Neuromodulation

(1)

IPM Medical Group, Inc., Walnut Creek, CA, USA

Keywords

Chronic painNeuromodulationSpinal cordStimulationIntrathecal drug deliveryPumpAxial painLow back painLimb painTonicHF10 therapyBurstDorsal root ganglionPost-lumbar laminectomyFBSSRadiculopathy

Key Points

Neuromodulation is quickly evolving to keep pace with patients’ needs.
Advancements in neuromodulation include paresthesia-free therapies, novel neuraxial targets, innovative waveforms and frequencies and new intrathecal dosing regimens and pump platforms.
Positioning of candidacy for advanced pain care therapies and placement in the pain care algorithm is evolving by moving away from salvage therapy, with earlier intervention improving treatment efficacy and safety.
Intrathecal therapy is enjoying a rapidly evolving strategy and new offerings may provide improved accuracy.

Introduction

The efficient, effective, and long-term treatment of chronic pain has continued to be a challenging issue in modern medicine [1]. Until recently, the armamentarium of choices for treatment has been limited to rehabilitation, medications, injections, and nerve ablation. The developments in neuromodulation over the past four decades have been key in emerging this technology as one of the best-studied and most effective choices for the long-term control of chronic pain.

The North American Neuromodulation Society defines neuromodulation as a therapeutic alteration of activity, either through stimulation or medication, both of which are introduced by implanted devices [2]. Neuromodulation devices are not only used for the treatment of acute and chronic pain. Their utilization is also quite important in other conditions, such as epilepsy, spasticity, and movement disorders, including the emerging field of prosthetic neuromodulation [2].

Spinal cord stimulation (SCS) is arguably the best known and most utilized neuromodulation device for the treatment of chronic pain in the USA and around the world [3]. As such, it has also been extensively studied for both safety and efficacy. In 1967, Shealy and Mortimer were the first to describe the treatment of pain, via electrical stimulation, with electrodes placed directly over the dorsal column, in the intrathecal space of a patient with terminal cancer [4]. The first epidural placement of electrodes over the dorsal column was described in 1971. Shimogi and colleagues reported improved pain control with this type of placement [5]. Their efforts paved the way for the advances achieved in this field.

Over the next four decades, the spinal cord stimulator has undergone numerous iterations, including rechargeable internal power generators (IPGs), multiple contacts and electrodes, as well as improved software, in order to maximize their efficiency [6]. Throughout their evolution thus far, spinal cord stimulators have become increasingly effective in controlling neuropathic pain in the trunk and limbs. However there is now new evidence for sustained control of low back pain as well [7]. These devices are now an integral piece of the standard of care for long-term pain control in the USA and the rest of the developed world.

The first intrathecal delivery of drug has been credited to Leonard Corning, who administered intrathecal (IT) local anesthetic for pain control in 1885 [8]. The modern format of the intrathecal drug delivery systems (IDDS) began to gain traction after Wang and colleagues described improved pain control for cancer patients with IT morphine in 1979 [9]. The efficacy of IT opioid analgesic infusion has been verified in a number of published studies, as well as our own clinical practices. The best improvement with opioid IDDS is evident in chronic pain patients who have had analgesia, with conservative dosing of systemic opioid medications, but were intolerant to their side effects [10]. Alternatively, in patients with a suboptimal response to systemic or IT opioid medications, ziconotide has proven to be effective as a novel IT agent for pain control [11].

Evidence

Although both intrathecal drug delivery systems (IDDS) and spinal cord stimulators (SCS) are commonly utilized in the treatment of chronic pain, SCS has enjoyed a recent insurgence in technical advancements and popularity as the neuromodulation device of choice. This is based on its ease of implementation, efficacy, and low complication rates reported in the literature [12]. Nonetheless, IDDS continues to be a viable and strong choice for patients who would be candidates for neuromodulation. However, IDDS is typically reserved for patients who have either been inappropriate candidates for SCS, due to various relative or absolute contraindications, or failed an SCS trial [13].

Spinal Cord Stimulation

Since their inception, the SCS devices have been extensively studied for safety and efficacy [14]. SCS is commonly used in post-lumbar laminectomy syndrome (FBSS) patients, after surgical options have been exhausted and the patient continues to have low back and/or limb pain. However, there is evidence in the literature indicating that SCS may be a more effective and less costly modality than re-operation for patients with a history of previous lumbar surgery [15]. Moreover, patients who underwent an SCS implantation, after such re-operation, had a less optimal outcome with SCS [15]. SCS has also been shown to be extremely cost effective when compared with conventional medical management of FBSS patients, among many other diagnoses where SCS would be indicated [16].

