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Finding Optimal Neuromodulation for Chronic Pain: Waves, Bursts, and Beyond
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302465
Keywords: Conventional spinal cord stimulation, neurostimulation, new modalities of spinal cord stimulation, paraesthesia-free stimulation, SCS waveforms, subthreshold stimulation
The initial efforts of spinal cord stimulation (SCS) are attributed to Shealy in 1967[1] following the seminal “gate-control network’’ theory by Melzack and Wall in 1965.[2] Since then, neuromodulation has evolved as a state-of-the-art, minimally invasive treatment for attenuating chronic spinal and/or peripheral nerve pain that is becoming evidence based. In the last decade, in addition to improvement in electrode and controller (implanted pulse generator) design, a variety of options in waveform shape and patterns have emerged showing favorable results in reducing intractable pain of the back and limbs. We present a short review of SCS literature in reference to recent innovations and clinical experiences with the newer waveforms. Background of SCS parameters and waves In SCS, electrical stimulation that is applied through contacts located on the paddle or cylindrical electrode arrays placed in the posterior epidural space overlying the spinal cord (typically in the lower thoracic region for treating back and leg pain and cervical region for treating neck and arm pain) [Figure 1]. Electrical current can be delivered in a number of ways that are still being explored. The basic simulation parameters—frequency (Hz), pulse width (msec), and amplitude (V or mA) are manipulated for the desired outcome.[3] More recently due to advances in implanted pulse generator (IPG) technology, changes in shape, frequency, and state (tonic versus burst) of the waveform have been tried with varying success.[3] Impedance (ohms) is also commonly measured by most IPGs and is a property mostly relating to tissue healing around the implant. All these electrical parameters (pulse, frequency, intensity, and impedance) are important parameters that underlie the total energy being delivered to the patient and factor into the allowed safety limits of the device.[3],[4],[5]
Tonic conventional stimulation (TCS) or paraesthesia-based SCS (PB-SCS) Since 1967, TCS also known as low-frequency SCS (LF-SCS) was the only stimulation paradigm available in clinical practice until last decade. This stimulation paradigm is characterized by a steady sinusoidal wave [Figure 2]a with low frequency (40–120 Hz), high amplitude (3.6–10 mA), and pulsed wave (PW) (300–600 μs).[3] The constant, low frequency stimulation induces a noticeable tingling sensation called paraesthesia and the dogma has been to superimpose paraesthesias on the patient-specific region of pain for maximal pain relief.[7] Yearwood et al. showed that greater coverage, and some “caudal shift” of paresthesia coverage with increased PW that is accompanied by recruitment of larger number of Ab-fibers.[8] The amplitude impacts the number of fibers recruited, and the strength duration curve (SDC) for dorsal column fibers can be established by determining the amplitude needed for paraesthesia perception and discomfort thresholds at increasing pulse width.[9] The resulting “therapeutic window” may guide SCS programming for amplitude and pulse width to optimize pain relief while minimizing discomfort.
Evolution of newer waveforms and paraesthesia-free SCS (PF-SCS) PB-SCS is an effective treatment option for chronic neuropathic pain refractory to conventional medical management (CMM).[10] Stimulation-induced paraesthesias may not be pleasant for all patients, and sometimes patients do experience it beyond painful areas. This led to the search of new programming modes of SCS that deliver paraesthesia-free stimulation such as burst SCS and high frequency 10 KHz (HF10) SCS. High-frequency (HF) Stimulation: Traditionally the high frequency can range anywhere from 1 KHz to 10 KHz (ultra-high frequency), but this has undergone reassignment to 5–10 KHz.[11] A novel SCS device 10 KHz SCS (Nevro Corp) has been shown to deliver short-duration pulses (30 μs), high-frequency (10 kHz), low-amplitude (1–5 mA) pulses [Figure 2]b to the spinal cord without inducing any paraesthesia.[12] The HF10 SCS can be placed anatomically between T8 and T11 vertebral levels without the need for intraoperative paraesthesia mapping.[13] BurstDR stimulation: Burst paradigm developed by De Ridder[14] consists of a 40-Hz five impulse bursts (individual impulse at 1 ms duration and 1 ms interval) at an intraburst frequency of 500 Hz (or 1000 Hz) [Figure 2]c. The 500-Hz burst frequency (referred to simply as “burst”) is the primary programming mode used in most studies. Sub-perception SCS (SP-SCS): Strategies using the multiple combinations of PW and frequency on the SDC can be manipulated to deliver large amounts of energy to the dorsal column spinal structures without discomfort or even a perceptible sensation.[3] Sub-perception (SP-SCS) can be achieved utilizing frequencies between 1 KHz and 5 KHz [Figure 2]d.[11] Clinical utility and effectiveness of SCS waveforms Tonic SCS Studies have clearly demonstrated the medico-economic interest and clinical efficacy of SCS.[15] TCS remains the most widely used and studied technique in neuromodulation for pain. A randomized controlled trial (RCT) conducted in complex regional pain syndrome (CRPS) by Kemler et al. demonstrated higher pain relief and global perceived effect in SCS along with physical therapy (PT) group than PT alone.[16] North et al. in EVIDENCE study compared SCS to repeat lumbar spine surgery in failed back surgery syndrome (FBSS) and concluded favorably for SCS obviating the need for reoperation in the majority of patients.