Abstract
Burst stimulation and high-frequency stimulation have recently caused a shift in focus of neuromodulation research from better targeting efforts to better communication with the nervous system. The inception of burst stimulation was based on mimicking burst firing in the nervous system. It appears to be superior to classic tonic stimulation considering the amount of pain suppression, to have an additional pain reduction over tonic, and to have the capability to rescue nonresponders to tonic stimulation. Burst stimulation may be applied free of paresthesia, and seems to be able to suppress chronic neuropathic pain by affecting not only the lateral pathway but also the medial pathway, and perhaps even the descending inhibitory pathway.
Keywords
Burst stimulation, Future directions, Pain reduction, Paresthesia free, Placebo, Recapturing pain, Spinal cord stimulation
Outline
Introduction 669
Introducing Burst Stimulation 670
A Hypothesis on the Mechanisms of Action 670
Clinical Outcomes of Burst Stimulation 672
Pain Reduction and Further Improvement of Pain Reduction 672
Recapturing Pain 673
Paresthesia 673
Patient Preference 674
Other Outcomes and Adverse Events 674
Cost Effectiveness of Burst Stimulation 676
Future Directions 676
Conclusion 677
Disclosure [CR]
References 679
Further Reading 681
Disclosure
S. Schu is a consultant for St. Jude Medical Inc. for training and education. T. Vancamp reports no conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Introduction
Neuromodulation has gained significant acceptance as a standard treatment modality for intractable chronic neurological disorders. More specifically, spinal cord stimulation (SCS) has a history dating back to its first application in 1967 ( ). Since then it has been successfully used for the treatment of chronic neuropathic pain syndromes like chronic low-back and leg pain, failed back surgery syndrome (FBSS), complex regional pain syndromes (CRPS), and cardiovascular pathologies like peripheral vascular disease and refractory angina pectoris ( ). Metaanalyses and systematic reviews support the use of SCS, and long-term results have shown to be favorable in randomized controlled trials (RCTs) when compared to reoperation and conventional medical management (CMM) ( ).
Traditional neurostimulation of implantable pulse generators (IPGs) from most manufacturers use the same waveform, herein called “tonic stimulation.” Tonic waveforms are characterized by a simple, rhythmic, charge-balanced design, and the only modifications that can be altered, within a limited output, are the frequency, pulse width, electrode configuration (neutral, anode, or cathode), and amplitude. These traditional neurostimulation devices, initially adapted from cardiac pacemaker designs, have not changed much over the years. In most devices the output in all channels is the same, with the exception of one provider (Boston Scientific Neuromodulation Inc., Valencia, CA., USA) that allows individual channel output control. IPGs traditionally used constant voltage output (e.g., Medtronic Inc., Minneapolis, MN, USA) and were later followed by constant current regulated devices (e.g., Boston Scientific and St. Jude Medical Neuromodulation Inc., Plano, TX, USA). Although there have been attempts in the relevant literature to prove the superiority of one form of neurostimulation output over the other (constant voltage vs. constant current), the real question of whether one system is consistently more likely to have a better clinical outcome over the other has never been robustly investigated ( ).
Tonic stimulation has some challenges, even if proper patient selection has been performed and candidates seem clearly eligible for SCS. There is a substantial heterogeneity regarding pain relief with tonic stimulation, with up to 20%–30% of patients being classified as poor responders or nonresponders ( ). This failure of the therapy or lack of analgesic benefit is compounded by the inability to produce adequate paresthesia coverage in hard-to-reach areas (e.g., lower back), changes in intensity of paresthesia produced by changing body positions and movements, and intolerance to paresthesia sensations in some patients.
Introducing Burst Stimulation
The concept of burst stimulation arose from treating patients with tinnitus via auditory cortex stimulation. Early on it was noted that pure-tone tinnitus, but not noise-like tinnitus, was suppressed by tonic stimulation ( ). White-noise tinnitus may be caused by an augmented neuronal burst firing in the extralemniscal (nontonotopic) system, whereas pure-tone tinnitus may result from increased neuronal tonic firing in the lemniscal (tonotopic) system ( ). Electrical cortical burst stimulation also exerts an effect on the medial geniculate system, which predominantly fires in burst ( ). Based on anatomic pathways and pathophysiologic characteristics, the clinical similarities between tinnitus and pain, and the “know-how,” the experience with burst stimulation for tinnitus was translated to burst stimulation of the spinal cord, herein called burst SCS, in an attempt to modulate the medial pain pathways ( ).
