Pain relief and improvement in quality of life with 10 kHz SCS therapy: Summary of clinical evidence

Abstract Objective Chronic pain is a prevalent condition which has a significant effect on the lives of those it impacts. High‐frequency 10 kHz spinal cord stimulation (10 kHz SCS) has been shown to provide paresthesia‐free pain relief for a wide variety of pain indications. This article summarizes the current and emerging data as they relate to the clinical use of the therapy in various pain syndromes. Methods A literature search was conducted using the PubMed electronic database using keywords related to 10 kHz SCS. The database was queried from 2013 to May 2019. Articles reporting clinical studies that included human subjects permanently treated with 10 kHz SCS (Senza® system) were included in the review. Recent and relevant conference proceedings known to the authors were also included. Results The selected literature demonstrated significant evidence for the efficacy of 10 kHz SCS in treating chronic back and leg pain (CBLP), including a randomized, controlled trial as well as prospective and retrospective studies. One‐year follow‐up responder rates (pain relief ≥50%) ranged from 60% to 80%. Other studies and case series showed promising outcomes in specific conditions, including nonsurgical refractory back pain, neuropathic limb pain, complex regional pain syndrome, chronic widespread pain, chronic pelvic pain, and intractable headache. Subgroup analyses also pointed toward the potential of 10 kHz SCS being successful when low‐frequency SCS has failed. The vast majority of these studies reported improved quality of life (QOL) metrics and/or reduced opioid consumption. Conclusions Level I evidence already exists for the efficacy of 10 kHz SCS in treating CBLP, supported by real‐world clinical experience. Other studies demonstrate the potential of the therapy across a range of chronic pain etiologies, although larger confirmatory studies are recommended. Overall, the literature suggests that the therapy is associated with improved QOL as well as reduced opioid consumption.


| INTRODUC TI ON
Chronic pain is an escalating public health issue around the world.
It represents a significant challenge to individuals and their families, as well as healthcare providers and payers. Surveys estimate that around one in five adults report chronic pain. [1][2][3] Some studies indicate that the prevalence increases with age and is rising overall. 1,[4][5][6][7][8][9][10] Chronic pain is known to have a major impact on patients' well-being, relationships with others, ability to carry out everyday activities, and work productivity. 3,[11][12][13][14][15][16][17][18][19] The associated economic burden to society exceeds $500 billion annually in the United States and consumes 2%-10% of GDP in European countries. [20][21][22][23] The treatment of chronic pain is complex and challenging, encompassing many disciplines, including physical and psychological therapies, as well as pharmacological, interventional, and surgical treatments. 24 Opioid medication is often prescribed as part of a pain management strategy. While there is some evidence supporting the short-term use of opioids in chronic pain, long-term efficacy data are lacking. [25][26][27] For a variety of reasons, long-term opioid prescribing has been stable nonetheless. 28 Traditional low-frequency spinal cord stimulation (LF-SCS) is another therapeutic option for chronic pain and is most commonly used to treat leg pain associated with failed back surgery syndrome (FBSS). 29,30 The therapy has Level I-II efficacy evidence in this indication as well as established cost-effectiveness. [31][32][33][34][35][36][37] Despite the robust body of evidence in favor of its use in FBSS, the therapy is arguably underutilized with the vast majority of patients undergoing spinal reoperation (>97%) despite poor published success rates. 37,38 During LF-SCS, one or more thin percutaneous leads or a surgical paddle lead with integrated electrical contacts are placed in the epidural space of the spinal canal. The vertebral level is selected according to the area of pain and is mapped via patient feedback for each patient. Electrical pulses to the spinal cord are applied via a temporary or permanently implanted pulse generator at a fixed frequency, usually in the range of 40-60 Hz with a pulse width 150-500 µs. 39 Historically, it is understood that approximately half of patients achieve ≥50% pain relief. 31,32 However, some report uncomfortable paresthesia or experience discomfort related to under-or overstimulation resulting from postural changes. [40][41][42] Additionally, paresthesia can be difficult to isolate in very common regions of chronic pain such as the low back and foot. In some patients, habituation occurs, and pain relief can diminish after several years. [43][44][45][46][47][48] While several technological advances in LF-SCS have been made during the last decade, these gains have not translated into higher success rates. 33 Consequently, efforts have been made to develop new systems with more advanced stimulation waveforms. One such system, 10 kHz SCS (Senza® system), has been developed by Nevro Corp.
Along with a higher stimulation frequency compared with LF-SCS, it utilizes a shorter pulse width (30 µs) and lower amplitude electrical pulses (1.0-5.0 mA). 33 Patients do not experience paresthesia. Leads are implanted along the anatomical midline with lead tips located at T8 and T9 in a staggered fashion covering T8-T11 vertebral levels for back and leg pain patients. The implantation procedure is more predictable and reproducible than that required for LF-SCS due to the absence of paresthesia mapping and associated patient feedback. 49 In comparison with LF-SCS, where paresthesia mapping during the procedure is mandatory, leads are placed anatomically during 10 kHz SCS implantations without paresthesia mapping.
Over the last 5 years, a considerable evidence base has been established for the clinical use of 10 kHz SCS for the treatment of chronic pain in the trunk and/or limbs. Evidence has also been emerging for its utility in treating intractable headache as well as other common pain syndromes with limited therapeutic options. This purpose of this article is to provide a comprehensive summary of prospective and retrospective clinical studies in the field, as well as ongoing investigations, with a specific emphasis on clinical outcomes, including pain relief as well as changes in quality of life (QOL) and opioid consumption (Table 1).

