Written by Emily Liang and Cherry Tagra
Spinal cord stimulation (SCS) is an effective and minimally invasive therapy for neuropathic pain syndromes that are otherwise resistant to treatment, and it involves surgically implanting electrodes that generate electric fields in the epidural space. Although SCS has been around for decades, the exact mechanism by which it works is still unclear. To compound this, many new stimulation paradigms — such as high-frequency (HF) SCS and burst SCS — have been recently introduced whose mechanisms of action are even less known. This review outlines the current understanding of the neurophysiology involved in conventional and novel SCS paradigms, along with the state of clinical research on their effectiveness. Although conventional SCS appears to function mostly through the pathways outlined by the gate control theory of pain, novel SCS waveforms seem to operate through different mechanisms that are not yet well understood. Novel SCS waveforms show promise as being possibly even more effective than conventional SCS for certain patient populations, but more large, high-quality, placebo controlled RCTs are required. Though SCS technology continues to advance rapidly, patient outcomes have not followed; this suggests that the currently incomplete understanding of underlying neurophysiological mechanisms at play might be creating an impasse towards further therapeutic advancement.
Chronic pain ranks among the most prevalent medical conditions affecting humans, being among the 10 most prevalent diseases worldwide.1 Spinal cord stimulation (SCS), a neuromodulation technique that involves electrical stimulation of the spinal cord, has become a powerful therapeutic tool for treating otherwise intractable chronic neuropathic pain conditions over the past few decades.2,3 Today, SCS remains a rapidly growing field, with an estimated 50,000 spinal cord neurostimulators being implanted annually4and new stimulation paradigms being introduced regularly. The growth of SCS can be attributed in part to the increasing prevalence of neuropathic pain,5 particularly conditions such as failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) for which SCS has shown efficacy where other efforts to manage pain have failed.6
Though conventional or tonic SCS remains the oldest and most researched form of SCS,7 many new stimulation paradigms have been introduced within the past few years that show promise of being even more effective for certain types of pain.8–10 Predominantly, these paradigms include high-frequency (HF) SCS and burst SCS, and they vary in the frequency, pulse width, and pattern of electrical stimulation delivered.10 Regardless of the stimulation paradigm used, much of the neurophysiology involved in how SCS achieves pain relief remains to be elucidated, and this remains at the centre of current preclinical and clinical research.
Conventional Spinal Cord Stimulation
Conventional SCS originated as an application of Melzack and Wall’s gate control theory of pain,11,12 which has served as conventional SCS’s proposed mechanism of action since its introduction in 1967.10 According to the gate control theory, stimulation of the dorsal column could activate Aβ fibres that then modulate the transmission of painful signals, thereby providing pain relief.6,7 Though specific stimulation settings vary, conventional SCS is most often used with frequencies between 40-60 Hz and pulse widths between 130-150 μs; amplitudes used in conventional SCS are above the sensory threshold, which produces the characteristic paresthesia (tingling sensation) associated with this therapy.13
One way in which conventional SCS is theorized to alleviate neuropathic pain is by correcting the dorsal horn hyperexcitability that occurs in this condition. In neuropathic pain, wide-dynamic range (WDR) cells in the dorsal horn release above-basal levels of excitatory neurotransmitters like glutamate, and local GABA (an inhibitory neurotransmitter) systems are inhibited.13 In rat models of neuropathy, SCS inhibits WDR hyperexcitability while inducing the release of GABA, ultimately reducing extracellular glutamate concentrations.14–16 Alongside the modulation of the glutamate-GABA pathway, SCS has also been shown to induce acetylcholine, serotonin, adenosine, and norepinephrine release in the dorsal horn, molecules which may also play a role in pain reduction.13