Serendipitously, it was noticed that burst SCS needed to be applied at a subthreshold, paresthesia level to be comfortably tolerated by patients. Even though the applied energy levels of burst SCS were below the threshold for paresthesia sensation, its use resulted in pain control. This early use of burst SCS led to a series of preliminary studies to research its potential further ( ). Because burst SCS leads to paresthesia-free pain control, it has naturally led to placebo controlled studies ( ).
A Hypothesis on the Mechanisms of Action
The original concept of the gate-control theory, introduced by , postulates that stimulating large myelinated Aβ fibers suppresses pain transmission through small unmyelinated C fibers and small myelinated Aδ fibers. It is believed by some that tonic stimulation produces pain control by activation of large Aβ fibers that, in turn, inhibit small fibers (C, Aδ). However, not all working mechanisms of action (MOAs) of tonic stimulation are well understood or simply ascribed to gating mechanisms. Descartes assumed that there were only ascending pathways, but we now know there are also descending pathways and a combination of segmental (antidromic) and supraspinal mechanisms (orthodromic) is the most plausible explanation for the MOA of tonic stimulation ( ). For further explanations of the MOA for tonic stimulation see Chapter 31 .
Spontaneous rhythmic burst firing can be observed in high-threshold, unmyelinated C fibers when larger myelinated fibers degenerate ( ). Like tonic stimulation, localized electroencephalography (EEG) has demonstrated that burst SCS exerts a similar effect on the lateral pain pathway that shares some of the structures that are involved in somatosensory perception, encoding discriminatory components of pain ( ). An animal model showed that burst stimulation produces a significantly greater reduction in visceral nociception when compared to tonic stimulation, even at paresthesia subthreshold levels, due to a lack of increasing spontaneous activity of neurons in the gracile nucleus ( ).
Other MOAs may be involved in burst SCS for pain control, including the selective effect of burst on Aβ fibers, similar to what has been described for sine-wave stimulation at 2 kHz and augmenting the gate-control effect ( ). Studies of frequency-dependent neuronal activation have not been performed with the square-wave stimulation used in burst SCS, but increases in burst SCS pulse frequency may selectively activate more Aβ fibers and even inhibit larger numbers of wide dynamic range (WDR) and nociceptive-specific (NS) neurons. However, higher pulse frequencies may require accompanying changes in other parameters, as frequency alone may not directly correspond to decreased neuronal firing ( ).
The classical description of burst stimulation involves a unique design, in that burst trains are made up of five spikes, each with a 1 ms pulse duration and an interspike interval of 1 ms, and firing at 500 Hz. These burst packages are delivered at an overall lower frequency of 40 Hz ( Fig. 52.1 ) ( ). The design of this energy or charge delivery by itself may be an important factor to consider. In an open-label double-blinded RCT study, investigators could not find a difference between burst stimulation with spike frequency at 1000 Hz and pulse width = 500 μs when compared to a 500 Hz frequency, 1000 μs pulse width stimulation design in 15 patients ( ). Pain scores on the Pain Vigilance and Awareness Questionnaire (PVAQ) and Pain Catastrophizing Scale (PCS) did not show statistically significant differences between the two groups, which suggests that charge delivery may be as important as the way stimuli are delivered (packets of burst vs. tonic) ( ). Thus 500 Hz tonic SCS should have a different clinical effect on neuropathic pain than 500 Hz burst SCS, which has been confirmed by a placebo controlled RCT ( ).
In a preclinical neuropathic pain model of cervical radiculopathy it was shown that altering the electrophysiological parameters could exert different effects on reduction in neuronal responses to noxious stimuli ( ). Changes in neuronal response following burst SCS were mediated by the stimulation parameters, thus pointing out the importance of the stimulation design as previously mentioned. The number of pulses per burst, duration of pulses, and amplitude each significantly correlated to changes in neuronal responses after burst SCS, and frequency had a significant effect on the percentage of recorded neurons that responded. Furthermore, this study showed that there is a correlation between charge per burst delivered to the spinal cord and the decrease in responses of both WDR and NS neurons after burst SCS.
