A Randomized, Double-blind, Placebo-controlled, Crossover, Mechanistic Study Investigating the Pain-relieving Effects of Spinal Cord Stimulation

Introduction: Spinal cord stimulation (SCS) is widely used for chronic pain management. Traditional SCS delivers tonic low-frequency (~50Hz) stimulation pulses that generate buzzing sensations (“paresthesia”) that overlap the painful area. Newer paresthesia-free SCS waveforms (e.g., burst, kilohertz-frequency) produce no sensation and have been quickly adopted. However, the mechanistic differences between the various SCS therapies are poorly understood.

Methods: We conducted a prospective, single-center, randomized, double-blind, sham-controlled, crossover clinical trial (NCT04732325) to investigate how SCS affects somatosensory pathways in 25 chronic pain patients undergoing SCS. Over approximately four weeks, subjects received one-week periods of burst, 1kHz, or sham stimulation in a randomized, crossover design, followed by 50Hz stimulation. At the end of each one-week treatment allocation, we performed quantitative sensory testing (QST) of somatosensory function at both a painful site and a nonpainful control site and collected self-reported health-related questionnaires. SCS-induced changes in temporal summation (TS) of pain was the primary outcome measure.

Results: Overall, we did not find aggregate significant differences in TS between each active stimulation and sham. However, our a priori sub-group analysis demonstrated that female participants experienced statistically significant attenuation in TS with 1kHz and burst SCS compared to sham SCS at the painful site (but not at the control site). Male participants, however, reported slightly elevated (statistically non-significant) TS at the most painful site, suggesting sex-dependent heterogeneity in SCS effects. Interestingly, while we observed significant improvements in anxiety and depression scores with 1kHz stimulation regardless of sex, we did not observe differences in self-reported pain intensity scores between active stimulation and sham.

Conclusion: To our knowledge, this is the first clinical trial to systematically examine within-subject changes in TS in response to 1kHz, burst, and 50Hz stimulation from sham among chronic pain patients. Overall, we observed sex-dependent effects of SCS on central pain-processing mechanisms, warranting further investigation. We recommend additional sham-controlled trials to further elucidate sex-dependent differences in SCS to treat chronic pain.