The comparative evidence of efficacy of non-invasive brain and nerve stimulation in diabetic neuropathy: a systematic review and network meta-analysis

Background: Diabetes mellitus is a highly burdensome metabolic disorder, affecting over 100 million people worldwide and leading to numerous complications. Among these, diabetic neuropathy is one of the most common, with approximately 60% of individuals with diabetes developing this condition. Current pharmacological treatments for diabetic neuropathy are often inadequate, providing limited efficacy and accompanied by a range of adverse effects. Non-invasive brain and nerve stimulation techniques have been proposed as potentially beneficial for diabetic neuropathy, though existing evidence remains inconclusive. This systematic review and network meta-analysis (NMA) aimed to evaluate the comparative efficacy of various non-invasive brain and nerve stimulation interventions in patients with diabetic neuropathy. Methods: A systematic search of electronic databases was conducted to identify randomized controlled trials (RCTs) of non-invasive brain or nerve stimulation in patients with diabetic neuropathy, from inception to September 6, 2024. The primary outcome was the change in pain severity, while secondary outcomes included changes in quality of life and sleep disturbance. Acceptability was assessed through dropout rates (i.e., withdrawal from the study before completion for any reason). A frequentist-based NMA was performed, utilizing odds ratios (OR) and standardized mean differences (SMD) with 95% confidence intervals (95%CIs) as effect size measures. Results: The NMA, which included 15 RCTs (totaling 1,139 participants, with a mean age of 61.2 years and a mean female proportion of 53.8%), evaluated 10 experimental interventions (1 control group, 4 non-invasive brain stimulation methods, and 5 non-invasive nerve stimulation methods). The analysis revealed that only transcutaneous electrical nerve stimulation (TENS) was associated with significantly greater improvements in pain severity (SMD = − 1.67, 95%CIs = − 2.64 to − 0.71) and sleep disruption (SMD = − 1.63, 95%CIs = − 2.27 to − 0.99) compared to the control group. None of the studied interventions showed significant differences in dropout rates or all-cause mortality compared to the control group. Conclusion: This study provides comparative evidence supporting the use of specific brain and nerve stimulation interventions in managing diabetic neuropathy. Future well-designed RCTs with longer treatment durations are recommended to further validate the long-term efficacy of these interventions. Trial registration PROSPERO CRD42024587660.