Primary Indications for SCS

Failed back surgery syndrome (FBSS)

Lumbar radiculopathy

Arachnoiditis

Complex regional pain syndrome (CRPS)

Causalgia

Cervical radiculopathy

Diabetic and peripheral neuropathy

The low complication rates associated with these implants have been reported in multiple studies [12]. More importantly, the efficacy, in terms of optimal pain control [17], reduction in medications [14], and increase in function, including return to work [18], has also been demonstrated in the published literature.

SCS devices have enjoyed increasing popularity not only based on their long-term pain control, but also for their safety (Fig. 13.1). There is a significant lack of similar strong evidence for other treatment options, including opioids [1] and interventional management techniques, such as epidural injections [19]. Furthermore, there is research suggesting that earlier intervention with SCS after spinal surgery may be significantly more successful versus later consideration in the treatment algorithm [17].

Fig. 13.1

Tonic SCS generator with software upgrade capability (courtesy of St. Jude Medical)

The literature also suggests that SCS may be more effective than re-operation in patients who have undergone a technically successful spinal surgery [20]. As such, a growing number of pain physicians believe that SCS may not only be considered for patients with FBSS, but also for patients who have multilevel degenerative disc disease without a clear surgical option to alleviate their low back and leg pain.

Various SCS modalities currently available or under near-term investigation can be categorized as the following:

Tonic or traditional stimulation

Adaptive stimulation

High-frequency stimulation (HF-10 Therapy™)

Burst stimulation

Dorsal root ganglion stimulation (DRG)

Each of these categories of SCS contains unique properties and advantages as described below:

Tonic or Traditional Stimulation

Tonic SCS , also known as traditional stimulation or low frequency SCS , has been highly utilized around the world, as it was the pioneer modality in this category of neuromodulation. Tonic stimulation waveform frequency ranges between 1 and 50 Hz. It has been shown that tonic SCS is most effective within this range in the attenuation of the pain signal at the dorsal column [21]. Traditional stimulators depend on paresthesia mapping of the patient for a successful outcome. In other words, the paresthesia sensation will need to overlap the painful areas of the patient in order to attenuate their pain [22]. Therefore, intraoperative paresthesia mapping for placement of the leads within the epidural space, based on Barolat mapping, is a requirement for this type of stimulation [22].

Adaptive Stimulation

Adaptive Stimulation was designed to address overstimulation and understimulation resulting from posture changes, thereby enhancing SCS therapy. Changes in body position cause the spinal cord to move within the intrathecal space resulting in variations in the distance between the spinal cord and stimulating electrodes [23]. The resulting change in distance between the spinal cord and the stimulating electrodes may cause transient overstimulation or understimulation which may require patient or clinician adjustment of stimulation parameters to accommodate changes in body position or physical activity [24].

The AdaptiveStim™ feature automatically adjusts the electrodes and stimulation parameters, including amplitude, in response to changes in body position or physical activity. These changes are detected by an integrated three-axis accelerometer and associated software contained in the neurostimulator (Fig. 13.2). Results from a multicenter, prospective randomized cross-over study show patient preference for AdaptiveStim when compared to spinal cord stimulation without automatic adjustment [25]. With AdaptiveStim, 88.7 % patients reported better pain relief and 90.1 % reported better convenience compared to conventional stimulation.

Fig. 13.2

Medtronic restore sensor generator. Courtesy of medtronic, Inc

High-Frequency Stimulation

A form of high-frequency SCS at 10,000 Hz (10 kHz), known as HF10™ therapy, has been the subject of growing interest with emerging published evidence in the literature. Van Buyten and colleagues first introduced the HF10 technology to pain physicians in a multicenter European study in 2013 [26]. They demonstrated significant improvement of back pain at 6 months, in this pilot study. Tiede and colleagues also reported similar results in the USA as part of an initial feasibility study [27].

A randomized, controlled trial (RCT) comparing HF10 stimulation to traditional (tonic) stimulation, the first of its kind in neuromodulation, was recently completed in the USA. This historic study demonstrated superior efficacy of HF10 therapy SCS over traditional (tonic-low frequency) SCS for both back and leg pain at 12 months. The results were presented at the 2014 North American Neuromodulation Society (NANS) meeting and the subsequently publsihed int he Journal of Anesthesiology [7]. There are no paresthesias perceived by the patient at 10,000 Hz. As such, HF10 therapy does not rely on paresthesia mapping for pain control. The advantages of this phenomenon, aside from its superiority for back and leg pain control, include eliminated negative positional effects of traditional SCS and loss of pain control due to loss of paresthesia overlap.

