Evolving Insights Into the Biology of Pain & Advances in Neuromodulation Technology Enable New Paradigms in the Treatment of Chronic Low Back Pain

More than 50 years ago, Melzack and Wall proposed the gate control theory of pain inhibition,¹ opening the door to the development of spinal cord stimulation (SCS) as an intervention designed to reduce nociceptive pain through electrical stimulation targeted to neurons. In the intervening decades, basic and translational research efforts have established that glial cells and neuroglial interactions play important roles in the development and persistence of pain and that pain relief may involve contributions from diverse neural cell types, including microglia, astrocytes, oligodendrocytes, and neurons.^2-4 This evolving understanding of the biology of pain has sparked research into SCS waveforms that may influence both neuronal and glial cells, particularly through investigating waveform influence on gene expression profiles.^5-9

Differential Target Multiplexed Spinal Cord Stimulation (DTM SCS therapy), which has a proposed mechanism of action beyond that of conventional SCS, targets different spinal areas (differential target) along the spinal cord with the use of different frequencies (multiplexed). A potential benefit of having the DTM SCS therapy available on the Intellis SCS Platform is the ability to conduct full body MRI scans under certain conditions. Additionally, recently published data from a randomized controlled trial (RCT) demonstrate that DTM SCS therapy provides superior pain relief compared with conventional SCS.^10-12

DTM SCS Therapy: An Evidence-Based Approach to Neuromodulation

While it has been known for more than 20 years that glial cells outnumber neuronal cells in the spinal cord by 12:1,^2-4,13 conventional SCS has been designed with a neuronal target in mind.

More recent investigations have shown that the use of customized waveforms that are hypothesized to differentially target neurons and glial cells can provide therapeutic benefit.

Additional preclinical studies in animals have shown that chronic pain behaviors are associated with changes in a variety of gene expression patterns and that the DTM SCS waveform shifts gene expression back toward pre-pain levels more effectively than high- or low-rate SCS.¹⁴

Evaluation of the DTM SCS waveform in preclinical models demonstrated greater ability to rebalance neuron/glial gene expression patterns compared with high-rate (HR) or low-rate (LR) SCS.¹⁴ The spared nerve injury (SNI) model in animals creates an imbalance in inflammatory response for neurons and microglia. The DTM SCS waveform was more effective than HR- or LR-SCS in rebalancing neuron and microglial inflammasomes in this model; it also altered the expression patterns of inflammatory genes in neurons and microglia that were unaffected by HR-SCS or LR-SCS.⁹ The DTM SCS waveform was also more effective than HR- and LR-SCS in relieving mechanical hypersensitivity.¹⁴ DTM SCS therapy significantly improved hot and cold sensitivity in a 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 HR or LR SCS.^9,14

RCT data demonstrate that DTM SCS therapy provides superior back pain relief compared with conventional SCS therapy

A RCT of 94 patients implanted with SCS who were randomized to either the treatment (DTM SCS therapy) or control arm (conventional SCS), followed over the course of 12 months (N=79), 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 as highly significant. Based on the results of the RCT, the FDA recently approved updated U.S. labeling of the Intellis platform to reflect the outcomes of the RCT showing superior back pain relief when using DTM SCS therapy.

Key findings from the RCT are a back pain responder rate (defined as >50% improvement) of 84% (P=0.0005) with DTM SCS therapy compared with conventional SCS, the highest back pain responder rate reported at 12 months in similar RCTs.* Notably, 69% of patients with DTM SCS therapy were profound back pain responders (>80% improvement) at 12 months, compared with only 35% with conventional SCS. Benefits with DTM SCS therapy compared with conventional SCS were also reported for average VAS back pain score reduction (75% with DTM SCS therapy compared with 50% for conventional SCS); sustained back pain relief at 12 months (mean VAS score of 1.74 vs 5.71, respectively); and sustained leg pain relief at 12 months (mean VAS score of 1.45 vs 2.25, respectively).

DTM SCS therapy also provided sustained improvements in several secondary endpoints, including degree of disability and quality of life at 12-months follow-up. In the DTM SCS therapy group, the proportion of subjects with minimal/moderate disability as assessed using Oswestry Disability Index (ODI) scores increased from 27% at baseline to 76% at 12 months. Similarly, the proportion of patients with excellent/very good/good/fair outcomes as assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) scores increased from 39% to 88% of subjects in the same time period. Additionally, 62% of subjects with DTM SCS therapy were very satisfied, while 46% were very satisfied with standard SCS.

A new perspective on the clinical use of DTM SCS therapy

For patients with chronic back pain, 10%-46% of lumbar surgeries do not resolve chronic pain, and less than 30%, 15%, and 5% of patients experience a successful outcome after their second, third, and fourth back surgeries, respectively. The recently reported RCT data demonstrate that DTM SCS therapy provides improved rates of response and profound response compared with conventional SCS and improves both back and leg pain. Patients receiving DTM SCS also benefit from MRI compatibility under certain conditions, providing additional flexibility for future medical care. Given the significant unmet need in patients with failed back surgeries, DTM SCS therapy should be considered a standard of care in this setting. Additional studies will help further define the potential role of DTM SCS therapy earlier in back pain treatment paradigms.

*Descriptive comparison including studies with similar design (RCT; randomization >100 subjects; comparing two SCS therapies; with at least 12 months of follow-up) and patient populations (inclusion/exclusion criteria, baseline demographics) with back pain responder rates reported. This is not based on a statistical analysis of outcomes between studies.