[17] Kumar et al., compared SCS in PROCESS RCT with CMM in FBSS population. SCS proved superior for alleviating leg pain and improved quality of life at 6, 12, and 24 months.[10] TCS was compared to CMM in patients with painful diabetic peripheral neuropathy in two prospective RCTs. These studies demonstrated not only the superiority of neuromodulation over CMM but also one of the trials showed sustained improvement in pain relief in the SCS group at 5 years.[18],[19] Rigoard et al. in a large multicenter trial compared multicolumn SCS along with the optimal medical management (OMM) to OMM alone in FBSS with predominant low back pain, and showed the significantly improved pain relief, quality of life, and function in a traditionally difficult-to-treat population, and theses outcomes were maintained at 24 months.[20] The clinical experiences and the evidences from the clinical trials established SCS, specifically TCS as one of the best evidence-based cost-effective treatment to treat certain refractory neuropathic pain conditions. Burst SCS The first peer-reviewed evidence on burst SCS was published by De Ridder et al. in 2010 who demonstrated significant reduction of axial back and limb visual analog scale (VAS) scores at 12-month follow-up in 12 patients.[14] In an open-label short-term multi-site study, Courtney et al. investigated the effect of burst stimulation in 22 subjects who were previously using TCS for at least 90 days. Significant reductions in global, trunk, and limb pain was reported during burst SCS with majority of the patients preferring burst stimulation over TCS.[21] Higher frequency burst stimulation (1000 Hz) against the standard burst (500 Hz) was explored in another study, however, no significant difference in back pain, limb pain, or general pain scores were reported between standard burst and high frequency burst frequencies.[22] de Vos et al. conducted a 2-week burst SCS study of 48 patients who had already received tonic SCS treatment for a period of at least 6 months for mixed pain states (painful diabetic neuropathy, FBSS, FBSS who were poor responders to tonic SCS) and concluded favorably for burst stimulation.[23] In 2013, De Ridder et al. conducted an RCT comparing burst SCS, tonic SCS, and placebo in 15 SCS naive FBSS patients who were randomized to receive each stimulation for a week. Burst SCS, but not tonic SCS, significantly reduced global VAS scores but did not significantly reduce axial pain or limb pain VAS scores.[24] Similar positive results for burst stimulation was reported by Schu et al., in their study conducting a sham-controlled randomized trial comparing burst SCS with both placebo control, traditional (40 Hz) tonic SCS, and a continuous 500-Hz tonic paradigm in 20 patients with FBSS already receiving PB-SCS.[25] These findings were supported by Deer et al. in SUNBURST RCT evaluating burst stimulation and TCS in 100 patients. They reported superior pain relief for trunk pain and limb pain, and burst SCS was preferred treatment in 68% of patients at the end of one year open-label phase period.[26] In a prospective study Vesper et al., studied microdosing programs against standard burst for IPG energy conservation strategy and found slightly higher satisfaction and preference with “microdosing” strategies but no significant advantage in terms of pain relief.[27] High frequency stimulation A double-blind, sham-controlled HF-SCS (HF 5 KHz) study of 40 patients found promising results with Patient Global Impression of Change in favor of HF-SCS compared to sham stimulation.[28] The pivotal SENZA-EU study conducted by Van Buyten and Al-Kaisy et al. enrolled 83 subjects with significant axial low back pain. 60% of the implanted patients had at least 50% back pain relief and 71% had at least 50% leg pain relief (follow-up to 24 months in 90% of patients).[29],[30] Kapural et al. to assess the non-inferiority of HF 10 KHz over TCS conducted the Food and Drug Administration-approved SENZA RCT which demonstrated superiority of 10 KHz compared to TCS treatment in 198 patients with axial back and/or leg pain (66.9%, 65% Vs 41.1%, 46%) with 1:1 randomization at 24-month follow-up.[31],[32] A post hoc analysis of the two studies SENZA-EU and SENZA-RCT reported an average reduction of opioid use by 46% in high-risk category patients with ≥90 morphine milligrams equivalent presenting with leg pain and/or low back pain at 12 months of HF10 SCS therapy.[33] A proof-of-concept study evaluating HF10 stimulation in 20 patients with low back pain who were not surgical candidates, reported pain VAS and Oswestry Disability Index scores reduction to an average of 73% and 48% from baseline at 12 months.[34] Follow-up data at 36 months from 17 patients showed significant sustained reductions in back pain VAS scores with 88% of patients not taking opioids.[35] Similar to these experiences, an Australian study from three large pain clinics reported higher trial conversion rate with HF stimulation. The numeric rating scale scores for the entire cohort were significantly reduced for six months and even prior non-responders with TCS also reported positive outcomes with HF stimulation.[36] However, results are not uniformly favorable with burst stimulation across all the studies. Kinfe et al. performed a prospective observational study in 16 SCS-eligible FBSS patients to receive either burst or HF10 SCS. Study reported no differences between the modalities in back pain, though leg pain was better controlled with burst SCS.[37] In one non-industry-funded study, investigators compared HFS with TCS in 60 patients and reported minimal difference between the two groups at one year.