Evaluating the Statistical Robustness of Randomized Controlled Trials of Spinal Cord Stimulation for Pain through the Use of Fragility Index

Background: The use of spinal cord stimulation (SCS) for managing severe refractory chronic pain has expanded considerably due to positive statistical evidence regarding its use; however, the statistical robustness of the underlying randomized controlled trials (RCTs) requires further scrutiny. One such tool that can be used for this purpose is the fragility index, which quantifies how many individual outcome events must be altered for an outcome to lose statistical significance. Thus the index can be used quantitatively to assess the stability and robustness of an RCT’s conclusions, with higher values indicating increased trial stability. This study assesses the fragility of pain outcomes across RCTs investigating SCS for chronic pain to better understand the quality and robustness of evidence. Methods: A systematic search was conducted for RCTs assessing SCS for any chronic pain indication. The primary outcome was an evaluation of the trial-specific fragility index for the prespecified pain primary outcomes of RCTs. Secondary outcomes included an evaluation of fragility for (1) specified indications for SCS therapy, (2) reported pain outcomes appearing in three or more RCTs, (3) the presence/absence of a conflict of interest, and (4) comparisons of SCS to conservative management or different SCS waveform modalities. Results: A total of 30 RCTs were included. The median (interquartile range [IQR]) fragility index across the primary outcome of all trials was 5.45 (3.00 to 11.45). There was no statistical difference between the (1) types of outcomes (dichotomous vs. continuous; P = 0.710), (2) primary versus secondary pain outcomes ( P = 0.771), or (3) presence versus absence of trial conflict of interest ( P = 0.753). Indications with a median (IQR) fragility score greater than three included persistent spinal pain syndrome type 2 with a score of 8.00 (2.80 to 12.60), painful diabetic neuropathy with a score of 6.00 (3.00 to 11.80), complex regional pain syndrome with a score of 7.20 (4.62 to 81.50), mixed etiologies with a score of 9.00 (3.00 to 38.00), and other etiologies with a score of 3.00 (1.00 to 8.55). Conclusions: This study suggests that the majority of RCTs investigating primary pain outcomes after SCS therapy are robust with relatively high fragility scores. Reporting the fragility of outcomes in trials can provide a more comprehensive assessment of trial robustness and can further aid clinicians in interpreting trial results and making informed treatment decisions.