Krishnan Chakravarthy, MD, Ph.D., Interventional Pain Specialist10.29.21
An estimated 100 million adults have chronic back pain and 19.6 million have high-impact chronic pain that limits their work activities on most days or every day for six months, based on 2016 data.1-2 The most common causes of chronic back pain can include herniated disc, degenerative disc disease, spinal stenosis,3 and post-laminectomy or failed back surgical syndrome.4
According to the National Institutes of Health (NIH), approximately 20 percent of back pain patients have a chronic condition, and new treatment approaches are needed to provide them with effective and durable pain relief. Device-delivered pain management options have emerged as an alternative or adjunct to pharmaceuticals, including opioids. Recent data demonstrate that Differential Target Multiplexed (DTM) spinal cord stimulation (SCS) therapy using the Medtronic Intellis platform provides superior back pain relief compared with conventional SCS therapy in a randomized controlled trial (RCT).
Incorporating this evolving understanding of the roles neurons and glial cells play in pain development and progression from acute to chronic pain states provides an opportunity to enhance the utility of neurostimulation approaches such as SCS. This is because the differential target multiplexed (DTM) waveform may modulate both neurons and glial cells to a different extent than single-waveform approaches.
The DTM SCS waveform is the culmination of decades of research into the mechanisms by which neurostimulation provides pain relief and technologies that enable differential modulation of distinct cell types that contribute to the development and maintenance of pain. In 1965, Melzack and Wall proposed the gate-control theory of pain inhibition, which spurred the initial development of SCS.12 Although the gate-control theory initially postulated a reduction in nociceptive pain in response to SCS, clinical experience demonstrated patients with neuropathic and other rarer pain syndromes also received benefits.13
Over subsequent decades, SCS therapies evolved through multiple clinical and pre-clinical studies combined with advances in neurostimulation device technology. One example is the Senza SCS systems (approved by the U.S. Food and Drug Administration in 2015), which use high-frequency stimulation and was demonstrated to have better back and leg pain outcomes compared with conventional SCS in a RCT. High-frequency stimulation also revealed SCS could provide significant pain relief independent of the paresthesia’s characteristic of lower frequency SCS.
DTM SCS represents the latest advancements in science and research on the mechanisms underpinning the therapeutic benefits of SCS. Application of the DTM SCS waveform with electric current in animal models has been shown to change gene expression in glial cells and neurons, enabling a new hypothesized approach to treating chronic back pain.14-16 Additional data also suggest DTM SCS may impact the neuronal-glial interaction,15-17 and in preclinical studies the DTM SCS waveform best modulated glial and neuronal gene expression back toward the non-pain state.15-17
DTM SCS therapy is delivered as a programming option via the Medtronic Intellis SCS platform. Importantly, DTM SCS utilizes a standard implant device with a novel therapy to achieve improved outcomes, allowing physicians to integrate this approach into their clinical practice without learning a new implant procedure.
The RCT study18 comprised 94 implanted SCS patients who were randomized to either the treatment (DTM SCS) or control arm (conventional SCS), both using the Intellis platform, and followed over the course of 12 months. The RCT met its primary endpoint of noninferiority compared with conventional SCS, and a pre-specified secondary statistical test for superiority showing the difference between DTM SCS and conventional SCS as highly significant. The rate of back pain response (defined as >50 percent improvement) at 12 months for DTM SCS was 84 percent, which was significantly greater (p=0.0005) compared with conventional SCS. Importantly, 69 percent of patients treated with DTM SCS were profound back pain responders (>80 percent improvement) at 12 months, compared with only 35 percent with conventional SCS.
DTM SCS resulted in improved sustained back pain relief, with a mean VAS score less than 2 (1.74) at 12 months compared with 3.71 for conventional SCS at the same time point. Additionally, patients treated with DTM SCS also achieved sustained leg pain relief, with a mean VAS score less than 2 (1.45) at 12 months compared with 2.25 for conventional SCS.