There may be also a more optimal endogenous opioid release in the dorsal horn, with a maximal release at 500 Hz stimulation ( ). Hypothetical selective activation of mixed electrical and chemical synapses at 500 Hz may be involved as well, permitting subthreshold oscillatory synchronization of functionally connected areas (via gap junctions) ( ). Furthermore, burst SCS may modulate the μ-opiodergic, antinociceptive, descending pain-modulating pathways that activate off cells in the rostroventral medulla, thereby preventing further pain signals from reaching the cortex. It also may be possible that low-threshold tactile C fibers are activated, which have an antinociceptive function ( ). Activation of the nucleus raphe magnus descending inhibitory pathways preferentially attenuates C fiber activity more than Aδ fiber-mediated activity ( ).
Burst stimulation, in contrast to tonic stimulation, also seems to have an effect on the attention to pain and changes in pain that are mediated via the anterior cingulate cortex (ACC), which is part of the medial pain system ( ). Thus burst SCS exerts not only a modulatory effect on the lateral discriminatory pathway, but also an effect on the medial affective–attentional pathway. Indeed, changes in PVAQ scores demonstrate that burst is significantly better than both placebo and tonic SCS in altering the patient’s attention to pain and pain changes ( ). Burst SCS also is significantly better than tonic SCS in addressing the concept of worst and least pain, further supporting its effect on the medial pathway. Source-localized EEG data obtained in patients supports these findings. Burst SCS showed a significantly larger alpha activity in the dorsal ACC and activation for both alpha and beta oscillatory activity in the dorsolateral prefrontal cortex when compared to tonic SCS ( ).
A study by suggests that both burst and tonic SCS, without a statistically significant difference, result in suppression of nociception by attenuating dorsal horn neuronal hyperexcitability and tactile allodynia. In their study they also found that a GABA B (gamma-aminobutyric acid B) antagonist blocks the effects of tonic stimulation but not the effects of burst stimulation, suggesting that the effects of burst stimulation are not GABA dependent. In contrast to tonic stimulation, which mitigates injury-induced decreases in GABA, burst has no mitigating effect on such decreases. Burst stimulation may not activate GABAergic signaling mechanisms and may elicit a unique MOA for the benefits it exerts ( ).
In a case report looking at the effect of different SCS modalities, investigators found that both paresthesia-inducing and paresthesia-free SCS affect somatosensory evoked potentials in the same manner, suggesting that the inhibitory effect during paresthesia-free modalities is independent of the generation of action potentials, with a probable MOA at the stimulation site ( ).
In a rat model of radicular pain, the investigators compared the effects of tonic and burst SCS on pain, thalamic neuronal firing, and spinal neuropeptide expression ( ). Both tonic and burst SCS attenuated sensitivity and reduced thalamic firing for all stimuli. Both spinal substance-P and calcitonin gene-related peptide were lower for tonic and burst SCS when compared to no SCS. This study suggests that there is a similar working MOA for the parameters researched at both the spinal and supraspinal levels. In yet another study using quantitative sensory testing in 18 patients, it was found that both burst and tonic SCS increase mechanical detection thresholds, confirming findings in animal studies. Furthermore, burst tended to modulate thermal perception ( ).
In a rat study comparing tonic and burst stimulation on trigeminal allodynia using occipital nerve stimulation (ONS), it was found that both stimulation forms significantly improved symptoms, but there was a latent positive response associated with burst stimulation that made it superior to tonic stimulation ( ). Also the burst group exhibited a longer-lasting therapeutic carry-over effect than tonic stimulation.
