Neuromodulation using ultra low frequency current waveform reversibly blocks axonal conduction and chronic pain

Abstract

Chronic pain remains a leading cause of disability worldwide, and there is still a clinical reliance on opioids despite the medical side effects associated with their use and societal impacts associated with their abuse. An alternative approach is the use of electrical neuromodulation to produce analgesia. Direct current can block action potential propagation but leads to tissue damage if maintained. We have developed a form of ultra low frequency (ULF) biphasic current and studied its effects. In anesthetized rats, this waveform produced a rapidly developing and completely reversible conduction block in >85% of spinal sensory nerve fibers excited by peripheral stimulation. Sustained ULF currents at lower amplitudes led to a slower onset but reversible conduction block. Similar changes were seen in an animal model of neuropathic pain, where ULF waveforms blocked sensory neuron ectopic activity, known to be an important driver of clinical neuropathic pain. Using a computational model, we showed that prolonged ULF currents could induce accumulation of extracellular potassium, accounting for the slowly developing block observed in rats. Last, we tested the analgesic effects of epidural ULF currents in 20 subjects with chronic leg and back pain. Pain ratings improved by 90% after 2 weeks. One week after explanting the electrodes, pain ratings reverted to 72% of pretreatment screening value. We conclude that epidural spinal ULF neuromodulation represents a promising therapy for treating chronic pain.