DTM SCS was also observed to provide multiple ancillary benefits beyond pain relief.19 DTM SCS achieved sustained improvements in the degree of disability and quality of life at 12-months follow-up. The number of patients treated with DTM SCS with minimal/moderate disability as assessed using the Oswestry Disability Index (ODI) scores increased from 27 percent to 76 percent of subjects, and PROMIS scores also improved with DTM SCS, with 88 percent of subjects scoring excellent/very good/good/fair at 12 months compared with 39 percent at baseline. Additionally, 62 percent of subjects treated with DTM SCS were Very Satisfied (the highest category of satisfaction) while 46 percent were “Very Satisfied” with conventional SCS.
A growing body of evidence, including the recent RCT data cited above, support DTM SCS in chronic back pain treatment and suggest the treatment landscape for chronic pain will continue to experience a profound shift toward use of SCS therapy. Other RCTs have demonstrated the long-term superiority of 10-kHz high-frequency SCS compared with traditional SCS.22 Data from the SUNBURST study demonstrated the safety, efficacy, and superiority of burst SCS compared with tonic SCS in patients with chronic pain in trunk/limbs,23 and the EVOKE trial demonstrated the benefit of closed-loop SCS compared with open-loop SCS.24
References
1 Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington DC, United States: The National Academies Press; 2011.
2 Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016. MMWR. Morbidity and mortality weekly report.2018;67(36):1001-1006.
3 Peloza J. Causes of lower back pain. Spine-health. April 20, 2017. Available at: https://www.spine-health.com/conditions/lower-back-pain/causes-lower-back-pain
4 Thomson S. Failed back surgery syndrome – definition, epidemiology and demographics. British J Pain. 2013;7(1):56-59.
5 Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36.
6 Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010 May-Jun;10(3):167-84.
7 De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: Path to CNS centralization and chronic pain. Pain. 2006; 122:17-21.
8 Cleary J, Gerken M and Pratt A. Analgesics of the future: inside the potential of glial cell modulators. Practical Pain Management. 2020;19:56-59.
9 Ruiz-Sauri A., Orduña-Valls J.M., Blasco-Serra A. et al. Glia to neuron ratio in the posterior aspect of the human spinal cord at thoracic segments relevant to spinal cord stimulation. Journal of Anatomy, vol. 235, no. 5, 2019, pp. 997-1006.
10 Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010 May-Jun;10(3):167-84.
11 Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36.
12 De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: Path to CNS centralization and chronic pain. Pain. 2006; 122:17-21.
13 Caylor J, Redy R, , Yin S, et al. Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action. Bioelectron Med. 2019;5:12.
14 Cedeno DL, Smith WJ, Kelley CA, Tilley DM, Sanapati S and Vallejo R. DTM-SCS enhances neuron-glial inflammasome relative to high rate and low rate. Abstract. Presented at the 2020 North American Neuromodulation Society Annual Meeting.
15 Vallejo R, Kelley CA, Gupta A, Smith WJ, Vallejo A, Cedeño DL. Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. Mol Pain. 2020 Jan-Dec;16:1744806920918057.
16 Cedeno DL, Smith WJ, Kelley CA, Vallejo R. 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
17 Smith WJ, Cedeño DL, Thomas SM, Kelley CA, Vetri F, Vallejo R. Modulation of microglial activation states by spinal cord stimulation in an animal model of neuropathic pain: Comparing high rate, low rate, and differential target multiplexed programming. Mol Pain. 2021 Jan-Dec;17:1744806921999013. doi: 10.1177/1744806921999013. PMID: 33626981.
18 Fishman M, Cordner H, Justiz R, et al. Randomized Controlled Clinical Trial to Study the Effects of Differential Target Multiplexed™ SCS (DTMTM SCS) in Treating Intractable Chronic Low Back Pain: Long-term Follow-Up Results. Presented at: North American Neuromodulation Society 24th Annual Meeting. Jan 15-16, 2021. Virtual.
