10 kHz SCS therapy for chronic pain, effects on opioid usage: Post hoc analysis of data from two prospective studies

Chronic pain, including chronic low back and leg pain are prominent causes of disability worldwide. While patient management aims to reduce pain and improve daily function, prescription of opioids remains widespread despite significant adverse effects. This study pooled data from two large prospective trials on 10 kHz spinal cord stimulation (10 kHz SCS) in subjects with chronic low back pain and/or leg pain and performed post hoc analysis on changes in opioid dosage 12 months post 10 kHz SCS treatment. Patient-reported back and leg pain using the visual analog scale (VAS) and opioid dose (milligrams morphine equivalent/day, MME/day) were compared at 12 months post-10 kHz SCS therapy to baseline. Results showed that in the combined dataset, 39.3% of subjects were taking >90 MME dose of opioids at baseline compared to 23.0% at 12 months post-10 kHz SCS therapy (p = 0.007). The average dose of opioids in >90 MME group was significantly reduced by 46% following 10 kHz SCS therapy (p < 0.001), which was paralleled by significant pain relief (P < 0.001). In conclusion, current analysis demonstrates the benefits of 10 kHz SCS therapy and offers an evidence-based, non-pharmaceutical alternative to opioid therapy and/or an adjunctive therapy to facilitate opioid dose reduction whilst delivering significant pain relief. Healthcare providers involved in management of chronic non-cancer pain can include reduction or elimination of opioid use as part of treatment plan when contemplating 10 kHz SCS.


Results
Patient demographics. In SENZA-RCT, 89 subjects were successfully included through 12 months and in SENZA-EU, 68 subjects were included through 12 months. Out of the subjects with pain relief data, 83 subjects in SENZA-RCT and 54 subjects in SENZA-EU (137 subjects in the combined population) had opioid usage data at baseline or 12-month assessment. They were included in initial analyses of demographics and clinical characteristics.
As listed in Tables 1, 60.2% subjects were female in SENZA-RCT, 53.7% in SENZA-EU and 57.7% in combined dataset. The average age of the combined population was 51.8 ± 11.7 years (mean ± standard deviation [SD]) and the mean duration since diagnosis was 11.3 ± 9.5 years. Majority of subjects reported having previous back surgery (85.4%) and were diagnosed with FBSS (81.8%). Due to minor differences in inclusion criteria between SENZA-EU and SENZA-RCT studies, such as requirement of back pain with VAS score ≥5 cm regardless of leg pain in the former study and requirement of both back and leg pain VAS scores ≥5 cm in the latter study, the baseline average back pain VAS score (mean ± standard error of the mean [SEM])was 1 cm higher than SENZA-EU study (8.4 ± 0.2 cm compared with 7.5 ± 0.1 cm), while the average leg pain score was 2 cm lower (5.1 ± 0.4 cm compared with 7.1 ± 0.2 cm). In the combined dataset, 39.5% of subjects were taking >90 MME dose of opioids prior to 10 kHz SCS treatment; 48.0% in SENZA-RCT and 27.8% in SENZA-EU.
Mean opioid reduction. Further analyses on mean opioid reduction, reduction in pain intensity scores and classification of subjects based on opioid dose were carried out in subjects with information on opioid dose. At baseline, dose information was available in 75 subjects in SENZA-RCT, 54 subjects in SENZA-EU and 129 subjects in the combined dataset ( Fig. 1). At 12-month follow-up, dose information was available in 68 subjects in SENZA-RCT, 54 subjects in SENZA-EU and 122 subjects in the combined data set (Fig. 1).
As illustrated in Fig. 2, though the primary endpoint of the studies was pain scores and opioid reduction was not emphasized in the study, decreases in opioid dosage were noted in the subjects following 10 kHz SCS treatment. In both studies, there was a reduction in the mean opioid dose 12-months following 10 kHz SCS therapy compared with baseline ( Fig. 2A). In the combined dataset, there was a 41.0% reduction (p < 0.001) in the mean opioid dose at 12 months from 104.2 ± 9.0 MME (N = 129) to 61.4 ± 6.9 MME (N = 122). Separately, in the SENZA-EU study, the mean opioid dose at 12 months post-10 kHz SCS therapy significantly reduced from 92.3 ± 15.6 MME (N = 54) to 28.1 ± 6.0 MME (N = 54, p < 0.001). Whereas in the SENZA-RCT study, the mean opioid dose significantly decreased from 112.7 ± 10.5 MME (N = 75) to 87.9 ± 10.3 MME (N = 68) at 12 months post-10 kHz SCS therapy (p < 0.001).

