Jason Pope (Santa Rosa, USA) discusses closed-loop spinal cord stimulation (SCS) and its potential to provide sustained, holistic outcomes for chronic pain patients. In addition to describing these theoretical benefits and the mechanisms of action by which they can be achieved, Pope discusses the significance of recent data from the EVOKE study.
SCS has been an established treatment in refractory neuropathic chronic pain for more than 50 years. It works by sending small electrical pulses to electrodes in the epidural space that stimulate the spinal cord to inhibit pain signals to the brain. Randomised controlled trials (RCTs),1,2 systematic reviews3,4 and economic evaluations3,5,6 have demonstrated the clinical effectiveness and cost-effectiveness, and opioid-sparing effects, of SCS for the management of chronic pain—although, recently, poorly developed reviews and investigations with significant methodologic errors have been published.
SCS requires placement of the electrode within the epidural space for delivery of electricity to the target intradural neural structure (with location typically defined by spinal level). A significant challenge with stimulation of the spinal cord is the ever-changing distance between the stimulating electrode(s) relative to their spinal cord target. This occurs predictively, because of the anatomic considerations inherent to the epidural and intrathecal space; and is largely contingent to cerebrospinal fluid (CSF) volume and the positional effects of the lead within the epidural space, influenced by body position. This distance, therefore, constantly changes, and is influenced by physiologic activities like breathing and coughing, but also by postural changes and activity. These small changes in the distance between the electrode and spinal cord result in large changes in the electricity reaching the spinal cord, impacting the necessary treatment pathway.
Therefore, employing SCS with a fixed-output system inherently defines a system that will be limited by activating the spinal cord with high variability and inaccuracy, not addressing the aforementioned challenges and potentially compromising clinical outcomes.
To date, all commercially available SCS devices—regardless of the stimulation parameters and waveforms—are fixed-output, ‘open-loop’ systems. As a consequence, the stimulation paradigm is limited by a lack of identification and maintenance of target neural activation. Without the ability to both continually measure and adjust stimulation intensity on every stimulation pulse, these turbulent neurophysiological conditions result in frequent and substantial fluctuations in activation of the spinal cord, limiting efficacy and potentially impacting long-term successful outcomes. As such, these traditional systems are challenged by the absence of a physiologic measurement of neural activation and the inability to adjust stimulation in response to it. To date, open-loop systems are reliant on patient-reported validation of neural activation success and, therefore, titration of therapy is often from failure.
In contrast, a ‘closed-loop’ spinal cord stimulator first measures the neural response elicited by stimulation of the spinal cord through the direct measurement of Evoked Compound Action Potentials (ECAPs), and then responds to that measurement by adjusting the next stimulation dose in real time to maintain a consistent neural activation target, accommodating the neurophysiologic environment. Therefore, this SCS system is described as a closed-loop, variable-output SCS system.
The theoretical benefit to the patient of a closed-loop physiologic feedback mechanism with consistent neural activation seems simple enough and logically appears to be the next smart focus for innovation. In an effort to validate this ‘smart loop’, a study was performed, in a double-blinded, multicentre, prospective fashion, with follow-up out to 36 months, comparing the traditional stimulation paradigm (open-fixed) to the smart system (closed-variable). The EVOKE trial, sponsored by Saluda Medical, was conducted as an investigational device exemption (IDE) study with oversight from the US Food and Drug Administration (FDA), and demonstrated that smart-loop (ECAP-controlled, closed-loop) SCS delivers superior long-term pain reduction compared to traditional (open-loop, fixed) SCS. The three-year data from EVOKE were presented earlier this year at the North American Neuromodulation Society (NANS) annual meeting (12–15 January 2023, Las Vegas, USA).
Further, the consistent neural activation provided by the smart-loop system leads to improvements in patient outcomes—not only in pain intensity reduction, but also statistical improvements in holistic views of patient outcomes, including quality of life, functional status, mood, and sleep quality and quantity. Additionally, smart-loop patients voluntarily reduced or eliminated opioids due to pain relief with their SCS device that was much greater than in the traditional stimulation arm.
Based on the cumulative smart-loop data, aggregating the RCT, the ECAP IDE—a real-world, single-arm, prospective multicentre study—and the Avalon study, all demonstrating replicable, sustained, holistic benefits, this paradigm shift moves to titrating SCS therapy toward success by physiologic measurement and maintenance of neural activation, as compared to titration from failure.
The potential utility of physiologic closed-loop technology has applications in the broader field of neuromodulation, including therapies like vagal nerve, sacral nerve and deep brain stimulation. There are early clinical studies underway in these areas. Further, enhanced strategies to monitor device performance and use, away from the clinic, may also improve outcomes and maintain therapy.
The pathway forward for SCS therapy is to address known challenges with its implementation—with one categorically being the consistency of neural activation. To turn a blind eye, employing open-fixed systems, would ignore the importance of physiologic measurement of neural activation, location, consistency, and accuracy, contributing less optimal outcomes. Smart-loop systems are creating a new required standard.
References:
- Slangen R, Schaper N C, Faber C G, et al. Spinal cord stimulation and pain relief in painful diabetic peripheral neuropathy: a prospective two-center randomized controlled trial. Diabetes Care. 2014; 37(11): 3016–24.
- Mekhail N, Levy R M, Deer T R, 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. The Lancet Neurology. 2020; 19(2): 123–34.
- Petersen E A, Stauss T G, Scowcroft J A, et al. Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial. JAMA Neurology. 2021; 78(6): 687–98.
- Kemler M A, Barendse G A, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. New England Journal of Medicine. 2000; 343(9): 618–24.
- Mekhail N, Levy R M, Deer T R, et al. Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial. JAMA Neurology. 2022; 79(3): 251–60.
- Russo M, Brooker C, Cousins M J, et al. Sustained Long-Term Outcomes With Closed-Loop Spinal Cord Stimulation: 12-Month Results of the Prospective, Multicenter, Open-Label Avalon Study. Neurosurgery. 2020; 87(4): e485–e495.
Jason Pope is the president and CEO of the Evolve Restorative Center in Santa Rosa, USA. A double-boarded pain management specialist and anaesthesiologist by trade, he is also the current president of the American Society of Pain and Neuroscience (ASPN) and chairman of the Pacific Spine and Pain Society (PSPS). Pope previously served two terms on the board of the North American Neuromodulation Society (NANS), and the International Neuromodulation Society (INS).
DISCLOSURES: The author serves as a consultant for Abbott, Medtronic, Saluda, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific and Thermaquil; has received grant and research support from Abbott, Flowonix, Saluda, Aurora, PainTeq, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS and Thermaquil; and is a shareholder of Vertos, SPR Therapeutics, PainTeq, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil and Anesthetic Gas Reclamation.