19 Vallejo R, Fishman M, Cordner H, et al. Differential Target Multiplexed™ SCS (DTMTM SCS) for Treating Intractable Chronic Low Back and Leg Pain: Profound Response and Long-Term Benefits in Quality of Life. Presented at: North American Neuromodulation Society 24th Annual Meeting. Jan 15-16, 2021. Virtual.
20 Kieserman JM, Myers VD, Dubey P, et al. Current landscape of heart failure gene therapy. J Am Heart Assoc. 2019;8(10).
21 Tehzeeb J, Manzoor A and Ahmed MM. Is stem cell therapy an answer to heart failure: a literature search. Cureus. 2019;11 doi: 10.7759/cureus.5959
22 Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz high-frequency and traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery. 2016;79(5):667-677.
23 Deer T, Slavin KV, Amirdelfan, K, et al. Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform. Neuromodulation. 2018;21(1):56-66.
24Mekhail N, Levy R, Deer TR et al. Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial. Lancet Neurol. 2020;9(2):123-134.
Krishnan Chakravarthy, MD, Ph.D., is an interventional pain management specialist based in San Diego, Calif. He is a consultant for Medtronic, and Medtronic provided technical support for and reviewed the contents of this article prior to publication.
According to the National Institutes of Health (NIH), approximately 20 percent of back pain patients have a chronic condition, and new treatment approaches are needed to provide them with effective and durable pain relief. Device-delivered pain management options have emerged as an alternative or adjunct to pharmaceuticals, including opioids. Recent data demonstrate that Differential Target Multiplexed (DTM) spinal cord stimulation (SCS) therapy using the Medtronic Intellis platform provides superior back pain relief compared with conventional SCS therapy in a randomized controlled trial (RCT).
The Evolving Landscape of Neurostimulation in Chronic Back Pain Treatment
From an anatomic perspective, both glial cells and neuronal cells play critical roles in chronic pain. The role of glial cells in pain has long been explored,5-7 and they have been evaluated as a target for pharmaceutical interventions. For example, ibudilast, which is used in Japan and is being evaluated in U.S. clinical trials, is a phosophodiesterase inhibitor that modulates proinflammatory glial cell activity, leading to reduced levels of the inflammatory cytokine IL-1.8 The phosphodiesterase inhibitor propentofylline is another glial cell modulator that has been shown in rats to reduce pain behavior and allodynia.7 Glial cells, which outnumber neurons in the spinal cord by 12:1,9 are electrically responsive cells in the spinal cord,10 and chronic pain occurs when neuro-glial interactions get out of sync.10-12Incorporating this evolving understanding of the roles neurons and glial cells play in pain development and progression from acute to chronic pain states provides an opportunity to enhance the utility of neurostimulation approaches such as SCS. This is because the differential target multiplexed (DTM) waveform may modulate both neurons and glial cells to a different extent than single-waveform approaches.
The DTM SCS waveform is the culmination of decades of research into the mechanisms by which neurostimulation provides pain relief and technologies that enable differential modulation of distinct cell types that contribute to the development and maintenance of pain. In 1965, Melzack and Wall proposed the gate-control theory of pain inhibition, which spurred the initial development of SCS.12 Although the gate-control theory initially postulated a reduction in nociceptive pain in response to SCS, clinical experience demonstrated patients with neuropathic and other rarer pain syndromes also received benefits.13
Over subsequent decades, SCS therapies evolved through multiple clinical and pre-clinical studies combined with advances in neurostimulation device technology. One example is the Senza SCS systems (approved by the U.S. Food and Drug Administration in 2015), which use high-frequency stimulation and was demonstrated to have better back and leg pain outcomes compared with conventional SCS in a RCT. High-frequency stimulation also revealed SCS could provide significant pain relief independent of the paresthesia’s characteristic of lower frequency SCS.