| ME THODS
A literature search was conducted using the PubMed electronic database using keywords related to 10 kHz SCS, such as spinal cord stimulation, 10 kHz, and HF10. The database was queried from 2013 to May 2019. Results were limited to English-language articles reporting clinical studies that included human subjects permanently treated with 10 kHz SCS (Senza® system). Recent and relevant conference proceedings known to the authors were also included in the review.

| SENZA-RCT study
A pivotal, multicenter, randomized, controlled trial (RCT) published in 2015 by Kapural et al established Level I evidence for the efficacy of 10 kHz SCS in treating chronic back and leg pain (SENZA-RCT). 33 The study inclusion criteria specified both back and leg pain scores ≥5 cm on the visual analog scale (VAS). Subjects were randomly assigned (1:1) to receive either 10 kHz SCS or traditional LF-SCS. Most had undergone previous spinal surgery (87%) while just over half of each group reported predominant back pain.
Ninety of 97 subjects (93%) in the 10 kHz SCS group and 81 of 92 subjects (88%) in the LF-SCS group completed a successful trial and received a permanent system. Outcomes were compared up to 12 months postimplantation. Response to therapy was defined as ≥50% reduction in pain score. At the 3-month primary endpoint, 84% and 83% of the 10 kHz SCS group were responders for back pain and leg pain, respectively, compared with 44% and 55% of the LF-SCS group (P < .001 for both noninferiority and superiority in both pain categories). At 12 months, outcomes were available for 89 and 80 subjects in the 10 kHz SCS and LF-SCS groups, respectively. Responder rates were sustained in both groups and pain categories but remained higher in the 10  pain: 79% vs 51%; leg pain: 79% vs 51%, P < .001 for both noninferiority and superiority in both pain categories). Moreover, at Of those who answered general survey questions, a higher proportion of 10 kHz SCS subjects indicated sleeping and driving with their devices switched on (sleeping: 95% vs 60%, P < .001; driving: 94% vs 66%, P < .001).
Follow-up was extended for a year to evaluate 24-month outcomes. 51 Data were available for 85 and 71 subjects in the 10 kHz SCS and LF-SCS groups, respectively. Responder rates for both back pain and leg pain remained statistically superior among the former group (back pain: 76% vs 49%, P < .001 for both noninferiority and superiority; leg pain: 73% vs 49%, P < .001 for noninferiority and P = .003 for superiority). The decrease in both back pain and leg pain was sustained in both groups and remained greater among 10 kHz SCS subjects (back pain: −5.0 vs −3.2 cm, P < .001 for both noninferiority and superiority; leg pain: −4.7 vs −3.7 cm, P < .001 for noninferiority and P = .03 for superiority). Secondary outcomes also reflected the long-term benefits of 10 kHz SCS with more of this group reporting minimal disability on the ODI (23% vs 10%). Greater numbers were also rated by both clinicians and patients as "a great deal better" on their respective GIC scales (CGIC: 41% vs 20%; PGIC: 34% vs 21%) and reported being "very satisfied" with their therapy (60% vs 40%). The distribution among categories for the ODI, CGIC, and PGIC scales favored 10 kHz SCS (ODI: P = .02; CGIC: P = .002; PGIC: P = .004). A smaller cohort with available data also indicated at 24 months that more LF-SCS subjects used their device programmer daily (35% vs 0%) and carried it around away from home (85% vs 38%). 50 Increased reliance on the device programmer may have arisen from uncomfortable paresthesia or discomfort felt during postural changes experienced by 11% and 40%, respectively, of the LF-SCS subjects who experienced paresthesia (95.5%).
The reported limitations of the study included heterogeneity of pain diagnoses within the subject population. Such diversity in etiology is typically found within the chronic back and leg pain F I G U R E 1 10 kHz SCS benefits for low back and leg pain patients. A, Mean pain relief B, Responder rate indication. In addition, the study protocol allowed pain medication changes after stimulation activation, although increase in opioid medication was considered as SCS treatment failure. A further limitation was the lack of treatment allocation blinding to the investigator and subject due to the necessity of paresthesia in the LF-SCS group.

