta-analysis because stimulation paradigms, experimental pain conditions, and outcome measures were too diverse. Based on these results and on doubts about the transferability of data produced by experimental pain studies into clinically meaningful results, a RCT on tDCS for the reduction of NSCLBP was designed (Chapter 4). It was the first RCT that focussed exclusively on NSCLBP and the first clinical trial that showed a low risk of bias. Furthermore, it was the first adequately powered clinical trial on tDCS for the reduction of pain using a sample size calculation that was based on clinically relevant change recommendations and on previous trials on tDCS as well as on NSCLBP.

A feasibility study indicated that planned trial procedures were feasible to conduct in practice and showed good patient acceptability for tDCS as an intervention for NSCLBP (Chapter 5). It further detected that potential trial participants had pain and disability values that were lower than anticipated and that they did not allow for an improvement that satisfied minimum clinically relevant change recommendations.

Subsequently, the inclusion criteria for the trial were amended to include a minimum level of VAS pain of 15 mm and a minimum ODI score of 8 points.

The results of the main trial (Chapter 6) indicated that tDCS was not effective to reduce pain or disability in patients with NSCLBP and that tDCS in combination with a CBT did not improve the outcome of the CBT. No adverse events were observed (defined as the participant requiring medical attention) but mild side effects were reported during / after most stimulation sessions. Participant, researcher, and assessor blinding was effective throughout the trial contrary to recently published doubts on the validity of the sham stimulation paradigm in tDCS research (O'Connell et al., 2012).

The systematic review of recent clinical trials on tDCS (Chapter 7) showed that results differed widely regarding the effectiveness of tDCS for pain reduction. Since the cut off date for the initial systematic review, negative results on the effectiveness of tDCS had been published, but the level of evidence was still low due to an unclear

or high risk of bias in all trials. The updated meta-analysis of published trials showed a combined mean effect of tDCS for the reduction of pain that was below 1 mm on a 0-10 mm VAS. Including the results of the current trial into the meta-analysis resulted in an even smaller effect size. Interestingly, all recent positive results were reported by 1 research team, an issue that compromises the credibility of the results in the light of the negative results published by other research teams. The systematic review of recent trials further indicated that experimental pain trials still have not agreed on a stimulation mode, duration, location or intensity that can be regarded as consistently effective for the reduction of experimental pain perception or the increase of pain thresholds. Owing to the diversity in outcome measures it was impossible to combine experimental pain trial results in a meta-analysis.

Trial results clearly indicated that anodal tDCS, applied over M1 with an intensity of 2 mA on 5 consecutive days for 20 min each day, was ineffective for the reduction of the pain intensity and disability in participants with NSCLBP and did not improve the outcome of CBT. Results from the updated meta-analysis additionally showed that the combined effect of anodal tDCS over M1 for the reduction of clinical pain, independent of the intensity, duration and frequency of the stimulation was smaller than 1 mm on a 0-10 mm VAS (Chapter 7). The current trial raised the level of the current evidence from "low" to "high" using the GRADE approach, since evidence was now based on 1 low risk of bias RCT. This can be interpreted as confidence that future research is unlikely to change the combined mean effect of tDCS for the reduction of clinical pain. The clinical use of tDCS can therefore not be recommended.