DTM SCS represents the latest advancements in science and research on the mechanisms underpinning the therapeutic benefits of SCS. Application of the DTM SCS waveform with electric current in animal models has been shown to change gene expression in glial cells and neurons, enabling a new hypothesized approach to treating chronic back pain.14-16 Additional data also suggest DTM SCS may impact the neuronal-glial interaction,15-17 and in preclinical studies the DTM SCS waveform best modulated glial and neuronal gene expression back toward the non-pain state.15-17
DTM SCS therapy is delivered as a programming option via the Medtronic Intellis SCS platform. Importantly, DTM SCS utilizes a standard implant device with a novel therapy to achieve improved outcomes, allowing physicians to integrate this approach into their clinical practice without learning a new implant procedure.
DTM SCS with Intellis Is an Evidence-Based Approach to Treating Chronic Back Pain
Recently reported data from a RCT demonstrated DTM SCS was superior to conventional stimulation and provided profound back pain (≥80 percent) relief at 12 months in the majority of patients.The RCT study18 comprised 94 implanted SCS patients who were randomized to either the treatment (DTM SCS) or control arm (conventional SCS), both using the Intellis platform, and followed over the course of 12 months. The RCT met its primary endpoint of noninferiority compared with conventional SCS, and a pre-specified secondary statistical test for superiority showing the difference between DTM SCS and conventional SCS as highly significant. The rate of back pain response (defined as >50 percent improvement) at 12 months for DTM SCS was 84 percent, which was significantly greater (p=0.0005) compared with conventional SCS. Importantly, 69 percent of patients treated with DTM SCS were profound back pain responders (>80 percent improvement) at 12 months, compared with only 35 percent with conventional SCS.
DTM SCS resulted in improved sustained back pain relief, with a mean VAS score less than 2 (1.74) at 12 months compared with 3.71 for conventional SCS at the same time point. Additionally, patients treated with DTM SCS also achieved sustained leg pain relief, with a mean VAS score less than 2 (1.45) at 12 months compared with 2.25 for conventional SCS.
DTM SCS was also observed to provide multiple ancillary benefits beyond pain relief.19 DTM SCS achieved sustained improvements in the degree of disability and quality of life at 12-months follow-up. The number of patients treated with DTM SCS with minimal/moderate disability as assessed using the Oswestry Disability Index (ODI) scores increased from 27 percent to 76 percent of subjects, and PROMIS scores also improved with DTM SCS, with 88 percent of subjects scoring excellent/very good/good/fair at 12 months compared with 39 percent at baseline. Additionally, 62 percent of subjects treated with DTM SCS were Very Satisfied (the highest category of satisfaction) while 46 percent were “Very Satisfied” with conventional SCS.
Evolving Treatment Algorithms to Maximize Benefit of DTM SCS
Evolving treatment paradigms based on expanded biologic insights and advanced technology is common practice in the medical field. The treatment landscape for chronic heart failure underwent a paradigm shift with the advent of stents—which replaced bypass surgery for many patients—and the landscape is poised to shift again as promising gene and cell therapies advance to late-stage clinical trials.20,21A growing body of evidence, including the recent RCT data cited above, support DTM SCS in chronic back pain treatment and suggest the treatment landscape for chronic pain will continue to experience a profound shift toward use of SCS therapy. Other RCTs have demonstrated the long-term superiority of 10-kHz high-frequency SCS compared with traditional SCS.22 Data from the SUNBURST study demonstrated the safety, efficacy, and superiority of burst SCS compared with tonic SCS in patients with chronic pain in trunk/limbs,23 and the EVOKE trial demonstrated the benefit of closed-loop SCS compared with open-loop SCS.24
References
1 Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington DC, United States: The National Academies Press; 2011.
2 Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016. MMWR. Morbidity and mortality weekly report.2018;67(36):1001-1006.
