Michael Fishman (Wilmington, USA) discusses the benefits of Differential Target Multiplexed spinal cord stimulation (DTM SCS; Medtronic)—when compared to more conventional SCS therapy options—and how this novel approach is driving an evolution in treatment paradigms for chronic low back pain.
Although the inflammatory neuroglial interaction involving both microglial and neuronal cells plays a central role in the development and persistence of pain, SCS has not historically studied the role of glial cells in pain modulation, and has instead focused almost entirely on mechanisms related to neurons. Similarly, SCS research has traditionally not focused on describing the impact on underlying inflammatory processes or gene expression changes.
Preclinical research has led to advances in our understanding of gene expression patterns in glial and neuronal cells, as well as of the interactions between glial and neuronal cells that contribute to pain.1 This work, in turn, is creating the foundation for new interventions that, in a clinical trial, have shown significantly improved efficacy in treating chronic pain.
DTM SCS therapy
DTM SCS therapy is prescribed for patients with chronic low back and leg pain. It targets different areas of the spinal cord—hence, Differential Target—with different signals or frequencies—hence, Multiplexed. With DTM SCS, therapy and settings can be customised to address each patient’s individual needs. In a randomised controlled trial (RCT), DTM SCS therapy was shown to provide profound back pain relief (≥80%) and significant reductions in leg pain for patients with chronic pain at 12 months.2,3 This study also showed that DTM SCS therapy was superior to conventional SCS with respect to back pain relief.
It has been known for more than 20 years that glial cells outnumber neuronal cells in the spinal cord by a ratio of 12:1.4,5,6 And, while SCS has historically been designed with a neuronal target in mind despite this knowledge, more recent investigations have shown that the use of customised waveforms—hypothesised to differentially target neurons and glial cells—can provide therapeutic benefit. DTM SCS therapy is the only neuromodulation approach that has shown, in animal models, robust modulation of both of these key cell types.
Additional preclinical studies have shown that chronic pain is associated with changes in a variety of gene expression patterns and that DTM SCS shifts expression back toward pre-pain levels more effectively than high- or low-rate SCS. With a mechanistic approach hypothesised to address the underlying biology of pain, DTM SCS therapy is a novel approach that warrants incorporation into standard clinical practice for appropriate patients.
Impact of SCS on gene expression patterns
Animal models of pain (spared-nerve injury [SNI] and chronic constriction injury [CCI]) show genomic changes that are related to injury and presumed to be related to pain. Genomic analysis of the effect of conventional SCS in uninjured and SNI animal models identified genetic changes associated with injury and with SCS in both the spinal cord and dorsal root ganglion (DRG).7 For example, RNA-seq analysis in nerve-injured rats with or without repetitive, conventional SCS identified a potential relationship between specific genes and the therapeutic effects observed in animals undergoing conventional SCS after CCI.8
Similarly, genomic analysis of the effects of 72 hours of continuous SCS in a non-pain animal model identified specific gene expression changes in both the spinal cord and DRG.9 Changes in gene expression patterns have also been identified in M1 and M2 glial cells following SNI, and high- and low-rate SCS had differential effects on shifting these patterns to a pain-naïve state.10
DTM SCS therapy was also investigated in these animal models and demonstrated a greater ability to rebalance neuron/glial gene expression patterns compared to high- or low-rate SCS alone. Single-cell RNA-seq in animals with and without nerve injury, and pre- and post-SCS, found that SNI creates an imbalance in inflammatory response for neurons and microglia—and that DTM SCS therapy:
- Was more effective than high- or low-rate SCS at rebalancing neuron and microglial inflammasomes
- Affected a population of inflammation genes in neurons and microglia that were unaffected by high- or low-rate SCS
- Was more effective than high- and low-rate SCS in relieving mechanical hypersensitivity11
A preclinical study evaluating the effect of DTM SCS therapy found that it significantly improved hot and cold sensitivity in an SNI animal model and, in specific neural tissue cell populations, showed a more significant shift to a pre-injury gene expression pattern in microglia, astrocytes, oligodendrocytes and neurons compared with high- or low-rate SCS.12,13
DTM SCS trial results on Intellis platform
DTM SCS therapy has been evaluated in an RCT in which 128 subjects were randomised to receive either DTM SCS or conventional SCS therapy. Subjects in both arms of the study were implanted using the Intellis platform (Medtronic) and followed over the course of 12 months. At 12 months, 84% of patients with chronic back pain treated with DTM SCS reported at least 50% pain relief, compared to 51% of patients treated with conventional SCS, as measured by the widely used visual analogue scale (VAS) for pain intensity. Some 69% of patients were profound back pain responders (>80% improvement) at 12 months with DTM SCS therapy, compared with only 35% with conventional SCS. Additionally, patients in the DTM SCS therapy arm had an average back VAS score reduction of 75%, compared with 50% for conventional SCS.
