Spinal Cord Stimulation: Current Knowledge and Future Directions

Image author: Joyce McCown (https://unsplash.com/photos/IG96K_HiDk0)

Written by Emily Liang and Cherry Tagra

Abstract 

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.

Introduction 

 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 

Future Research 

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 

Conclusion 

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.

References 

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24. De Ridder D, Vanneste S, Plazier M, van der Loo E, Menovsky T. Burst spinal cord  stimulation: Toward paresthesia-free pain suppression. Neurosurgery. 2010;66(5):986–90. Available from: doi:10.1227/01.NEU.0000368153.44883.B3. 

25. Tang R, Martinez M, Goodman-Keiser M, Farber JP, Qin C, Foreman RD. Comparison of  burst and tonic spinal cord stimulation on spinal neural processing in an animal model.  Neuromodulation. 2014;17(2):143–51. Available from: doi: 10.1111/ner.12117. 

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28. Grider JS, Manchikanti L, Carayannopoulos A, Sharma ML, Balog CC, Harned ME, et al.  Effectiveness of spinal cord stimulation in chronic spinal pain: A systematic review. Pain  Physician. 2016;19(1):E33-54. Available from: doi:10.36076/ppj/2016.19.E33. 

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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

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