3 Peloza J. Causes of lower back pain. Spine-health. April 20, 2017. Available at: https://www.spine-health.com/conditions/lower-back-pain/causes-lower-back-pain
4 Thomson S. Failed back surgery syndrome – definition, epidemiology and demographics. British J Pain. 2013;7(1):56-59.
5 Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36.
6 Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010 May-Jun;10(3):167-84.
7 De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: Path to CNS centralization and chronic pain. Pain. 2006; 122:17-21.
8 Cleary J, Gerken M and Pratt A. Analgesics of the future: inside the potential of glial cell modulators. Practical Pain Management. 2020;19:56-59.
9 Ruiz-Sauri A., Orduña-Valls J.M., Blasco-Serra A. et al. Glia to neuron ratio in the posterior aspect of the human spinal cord at thoracic segments relevant to spinal cord stimulation. Journal of Anatomy, vol. 235, no. 5, 2019, pp. 997-1006.
10 Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010 May-Jun;10(3):167-84.
11 Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36.
12 De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: Path to CNS centralization and chronic pain. Pain. 2006; 122:17-21.
13 Caylor J, Redy R, , Yin S, et al. Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action. Bioelectron Med. 2019;5:12.
14 Cedeno DL, Smith WJ, Kelley CA, Tilley DM, Sanapati S and Vallejo R. DTM-SCS enhances neuron-glial inflammasome relative to high rate and low rate. Abstract. Presented at the 2020 North American Neuromodulation Society Annual Meeting.
15 Vallejo R, Kelley CA, Gupta A, Smith WJ, Vallejo A, Cedeño DL. Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. Mol Pain. 2020 Jan-Dec;16:1744806920918057.
16 Cedeno DL, Smith WJ, Kelley CA, Vallejo R. 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
17 Smith WJ, Cedeño DL, Thomas SM, Kelley CA, Vetri F, Vallejo R. Modulation of microglial activation states by spinal cord stimulation in an animal model of neuropathic pain: Comparing high rate, low rate, and differential target multiplexed programming. Mol Pain. 2021 Jan-Dec;17:1744806921999013. doi: 10.1177/1744806921999013. PMID: 33626981.
18 Fishman M, Cordner H, Justiz R, et al. Randomized Controlled Clinical Trial to Study the Effects of Differential Target Multiplexed™ SCS (DTMTM SCS) in Treating Intractable Chronic Low Back Pain: Long-term Follow-Up Results. Presented at: North American Neuromodulation Society 24th Annual Meeting. Jan 15-16, 2021. Virtual.
19 Vallejo R, Fishman M, Cordner H, et al. Differential Target Multiplexed™ SCS (DTMTM SCS) for Treating Intractable Chronic Low Back and Leg Pain: Profound Response and Long-Term Benefits in Quality of Life. Presented at: North American Neuromodulation Society 24th Annual Meeting. Jan 15-16, 2021. Virtual.
20 Kieserman JM, Myers VD, Dubey P, et al. Current landscape of heart failure gene therapy. J Am Heart Assoc. 2019;8(10).
21 Tehzeeb J, Manzoor A and Ahmed MM. Is stem cell therapy an answer to heart failure: a literature search. Cureus. 2019;11 doi: 10.7759/cureus.5959
22 Kapural L, Yu C, Doust MW, et al. Comparison of 10-kHz high-frequency and traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery. 2016;79(5):667-677.
23 Deer T, Slavin KV, Amirdelfan, K, et al. Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform. Neuromodulation. 2018;21(1):56-66.
24Mekhail N, Levy R, Deer TR et al. Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial. Lancet Neurol. 2020;9(2):123-134.
Krishnan Chakravarthy, MD, Ph.D., is an interventional pain management specialist based in San Diego, Calif. He is a consultant for Medtronic, and Medtronic provided technical support for and reviewed the contents of this article prior to publication.