Beyond its effects at the spinal level, it is thought that up to 50% of the effects of conventional SCS may be due to the activation of inhibitory supraspinal circuits.17,18 Various fMRI and PET studies have demonstrated increased activation of the somatosensory cortices, sensorimotor cortex, thalamus, angular cingulate cortex, and prefrontal areas with SCS,19,20 which suggests that SCS may down-regulate pain signals and modulate pain thresholds.7,19,20 However, limited sample sizes, heterogeneous methodologies and sample characteristics, and inconsistent reporting makes it difficult to draw mechanistic conclusions about the effect of SCS on supraspinal circuits.21 Importantly, causality cannot be pinpointed with these studies: it is unclear whether these brain activity changes occur as a result of the SCS itself (and thereafter produce pain relief), or whether they occur due to the pain relief that is caused by the effects of SCS on the spinal cord.7
Novel Spinal Cord Stimulation Paradigms
The last decade has also seen the introduction of many new stimulation paradigms, including high-frequency stimulation (HF SCS), which uses frequencies of up to 10 kHz, and burst stimulation (burst SCS), which uses bursts of 5 pulses (internal frequency of 500 Hz) with a frequency of 40 Hz (see Figure 1).10 Notably, in HF and burst SCS, pain relief is achieved without paresthesia, challenging the traditional understanding of SCS through the gate control theory of pain. As such, these stimulation paradigms are hypothesized to work via a different physiological mechanism than conventional SCS.10
HF SCS is typically delivered at subthreshold amplitudes, meaning that it does not activate dorsal column Aβ fibres and, as a result, does not produce paresthesia.22 Hypotheses about the underlying mechanism of HF SCS vary. One working hypothesis, proposed by Chakravarthy et al.,22 suggests that the electric field generated by HF SCS may disrupt the pathway connecting the pain-responsive nerve fibres and neurons. Other hypotheses suggest that temporal summation, wherein HF pulses build upon each other to achieve activation, or depolarization blockade, wherein HF pulses differentially block action potentials, may also be involved.22,23 However, there remains much debate within this area of research; for example, it remains unclear whether the stimulation amplitudes typically used in clinical HF SCS are sufficient to induce temporal summation or depolarization blockades.13
Burst SCS is delivered in packets of high-frequency stimulation whereas conventional SCS is maintained at a constant frequency.24 De Ridder, 24 who initially proposed burst SCS, argued that burst firing more closely mimics normal neuronal activity, resulting in enhanced postsynaptic responses and greater strength in synaptic connectivity.10 Like HF SCS, burst SCS also provides pain relief without the sensation of paresthesia, suggesting that its mechanism of action does not involve activating Aβ fibres.25 There is some evidence that burst SCS may stimulate the medial spinothalamic tract, which includes brain areas that are involved in the cognitive, motivational, and emotional aspects of pain, thus possibly modulating the experience of pain from a supraspinal level.13,26,27
Clinical Efficacy of Spinal Cord Stimulation
Current research suggests that SCS is a viable therapy for patients with chronic neuropathic pain for which conservative treatment has failed. Two high-quality and one moderate-quality RCT demonstrates that there is significant (Level I-II) evidence for conventional SCS as a treatment for FBSS.28 Despite this, it must be noted that the field of SCS contains a very limited number of large, high-quality RCTs, and further research to characterize the patient populations that would best benefit from this therapy are needed.28,29 It must also be noted that therapeutic benefit from SCS often decreases over time, possibly due to stimulation tolerance.29 As such, it is important for future studies to assess both the short term and long term effects of SCS.