Burst Stimulation

The supporting theory for the efficacy of burst SCS is based on the inherent existence of neurons within the central nervous system (CNS) which produce action potentials in groups of “bursts.” Such bursts , typically at a frequency of 500 Hz, are physiologically present in parallel to tonic action potentials in the CNS [28]. Studies have also demonstrated a more powerful response from burst than tonic stimulation, particularly in the activation of the cerebral cortex [29]. DeRidder and colleagues were able to demonstrate improved efficacy of burst SCS over traditional SCS for axial back pain [30]. Furthermore, burst stimulation does not produce paresthesias for the majority of its patients secondary to its sub-sensory amplitudes, which may achieve efficacy before the sensory thresholds are reached [31]. A randomized, placebo-controlled trial for failed back surgery syndrome patients published by Schu and colleagues established the efficacy of burst SCS vs. 500 Hz tonic SCS and placebo [31]. A multicenter US RCT of burst SCS vs. tonic stimulation is currently under way. Figure 13.3 depicts the various waveforms and frequencies for HF10, burst, and traditional stimulation.

Fig. 13.3

SCS waveforms and frequencies

Dorsal Root Ganglion Stimulation (Fig. 13.4)

Fig. 13.4

DRG leads at the L5 level (courtesy of Kasra Amirdelfan, M.D.)

The dorsal root ganglion (DRG) has recently been established as a new target for SCS in the neuraxis, although it has been of interest as a target to treat chronic pain for some time [32]. The DRG is located bilaterally within the spine. The cell bodies for the primary afferent neurons are located directly caudal to the pedicles in the transforaminal space [33]. There are two main types of neurons (type A and B) within the DRG. The type B neurons are thought to be responsible for nociceptive sensation, whereas the type A neurons are largely responsible for touch, vibration, and proprioception [34].

The low amplitude of electrical stimulation at the DRG has been shown to promote growth factors involved in the regeneration of spinal neurons [35]. This promotion is mediated through specific growth factors, which are also associated with neuropathic pain. Electrical activity has been shown to modulate such growth factors [36]. As such, it is plausible that such neuro-secretory promotion via electrical stimulation may be responsible, in a direct or an indirect manner, for the attenuation of the pain signal at the DRG [37]. There is also evidence of wide dynamic range (WDR) neuron attenuation with DRG stimulation in the animal model, which could also be responsible for the analgesia with electrical stimulation at this structure [38].

In a single-arm, prospective pilot study, Deer and colleagues demonstrated up to 70 % pain relief in subjects suffering from chronic neuropathic pain with DRG spinal stimulation [39]. The long-term efficacy of the DRG SS has also been established in a number of studies. Liong and colleagues published the 12-month results of their multicenter European study, showing approximately 56 % overall pain relief in their subjects with intractable pain of the trunk and limbs [40]. A randomized RCT of DRG spinal stimulation versus tonic stimulation was recently completed in the USA. Finally, there is emerging evidence for the treatment of low back pain with DRG SCS placed at the L2 level [41]. Although promising, additional investigation is warranted for this utilization.

The study randomized patients in a 1:1 fashion with complex regional pain syndrome or peripheral causalgia of the lower extremity (defined as the iliac crest down), with a visual analog scale greater than 6, pain for at least 6 months, to treatment with either traditional SCS or DRG-SS, with endpoint of efficacy at 3 months and safety at 12 months.

152 patients were randomized, 146 were trialed (73 in each group). The results are compelling and demonstrated statistical superiority to SCS.

° 81.2 % of patients that underwent the trial with DRG experienced 50 % pain relief or greater at 3 months as compared to 55.7 % for SCS

° 74.2 % of the patients that underwent the trial with DRG experienced 50 % pain relief or greater at 12 months as compared to 53.0 % for SCS

° 93.3 % of patients that underwent the implant had 50 % pain relief or greater at 3 months, as compared to 72.2 % for SCS

° 86 % of the patients that underwent the implant had 50 % pain relief or greater at 12 months as compared to 70 % for SCS

° The DRG group demonstrated non-inferiority and superiority at 3 months when compared to SCS for all primary endpoints

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