At 12 months, patients in the DTM SCS arm had a mean VAS score of less than two (1.74), indicating sustained back pain relief, compared with 3.71 for conventional SCS. Similarly, patients in the DTM SCS arm had sustained leg pain relief with a mean VAS score of less than two (1.45) at 12 months, compared with 2.25 for conventional SCS. With these results, the study met its primary endpoint of noninferiority compared with conventional SCS, and a pre-specified secondary statistical test for superiority showed the difference between DTM SCS therapy and conventional SCS was highly significant.
This RCT also demonstrated positive responses to DTM SCS therapy on several secondary outcomes, including sustained improvements in degree of disability and quality of life at 12-month follow-up. In the DTM SCS therapy arm, the percentage of patients with minimal/moderate disability as assessed using the Oswestry Disability Index (ODI) increased from 27% at baseline to 76% at 12 months, while the percentage of subjects with excellent/very good/good/fair outcomes as assessed by patient-reported outcomes measurement information system (PROMIS) scores increased from 39% to 88%. Additionally, the majority of subjects (83%) in the DTM SCS therapy arm were satisfied or very satisfied with the therapy. The US Food and Drug Administration (FDA) recently approved updated US labelling of the Intellis platform to reflect outcomes from this RCT.
Evolving chronic back pain treatment paradigms
A robust and growing body of preclinical evidence demonstrates that DTM SCS therapy shifts gene expression patterns back toward pre-pain states, and the recently reported RCT data showed a clear, statistically significant benefit for DTM SCS therapy compared with conventional SCS in patients with back pain. The RCT data also showed that DTM SCS therapy provided profound back pain relief in the majority of patients and that patients with “long” pain duration of greater than 12 years, who have likely tried other options for pain relief, achieved pain relief with DTM SCS. Taken as a whole, the data provide a cogent rationale for incorporating DTM SCS therapy into routine clinical practice in patients who may benefit from this novel therapy.
References:
1Zheng D, Liwinski T, Elinav E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discovery. 2020;6: 36.
2Cedeno D L, Smith W J, Kelley C A, et al. Spinal cord stimulation using differential target multiplexed programming modulates neural cell-specific transcriptomes in an animal model of neuropathic pain. Mol Pain. 2020;16: 1744806920964360.
3Vallejo R, Fishman M, Cordner H, et al. Differential Target Multiplexed SCS (DTM SCS) for treating intractable chronic low back and leg pain: profound response and long-term benefits in quality of life. Presented at the 24th North American Neuromodulation Society (NANS) annual meeting. 15-16 Jan, 2021. Virtual.
4Milligan E D, Watkins L R. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10(1): 23-36.
5Vallejo R, Tilley D M, Vogel L, et al. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010;10(3): 167-84.
6De Leo J A, Tawfik V L, LaCroix-Fralish M L. The tetrapartite synapse: Path to CNS centralization and chronic pain. Pain. 2006;122: 17-21.
7Vallejo R, Tilley D M, Cedeno D L, et al. Genomics of the effect of spinal cord stimulation on an animal model of neuropathic pain. Neuromodulation. 2016;19(6): 576-586.
8Stephens K E, Chen Z, Sivanesan E, et al. RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation. Mol Pain. 2018;14: 1-13.
9Smith W J, Vallejo A, Cedeno D L, et al. The effects of SCS lead implantation and subsequent stimulation on biological processes expression. Abstract. Presented at the 22nd North American Neuromodulation Society (NANS) annual meeting. 17-20 Jan, 2019. Las Vegas, USA.
10Smith W J, Sanapati S, Cedeno D L, et al. Effects of SCS on M1 and M2 microglia activation. Abstract. Presented at the American Society of Regional Anesthesia and Pain Medicine 18th Annual Pain Medicine Meeting. 14-16 Nov, 2019. New Orleans, USA.
11Cedeno D L, Smith W J, Kelley C A, et al. DTM-SCS enhances neuron-glial inflammasome relative to high rate and low rate. Abstract. Presented at the 23rd North American Neuromodulation Society (NANS) annual meeting. 23-26 Jan, 2020. Las Vegas, USA.
12Vallejo R, Kelley C A, Gupta A, et al. Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. Mol Pain. 2020;16: 1744806920918057.
13Cedeno D L, Smith W J, Kelley C A, et al. Spinal cord stimulation using differential target multiplexed programming modulates neural cell-specific transcriptomes in an animal model of neuropathic pain. Mol Pain. 2020;16: 1744806920964360.
Michael Fishman is an interventional pain medicine specialist at the Center for Interventional Pain and Spine in Wilmington, USA.
Disclosures: The author was a principal investigator for the Stimgenics open-label, post-market study (SGX-SCS-RCT), and is a consultant for Medtronic. Medtronic provided technical support for and reviewed the contents of this article prior to publication.