A number of recent, high-quality RCTs further suggest that HF SCS and burst SCS may be more efficacious than conventional SCS. Kapural et al.,8in a study of 198 subjects, demonstrated the superiority of HF SCS over conventional SCS for leg and back pain, with 83- 85% of patients being responders for HF SCS while only 43-56% of patients were responders for conventional SCS. Multiple other RCTs have similarly demonstrated the superiority of burst SCS over conventional SCS: One study of 100 patients found that 60% of subjects responded (≥30% pain reduction rate) to burst SCS compared to 51% subjects to conventional SCS,9 while another much smaller RCT found that burst stimulation was able to improve back, limb, and general pain by 51%, 53%, and 55%, compared to 30%, 52%, and 31%, respectively for tonic stimulation.27
SCS is considered to be minimally invasive and a relatively safe procedure, and current findings present only minor complications.29 The most common complication is lead migration, or the accidental displacement of the paddle lead in the epidural space, and it has a reported incidence between 0-27%.30 Other complications include lead fracture (reported incidence of between 5% and 9%) and implantable pulse generator failure (reported incidence of 1.7%).30
Although SCS has been used for decades and its safety and efficacy have been well described, it remains that only 50-70% of patients with neuropathic pain achieve ≥50% pain reduction, and among these patients, average pain reduction is restricted to only 50-60%.6 Though many new stimulation paradigms have been introduced, some of which showing promise of being more effective than conventional SCS, patient outcomes have not significantly improved.7 For the most part, this lack of therapeutic advancement may be attributed to the current rudimentary understanding of SCS’s mechanisms,2,6 which forestalls the development of mechanism-based interventions.7 To this end, future research should investigate the effects of different stimulation parameters (frequency, pulse width, total charge, charge per pulse, etc.) on spinal and supraspinal circuits,6 with the eventual goal of deriving a model that can be used to predict optimal stimulation parameters for different types of pain.6,31
The current clinical research available on the efficacy of conventional SCS demonstrates that larger, long-term randomized control trials are needed given the chronicity and variability in the symptoms of chronic neuropathic pain. A fundamental limitation of clinical research on conventional SCS is the inability to conduct placebo-controlled testing due to the generation of paresthesia.2 One possible solution is the introduction of harmless paresthesia in the placebo condition, though there is always the possibility that such paresthesia may have a therapeutic effect of its own.32 Another possibility is to instead conduct placebo-controlled studies using paresthesia-free stimulation paradigms, such as HF SCS and burst SCS; however, depending on how the underlying mechanisms of paresthesia-free paradigms function, such results might not be translatable to conventional SCS.2
A number of other variables may affect SCS clinical efficacy, including implant experience, patient selection, patient pain etiology, the existence of comorbidities, and delays to SCS implantation following pain onset.29 Thus, it is imperative that future studies clearly consider these variables during patient selection and report on them transparently. Additionally, throughout the currently available research, there are significant variations in the outcome measures used to assess the level of pain reduction, which poses a challenge in drawing conclusions and assessing the overall efficacy of SCS. Examples of outcome measures used include VAS-Visual Analog Scale and subjectively-reported pain scores.33 There is a great need for selecting consistent, objective outcome measures (such as functional neuroimaging or the quantitative sensory testing technique)2 because these are less susceptible to patient bias.34 When assessed in combination with subjective self-reports of pain, such measures may also help identify which patients may benefit the most from SCS.2
Conventional spinal cord stimulation, as well as the different stimulation paradigm variations that have appeared over the years, show dramatic improvements in clinical efficacy for reducing chronic neuropathic pain. However, the mechanisms of action underlying SCS demand further exploration in order for this treatment to reach its full therapeutic potential. Future research will need to investigate the spinal and supraspinal effects of different stimulation parameters, and more large, placebo-controlled RCTs will be needed to determine which patient populations would benefit most from the different available paradigms.
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Figures and Tables
Figure 1: Waveforms of Available SCS Paradigms. a: Traditional or conventional SCS is characterized by frequencies between 30-80 Hz. b: Burst SCS is characterized by packets of 5 pulses with an internal pulse frequency of 500 Hz and a burst repetition rate of 40 Hz. c: High frequency SCS is characterized by frequencies of up to 10 kHz.12
Figure 2: SCS Implantation in the Epidural Space. A portion of the bony arch is cut and removed so that leads can be positioned into the epidural space above the spinal cord. In conventional SCS (P-SCS), burst SCS (B-SCS), and high-frequency SCS (HF-SCS), the leads are placed over the dorsal columns. Also shown are other stimulation paradigms that are not discussed in this review. The IPG is the Implantable Pulse Generator. During spinal cord stimulation, electrical impulses travel through the lead to the nerves and result in activation.12