[38] Sub perception SCS Clinical experiences with the sub-perception SCS have been favorable as well. North et al. compared LF-SCS (50 Hz) to SF-SCS (1 KHz) in a prospective RCT and found 95% of patients showed improvement in numeric rating scale scores, with pain relief better in 1 KHz cohort.[39] PROCO RCT, a double-blind crossover study evaluating different frequencies from 1 to 10 kHz (1, 4, 7, 10) in a cohort of 33 patients with 4 weeks at each frequency, which followed with a 3-month open-label phase allowing patients to choose their favorable frequency. Majority (50%) of patient chose 1 kHz, followed by 7 kHz (25%), 10 kHz (15%), and 4 kHz (10%). Interestingly, the overall pain reduction was sustained independent of chosen the stimulation frequency.[40] In WHISPER trial, the investigators compared sub perception <1.2 KHz with supraperception stimulation, and found significant improvement in pain relief with SP-SCS at 12 months, with positive outcomes in subjects who were paresthesia failures with previously implanted SCS patients.[41] Advanced programming of SCS waveforms in IPG platforms Various new algorithms and technological advances came up in the field of SCS to optimize the energy/electrical response and improve the outcome. High-dose (HD) stimulation allows large amounts of charge to be administered at the extreme ends of the curve (either narrow or wide PW), remaining below threshold (sub-perception) and thus avoiding “stimulation-induced paraesthesia”[42] and expanding to patient population who are otherwise intolerant to SCS-induced paresthesia.[42],[43] “Duty cycle” strategies have evolved using multiple combinations of PW and frequency on the SDC to deliver large amounts of energy to the spinal structures in the dorsal column without discomfort or even a perceptible sensation.[3] Medtronic's EvolveSM Workflow Algorithm platform from Intellis uses technology that can deliver both HD (1000 Hz, 90μs) and low-dose stimulation through an overdrive IPG and intrinsic accelerometer.[44] Boston Scientific's provides “WaveWriterTM” technology, which has an ability to layer tailored complex broad-spectrum sub-perception waveforms and low-frequency stimulation via an interactive feedback feature. The multiple-independent power sources (MICC technology) and anode intensification refine better control of the current delivery to each contact of SCS electrode for better neural targeting and electrical plasticity.[45] Recently, closed-loop spinal cord stimulation (Saluda Medical) was introduced to automatize the energy output based on the evoked compound action potentials with a significant improved outcome.[46],[47] Limitation and advantages of newer SCS waveform and studies PF-SCS has the inability to provide immediate relief as they have few days of the wash-in period, potentially requiring a lengthy evaluation to optimize settings. Anatomical placement of HF10 therapy based on “sweet spot” obviate the need for intraoperative mapping and may be preferred by surgeon, patient, and shorten the procedure time. Although early clinical trials of burst SCS have shown significant paraesthesia-free pain relief, it is important to note a small number of patients still experience some paraesthesia (unlike paraesthesia-independent HF10 SCS). A systematic review evaluating RCT identified deficiency in reporting, methodology, and the strength of the evidence.[48],[49],[50],[51],[52] Importance of placebo-responders and sham-effects in neuromodulation in clinical trials must not be underestimated.[53] There is need for a better designed study and transparency in the reporting, this especially hold true as many of SCS studies are industry sponsored. And above all, sometimes patient preference or beliefs dominate over the science behind the SCS waveform or the device selection, as reported by Duse et al., where 50% of patients in their series of 28 FBSS patients preferred PB-SCS due to the belief the functioning of SCS corresponded with the perception of paresthesia.[54] Although literature does not unanimously support one waveform over other especially study evaluating different waveforms[55] nevertheless, the advanced waveforms, pulse trains, and programming capabilities have expanded the clinical utility of SCS.
Chronic pain is a dynamic condition characterized by diverse patterns and variable severity over time. Early and pivotal studies evaluating tonic SCS laid the foundations of the evidence in the field of neuromodulation, and since then neuromodulation has had rapid technological advancements. Newer paraesthesia-free modes of SCS may provide an SCS salvage strategy for tonic SCS patients experiencing loss of efficacy over time or maybe preferred over TCS by patients/clinicians. Although there is no consensus for the ideal SCS waveform or stimulation, the newer SCS waveform, pulse trains, or central axial targets have been shown to be beneficial for certain pain states, however, stringent patient selection along with patient participation and education remains critical for the success of the individualized SCS therapy. The accumulated clinical evidence demonstrated the newer SCS waveforms are generally favorable giving additional options for the patient and the clinician. With all these variables, the proper understanding of waveforms and the selection of an ideal SCS system is more crucial than ever for an optimal clinical outcome. Larger controlled studies are needed to validate the application of specific SCS waveforms to facilitate individualized SCS therapy for complex pain disorders. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
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