In assessing effects of peripheral nerve stimulation (PNS) on nine subjects with ONS for migraine or trigeminal neuropathic pain and one coccygeal stimulation, investigators found an increased trend in heat pain threshold for burst when compared to tonic stimulation, with significantly greater heat pain thresholds for subjects with ONS when comparing burst to no stimulation ( ). Pressure pain thresholds were significantly greater in tonic stimulation mode when compared to no stimulation, showing that PNS is different from SCS. As the authors conclude, this may be caused by prolonged effects or an alternative pathway involved in PNS. As with tonic stimulation, not all MOAs underlying burst stimulation have been elucidated, necessitating further in-depth investigations to solve this puzzle. For a further discussion of the MOA of burst SCS see Chapter 14 .
Clinical Outcomes of Burst Stimulation
Pain Reduction and Further Improvement of Pain Reduction
The first clinical results for burst SCS were published in 2008, and showed significant differences between burst SCS versus baseline and tonic stimulation using the Visual Analog Scale (VAS) and Short Form McGill Pain Questionnaire (SFMPQ) scores in eight patients ( ). After these initial results, the first feasibility study of 12 patients was published in 2010 ( ), showing statistically significant reductions for tonic and burst SCS for both axial and limb pain, with burst having a greater effect than tonic stimulation during the trial phase. Furthermore, the researchers found that burst SCS induced a significant improvement in both sensory and affective dimensions of pain after a follow-up average of almost 2 years (20.5 months) when compared to baseline. These results support the fact that burst SCS is a safe and stable stimulation waveform, even at paresthesia-free levels.
The clinical results obtained by these investigators, plus the fact that burst yields significant pain-relieving effects at subthreshold levels and is stable for nearly 2 years, led to the design of the first double-blinded RCT in the history of SCS. In this study, conducted on 15 patients with FBSS, burst SCS had significantly and clinically better results when compared to tonic SCS for general pain and similar results to tonic SCS for limb pain ( ). Burst stimulation significantly differed from placebo stimulation for back pain, limb pain, and general pain. No statistically significant difference was found between tonic SCS and placebo for back pain in this small sample.
In a reproducibility and feasibility study by , the researchers found greater pain reduction during burst SCS when compared to tonic SCS for patients with chronic pain of the trunk and limbs, groin pain, abdominal pain, and occipital neuralgia. found in their prospective double-blinded cross-over RCT that burst SCS significantly reduces the numeric rating scores when compared to higher-frequency (500 Hz) traditional subthreshold tonic stimulation and placebo, further supporting the initial findings of De Ridder et al. These findings may relate to the delivery pattern of the burst signal, which is different to the design of the signal of tonic stimulation, including tonic 500 Hz subthreshold stimulation.
assessed the efficacy of burst SCS in a prospective study of patients with FBSS and painful diabetic neuropathy (PDN) who were poor responders over time to tonic SCS. They found that burst led to an additional reduction in pain over tonic stimulation, eliciting the greatest effect in PDN patients, followed by FBSS responders, followed by FBSS poor responders. In an Australian prospective multicenter open-label study, burst SCS reduced pain significantly when compared to tonic SCS ( ). Another double-blind cross-over RCT showed that 59% of the patients obtained over 30% additional pain reduction during high- and low-amplitude burst stimulation ( ). An Italian multicenter study found statistically significant reductions in VAS scores with burst, further supporting the effectiveness of paresthesia-free burst stimulation ( ).
In a recent prospective observational study by comparing high-frequency (HF) SCS at 10 kHz to burst SCS in patients diagnosed with FBSS with predominant back pain, two patients failed the HF trial. These patients stated that HF 10 kHz stimulation was less efficacious when compared to burst stimulation. The study found that back pain scores significantly decreased in both groups, but the burst group experienced significantly greater VAS reductions in leg pain. They also found that tolerance and amplitude levels were significantly higher in the HF group. The higher amplitude levels found in the HF group might be explained by the different stimulation designs applied, although both waveforms were subthreshold and paresthesia free.
An ongoing prospective randomized multicenter study (SUNSBURST) in the United States showed in the preliminary data (6-month first analysis of 85 patients who completed the 24-weeks visit) that burst SCS not only met the primary endpoint for noninferiority but also achieved statistical significance for its prespecified secondary endpoint of superiority when compared to tonic SCS.