| Prospective, multicenter, single-arm studies
Two prospective, multicenter, single-arm studies evaluated the benefits of 10 kHz SCS in subjects with a primary diagnosis of chronic back pain. In the first study, six-month data were pre- A considerable strength of this study was its large size and real-world setting, reflecting everyday clinical practice across several countries.
As such, the study provided complementary evidence to the SENZA-RCT. However, data were collected retrospectively, may not have been collected systematically, and analyses were performed as-observed.

| Chronic back pain ineligible for spinal surgery (maiden back or nonsurgical back pain)
The benefits of 10 kHz SCS therapy for subjects with chronic back pain ineligible for spinal surgery and no history of such intervention were evaluated in a separate, single-center, prospective study by Al-Kaisy and colleagues. 57

| Neuropathic limb pain
Al-Kaisy et al 59  the score doubled after six months. In addition, patients' catastrophic thinking related to their pain was markedly reduced over the same period. Most patients reported being satisfied with their therapy (91%). Overall, the study provided insight into the potential benefits of 10 kHz SCS treatment among this diverse patient population. However, the sample size was small, and data were collected retrospectively.

| Complex regional pain syndrome
Outcomes of 10 kHz SCS treatment for an exclusive series of CRPS patients were presented in a single-center, retrospective review by Gill et al. 60 Eleven of 13 patients (85%) with uni-or bilateral CRPS in their upper or lower limbs had a successful trial and received a full system. Despite failing their trial in regard to pain relief, one additional patient was implanted due to vastly improved allodynia. Pain relief (%) was reported during each clinic visit. At a mean follow-up of 12 months, 67% of patients were responders ( Figure 2D). Among the responders were five of seven patients with sympathetically mediated pain (SMP), three of five with sympathetically independent pain (SIP), and five of seven who had previously undergone failed LF-SCS.
Patients also reported significant improvement in all four SF-MPQ-2 pain descriptors (continuous, intermittent, neuropathic, and affective: P < .01 for all descriptors). While providing preliminary evidence of therapeutic benefit in this challenging pain syndrome, limitations of this study include its small number of patients and retrospective analysis.

| LF-SCS nonresponders
Three studies presented outcomes of 10 kHz SCS treatment in subgroups of LF-SCS nonresponders. Russo and colleagues retrospectively reviewed 256 patients from three centers who were either not candidates for LF-SCS or were nonresponders. 61  While subgroup analyses can help identify and optimize new therapeutic applications, they present many analytic challenges and pitfalls. As such, while the subgroup data for LF-SCS nonresponders presented above is certainly promising, it should be interpreted with caution.

