Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial

Abstract

Background Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain. Methods (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0–10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS. Results (1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI − 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen’s D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia. Conclusions Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663.

Chinese herbal medicine Buyang Huanwu Decoction in treatment of peripheral nerve injury: A systematic review and meta-analysis of randomized controlled trials

“…They are followed by partial recovery, muscle atrophy, chronic pain, and profound weakness. [4,33] Recently, there have been a number of investigations and efforts aimed at developing new treatment methods, as new surgical repairs, nerve guide conduits of the next generation, and other techniques, including nutritional therapy, gene therapy, and regenerative medicine are developed. [4,34,35] There are several types of mesenchymal stem cells that can promote peripheral nerve regeneration, as well as their secretome.…”

“…A primary objective of nerve repair is to allow reinnervation of the target organs by guiding regenerating sensory, motor, and autonomic axons into the environment of the distal nerve. [3,4] Typically, microsurgical treatments include direct repair, tension-free end-to-end suture, or autologous nerve grafts for larger gaps repair as the gold standard technique. Besides, a variety of other treatment methods are also available, including pharmacological treatments and cell-based therapies in combination with biomaterials in the form of tube guides.…”

Intensity-dependent modulation of cortical somatosensory processing during external, low-frequency peripheral nerve stimulation in humans

“…The current findings have potential implications for neuropathic pain treatment. Although preliminary investigations have demonstrated success with LFS ( 9 , 10 , 131 ), evidence is limited, and a recent randomized controlled trial in chronic peripheral nerve injury found no significant reduction in spontaneous pain symptoms following 3 mo of LFS treatment ( 132 ). However, these findings may have been affected by stimulation intensity, as patients were able to vary stimulus parameters including intensity as desired, which may have resulted in intensities below that required to activate Aδ fibers ( 11 , 15 ).…”

“…However, these findings may have been affected by stimulation intensity, as patients were able to vary stimulus parameters including intensity as desired, which may have resulted in intensities below that required to activate Aδ fibers ( 11 , 15 ). A mechanistic arm of the aforementioned trial reported significant effects of LFS on mechanical pain sensitivity and dynamic mechanical allodynia ( 132 ). Indeed, LFS has been shown to reverse and inhibit the development of primary hyperalgesia evoked by HFS, even at very low frequencies that would not independently result in LTD ( 32 ).…”

Correction: Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial

“…Following publication of the original article [ 1 ], we have been notified that there was incorrectly mentioned device in the text body of the article (Methods’ section). It should be as follows:…”