In several studies burst SCS has been shown to have the capacity to improve pain reduction further over tonic stimulation ( ) (see Table 52.1 ). Generally an average of 45.95% further reduction in pain from tonic stimulation levels can be expected, ranging as reported between 23.0% and 66.7%, when applying burst stimulation. Future studies of burst SCS should explore its use for different populations of patients by pain etiology, initial responses to other stimulation modalities to test superiority or inferiority, and different indications for its use to understand better its most appropriate applications, the success factors that might be involved, and possible predictors for burst responders and nonresponders.
| Study | Year | Overall Additional Pain Reduction Over Tonic Stimulation (%) |
|---|---|---|
| Bara et al. | 66.7 | |
| De Ridder et al. | 59.0 | |
| de Vos et al. | 25.0 | |
| Courtney et al. | 46.0 | |
| Pajuelo et al. | 56.0 | |
| Tjepkema-Cloostermans et al. | 23.0 | |
| Average: | 45.95 | |
Recapturing Pain
reported reduced VAS scores by 66.7% at 12 months follow-up in 29 patients diagnosed with FBSS who had failed long-term pain relief with conventional tonic SCS. In a two-center retrospective analysis, the investigators showed that burst stimulation has the ability to salvage nonresponders to tonic SCS ( ). Of the 23.5% (24/102) patients who failed to respond to tonic SCS, burst SCS recaptured pain relief in 62.5% (15/24) of them. In yet another study looking at 10 tonic SCS nonresponders, the authors reported a 65% decrease in numeric rating scores when compared to baseline and 56% when compared to tonic SCS when burst SCS was applied, and all of those patients were converted into reresponders ( ).
Interestingly, as noted in the study by , the time effect of trunk VAS scores showed no statistically significant differences at 7 days follow-up from baseline, but the scores evolved to significance at 14 days. This temporal effect has also been noticed in clinical practices by the authors of this chapter. Plausible working mechanisms for burst versus tonic SCS may partially be explained by the differential working MOAs of burst stimulation on the medial pathway as well as its different neuroplasticity effect. Furthermore, the typical “fine-tuning” of burst SCS, as applied by the authors as well, is done after 7 days. This topic warrants further investigation.
Paresthesia
Burst stimulation has the capacity to reduce pain at subthreshold levels and is paresthesia free. reported that 83% of patients did not feel paresthesia with burst stimulation. In an Australian study it was reported that 75% of patients were paresthesia free during burst stimulation ( ).
It should be pointed out that during the initial years of clinical research, studies were conducted using an investigational programming device. Thus a plausible explanation for some patients feeling some kind of paresthesia may be the lack of programmability and proper fine-tuning at the time. Also, some patients had paresthesia due to their neuropathy rather than stimulation-induced paresthesia. The fact that some patients with burst feel paresthesia warrants further investigation in the future. It is the authors’ experience that burst-induced paresthesia actually more often than not has a negative effect on patients’ symptoms, which may include, but are not limited to, increased pain, an uncomfortable feeling of warmth, a band-like compression feeling, an uncomfortable/intolerable paresthesia sensation, feeling of muscle twitching/cramps, etc. It is our experience and of others that intensity often needs to be lowered after the initial postoperative programming, thus explaining the 1-week interval for reprogramming. After this, patients are stable and need less or no reprogramming ( ). In the studies of and subthreshold parameters were used. Strangely enough, when comparing studies outside the United States, the initial communicated data of the SUNBURST study showed only 65% of the patients experience no paresthesia ( ). An explanation for this lower outcome has not been provided, but it could be due to lack of experience with burst, and more specifically burst programming, as burst programming has a learning curve. Another factor that needs to be taken into account to avoid unwanted paresthesia is proper patient education, especially with tonic-conditioned patients. More investigation is recommended to define optimal subthreshold stimulation parameters better.