| Chronic widespread pain (off-label indication for SCS)
A recent, single-center, retrospective review by Salmon et al

| Chronic pelvic pain
Simopoulos and associates presented three chronic pelvic pain case studies treated with 10 kHz SCS. 65 The first patient had severe, unilateral, coccydynia pain (without radiation) after coccygectomy. He These cases suggest that 10 kHz SCS therapy can provide relief for chronic visceral pain ( Figure 2E). However, the number of patients was small and the follow-up time was short. Further studies are warranted to define the place of SCS and 10 kHz SCS in visceral pain syndromes.

| Intractable headache (off-label indication for SCS)
Another possible indication for 10 kHz SCS to date beyond trunk and/or limb pain is intractable headache (HA). A prospective, openlabel study by Arcioni and associates trialed the therapy in 17 subjects with refractory chronic migraine (CM). 66 Of these, 15 elected to have a permanent system, and 14 completed six months of followup. All subjects had failed botulinum toxin therapy and were overusing medication at baseline. Continuation of usual medication was allowed throughout the study, including migraine preventatives (although none took any of the latter). The definition of a HA day was defined according to standard criteria (>4 hours of continuous HA, either with NRS > 4, or, if taking abortive medication, NRS > 0). 67 At six months, half of the cohort experienced more than 30% fewer monthly HA days, and 36% had more than 50% fewer monthly HA days, with an average reduction for the whole group of 7.0 days (P = .004). More than half of the subjects reverted to an episodic migraine pattern. Average HA intensity was noted to decrease by 37% (P < .001) while half of the cohort experienced at least a 30% reduction (mean reduction: −3.3 points). The total monthly number of HA hours reduced by 17% (P = .05) while 43% of subjects reported more than a 30% reduction (mean reduction: 92 hours).

| Chronic postsurgical pain
In a single-arm, chronic postsurgical pain study presented by Gupta and colleagues, 29 of 34 subjects (85%) trialed with 10 kHz SCS experienced adequate pain relief and were fully implanted. 73 The

| Chronic abdominal pain (off-label indication for SCS)
Kapural et al 74 presented outcomes from a series of 24 subjects with chronic abdominal pain. All but one (96%) had a successful trial and received a full system. Analysis of complete 12-month data demonstrated response (≥50% reduction in VAS pain score) in 78% of the cohort at 12 months with a decrease in baseline pain score of 6.0 cm.
Subjects further reported around 70% less sleep disturbance (PSQ3) while around three-quarters of the cohort reported being better (PGIC). Concomitant improvements in gastrointestinal symptoms were also noted.

| Chronic pelvic pain
In a single-arm study of chronic pelvic pain summarized by Tate et al, 21 subjects underwent a trial. 75 Of these, 17 (81%) achieved adequate pain relief and were implanted with a permanent system.
Follow-ups were scheduled up to 12 months postimplantation.

| Painful diabetic neuropathy
In the first of three RCTs outlined during the NANS conference, subjects with neuropathic limb pain secondary to PDN are being enrolled. 76 The study will compare 10 kHz SCS treatment plus CMM with CMM alone (NCT03228420). A total of 216 subjects will be randomized (1:1) and followed for 24 months. Outcome measures include pain score, health-related quality of life (HRQOL), and sleep quality. The primary endpoint will compare group responder rates at 3 months. Enrollment is expected to complete during 2019.

| Nonsurgical refractory back pain
The second RCT is currently recruiting subjects with chronic back pain who have not had spinal surgery and are not candidates for such surgery (NCT03680846). 77 The protocol specifies randomization (1:1) into two treatment groups: 10 kHz SCS plus CMM versus CMM alone. Subjects can cross over at 6 months and will be followed out to 12 months. Outcome measures include pain score, HRQOL, sleep, GIC, mental health, disability, opioid consumption, and healthcare utilization. The primary endpoint will compare group responder rates at 12 months. Enrollment is expected to continue until the end of 2019.

