Introduction
Chronic neuropathic pain is a significant clinical challenge affecting millions of patients and contributing substantially to healthcare costs and opioid dependence.1-2 Spinal cord stimulation (SCS) is an increasingly adopted therapy, with both traditional low-frequency and newer high-frequency paradigms demonstrating analgesic efficacy.3-5 However, the benefit of combining high- and low-frequency stimulation has not previously been evaluated, and the durability of SCS-induced analgesia beyond active stimulation remains uncertain. Understanding these mechanisms is critical for optimizing neuromodulation strategies and improving clinical outcomes.
Methods
Male Sprague-Dawley rats underwent spared nerve injury of the sciatic nerve, a widely used and clinically relevant model of neuropathic pain that produces persistent unilateral mechanical hypersensitivity and cold allodynia without motor impairment. Epidural SCS leads were implanted, and animals were randomly assigned to receive low-frequency (60 Hz), high-frequency (1 kHz), or combined stimulation paradigms delivered at sub-motor threshold intensities. Behavioral assessments included electronic von Frey testing to measure paw withdrawal thresholds (PWT) and acetone assays for cold allodynia. Testing occurred at baseline, during 2 hours of continuous SCS, serial intervals up to 5 hours (inclusive of stimulation) on days 1, 3, and 5 of SCS.
Results
Both high- and low-frequency stimulation independently produced significant analgesic effects, increasing PWTs and reducing nocifensive cold responses (p<0.05). Notably, combined high- and low-frequency SCS yielded superior analgesic efficacy, producing both a greater magnitude of pain relief and prolonged duration of effect relative to either paradigm alone (p<0.05). Importantly, the most robust and long-lasting effects were observed after repeated stimulation, with particularly durable analgesia (>5 hours) noted on day 5, suggesting potential cumulative or plasticity-related mechanisms.
Conclusion
This study demonstrates that combined high- and low-frequency SCS produces more robust, multimodal, and longer-lasting analgesia in rodent models of neuropathic pain. The persistence of benefit beyond active stimulation suggests mechanisms beyond classical gate control, potentially involving biomechanical or neuroimmune modulation of nociceptive pathways. Clinically, these findings highlight the promise of frequency optimization to maximize analgesic efficacy and durability. Future studies are needed to (1) define the mechanistic basis of sustained benefit and (2) refine stimulation paradigms to enhance translational impact and improve chronic pain management.
Figures and Tables
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References
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