Patient Preference
Patient preferences for burst SCS have been reported in several studies, averaging 87.6% ( Table 52.2 ). Interesting to note when looking at the studies that report preferences, in the SCS-naïve group 92.3% (range 69%–100%) of patients preferred burst over tonic SCS, while in the SCS-conditioned group the majority of patients still prefer burst SCS (78.3%; range 73%–91%). In one study the majority of patients preferred burst not due to the lack of paresthesia, as might initially be thought, but due to its greater pain-suppressing effect ( ). Double-blinded RCTs agree with these findings ( ).
| References | Year | Patient Type | Patients Preferring Burst Stimulation (%) |
|---|---|---|---|
| De Ridder et al. | SCS-naïve | 100 | |
| De Ridder et al. | SCS-naïve | 100 | |
| Schu et al. | SCS-conditioned | 91 | |
| Courtney et al. | SCS-conditioned | 80 | |
| Tjepkema-Cloostermans et al. | SCS-conditioned | 73 | |
| SUNBURST study | SCS-naïve | 69 | |
| Colini Baldeschi et al. | SCS-naïve | 100 | |
| Average total | 87.6% | ||
| Average SCS-conditioned | 78.3% | ||
| Average SCS-naïve | 92.3% | ||
Other Outcomes and Adverse Events
Several studies have looked at secondary outcomes that are important when evaluating outcomes for therapies for chronic neuropathic pain conditions. These include the SFMPQ, the PVAQ, the EuroQoL Five Dimensions Questionnaire, and more (see also Table 52.3 ). The Beck Depression Inventory and Pittsburgh Sleep Quality Index scores were significantly improved after the application of HF SCS and burst SCS in a prospective observational study ( ). In this study it was also mentioned that opioid intake was reduced in 78.6% (11 out of 14) of patients.
| References | Study Type | Follow-Up | Number of Patients | Secondary Outcome Measure | Result/Comment |
|---|---|---|---|---|---|
| Prospective, single-center, open-label | Burst SCS 20.5 months | 12 | SFMPQ | Significant improvement in sensory dimension ( P < 0.001) and affective dimension ( P = 0.022) for burst at last follow-up | |
| Randomized, double-blind, placebo controlled | Tonic, burst, sham SCS, 1 week | 15 | PVAQ | Only burst had an effect on “attention to pain” and “attention to changes in pain” ( P < .05) | |
| Worst pain | Significant difference versus tonic and placebo ( P < .05) | ||||
| Least pain | |||||
| Momentary pain | Significant difference versus placebo ( P < .05) | ||||
| Randomized, double-blind, placebo controlled, cross-over | Placebo, burst, 500 Hz tonic, 1 week | 20 | SF-MPQ | Burst significant difference from other groups ( P < .05) | |
| AEs | 0% | ||||
| Tonic, minimum 3 months prior to burst | ODI | Lowest mean observed under burst | |||
| PVAQ PCS | Not mentioned | ||||
| Prospective, multicenter, open-label | Burst 2 weeks | 22 | Satisfaction | 96% satisfied or very satisfied | |
| Tonic, minimum 6 months prior to burst | PCS | Significant difference on all three subscales: | |||
| Rumination ( P < .001) | |||||
| Magnification ( P < .001) | |||||
| Helplessness ( P = .002) | |||||
| Multicenter, open-label, cross-over | Burst, 1, 3, 6 months | 37 | EQ-5D | Significant difference ( P < .005) | |
| AEs | 0% | ||||
| Prospective follow-up | Burst, average 19.8 weeks | 15 | EQ-5D 5 L | Improved 20.9% | |
| Patient attention vigilance scores | Improved 20.7% | ||||
| Global impression of change | Much or very much improved: 73.3% of patients | ||||
| Retrospective follow-up | Average 3.85 months | 10 | Satisfaction | Satisfied or very satisfied: 100% | |
| Recommend therapy | 100% | ||||
| Double-blind, randomized | Burst 2 weeks | 39 | MPQ VAS for QoL | No significant differences | |
| Washout 2 weeks | |||||
| Tonic 2 weeks | |||||
| Prospective observational | 6.9 months average | 10 | Satisfaction | Satisfied or very satisfied: 80% of patients | |
| Correlation between tonic and burst outcome | No correlation found | ||||
| Recommend therapy | 90% of patients | ||||
| Prospective observational comparative study | Burst and HF stimulation in two groups, 3 months | 8 burst and 8 HF (2 failed trial) | BDI | Significantly improved for both modalities. | |
| PSQI | Significantly improved for both modalities. | ||||
| Opioid intake | Reduced in 78.6% |
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