| Chronic neuropathic low back pain
The third RCT is also underway and enrolling subjects with chronic neuropathic low back pain who are surgery naïve (NCT03470766). 78 The double-blind, multicenter study will compare active 10 kHz SCS plus usual care with sham 10 kHz SCS plus usual care. A total of 96 subjects will be randomized 1:1 and followed for six months.
Outcome measures include pain score, disability, emotional functioning, HRQOL, medication usage, and healthcare utilization.
Enrollment is expected to complete during 2020.

| SUMMARY
The primary aim of this review was to summarize the current clinical evidence for the use of 10 kHz SCS in the treatment of various chronic pain conditions. Several studies provide significant and converging evidence that this therapy is a clinically effective treatment for chronic back and leg pain, including an RCT as well as prospective and retrospective studies. Level I evidence was established by a pivotal, multicenter, RCT, which compared 10 kHz SCS with LF-SCS. 33,51 The study found long-term statistically superior pain relief among those treated with 10 kHz SCS. Two prospective, single-arm studies found similarly high levels of response to therapy, and two retrospective studies confirmed that 10 kHz SCS is effective in real-world settings. [52][53][54][55][56] Among the five studies, pain relief outcomes from >1000 subjects were evaluated at the end of follow-up (12-24 months). Twelve-month responder rates exceeded 70%, and 24-month responder rates ranged from 60% to 80%. Most of the studies reported quality of life and disability improvements as well as a reduction in opioid consumption. In general, at least 80% of subjects reported being satisfied with their therapy.
The results from studies and case series evaluating therapy outcomes in other indications, including chronic back pain ineligible for spinal surgery, neuropathic limb pain, CRPS, chronic widespread pain, chronic pelvic pain, and intractable headache, are promising.
In subjects with chronic, severe, low back pain who were not candidates for spinal surgery and were naïve to surgery, the 12-month response rate in the prospective study by Al-Kaisy and colleagues was strikingly high. 57 The results suggest that 10 kHz SCS may be a viable option in this population where treatment possibilities are limited. Promising reductions in pain were also found in retrospective studies of neuropathic limb pain, chronic widespread pain, and CRPS. 59,60,64 Given the difficulty in managing these pain syndromes and their particularly devastating impact on patients' lives, this certainly merits further exploration, which is currently being undertaken in the form of multicenter, randomized controlled trials.
Subgroup analyses also point toward the potential of 10 kHz SCS being successful even when LF-SCS has failed. 55,61 Individually, the studies provide preliminary evidence supporting the use of 10 kHz SCS in a wide variety of pain conditions. Larger confirmatory studies are necessary, and multiple randomized, controlled trials in these pain conditions are currently underway.
Our narrative review has several key limitations. Firstly, it was not designed as a formal systematic review. Furthermore, prospective case series published in peer-reviewed journals were single-arm in design while prospective data from ongoing studies were reported during conference proceedings. The evidence level provided by other case series is also limited by their retrospective design and, in many cases, small sample size. However, their findings may inform the implementation and design of future RCTs similar to the SENZA-RCT. The review also includes off-label applications of the therapy. Authors of this article do not recommend the use of SCS therapy for off-label applications in the US until stronger evidence and/or FDA approval is available for these indications, including intractable headache, chronic intractable neck pain, and chronic abdominal pain.
In conclusion, 10 kHz SCS has been shown to provide long-term pain relief in various chronic pain etiologies. The magnitude of the relief shown has been superior to previous studies and real-world data on low-frequency stimulation. This relief has also been associated with improved quality of life and reduced opioid consumption.
Ongoing and future research will continue to investigate the therapy in current and new indications, and the findings will be summarized in upcoming publications.

ACK N OWLED G M ENTS
Deborah Edgar PhD, Commexus Ltd, UK, prepared the manuscript in her capacity as an independent medical writer. For this service, she received a fee from Nevro Corp., Redwood City, CA. Madhuri Bhandaru PhD prepared the illustrations for the manuscript.