Pain response.
When the studies were compared for pain reduction following 10 kHz SCS therapy, there were significant reductions in pain relief (VAS score) across both back and leg pain (Fig. 2B, p < 0.001). Overall in the combined dataset, there was a 67.9% reduction in back pain from 7.8 ± 0.1 cm (N = 129) to 2.5 ± 0.2 cm (N = 122) and 68.2% reduction in leg pain from 6.3 ± 0.2 cm (N = 129) to 2.0 ± 0.2 cm (N = 122) reported by subjects that were opioid users at 12 months post-10 kHz SCS therapy compared with baseline.
Proportion of subjects and mean MME. Changes in medication and opioid doses (MME) are shown in Table 2  Proportion of subjects ≤90 and >90 MME. Figure 3B,D,F show the proportion of subjects in doses ≤90 MME and >90 MME categories. Overall there was a significant reduction in the percentage of subjects on high-risk MME doses >90 in the combined dataset (Fig. 3F, p = 0.007).
Changes in opioid dose in subjects in high-risk category (>90 MME). Subjects taking >90 MME of opioids at baseline were then studied further for changes in opioid dose following 10 kHz SCS therapy. At baseline, 36 subjects in SENZA-RCT, 15 subjects in SENZA-EU and 51 subjects in the combined dataset were taking >90 MME of opioids for management of pain (Fig. 1). Across both studies, within the high-risk category (>90 MME) there was a trend towards a reduced opioid dose in most individual subjects 12 months post-10 kHz SCS therapy (Fig. 4A). Twelve out of 15 subjects in SENZA-EU and 11 out of 36 subjects in SENZA-RCT were able to cease or reduce their opioid dose to ≤90 MME at 12 months. Despite more subjects remaining on lower MMEs of opioids compared to baseline, significant pain reduction was reported across both studies following 10 kHz SCS therapy. As shown in Fig. 4B, following 10 kHz SCS therapy, subjects initially on >90 MME dose of opioids at baseline reported a 72.4% reduction in back pain from 8.

Discussion
In North America, the opioid crisis is still at its peak 55 . Mortality rates associated with prescription opioid-related addiction and overdose have surpassed motor-vehicle accidents and patients with Human Immunodeficiency Virus, affecting people from all socio-economic classes 55 . Clear evidence is now available that demonstrates the rate of overdose of prescription opioids is directly proportional to the prescribed dose 56 . Despite efforts from regulatory bodies and clinical guidelines, opioids continue to be prescribed for patients with chronic pain conditions. In 2016, the CDC released its guideline on prescribing opioids for chronic pain and recommended avoiding or carefully justifying doses of above 90 MME 29 . Patients who do not achieve adequate pain relief and function at this dose are advised to seek alternative pain management options 29 . This recommendation received widespread criticism for its lack of guidance on suitable alternative options, leaving prescribers and patients with a dilemma regarding how to manage pain 57 . Patients are feeling left without options, and their quality of life is suffering as a consequence 58 .
Despite clear guidance on maximum doses of opioids and the rationale for high-dose opioids becoming weaker, patients continue to rely on doses > 90 MME for pain management. A recent retrospective analysis of 1,066 primary health care records of patients prescribed opioids for chronic non-cancer pain, 9.7% were receiving www.nature.com/scientificreports www.nature.com/scientificreports/ ≥90 MME 59 . In 2012, the CDC reported that 10% of patients on prescription opioids were receiving a high-dose (>100 MME) from one doctor, and of those who overdosed, 40% were also prescribed their pain relief from a single doctor 29 . Surveys have reported that 70% of long-term opioid users suffer from a chronic disease or disability which limits their daily function 29,60 . Assuming 10% of these patients may be on high-doses to maintain an adequate level of function and pain relief, feasible alternative options are required to reduce the risk of overdose. Clearly, patients suffering from CLBP and leg pain need evidence-based, safe and effective alternatives to long term opioid therapy.
In the current study, patients had CLBP and leg pain for an average of 11.3 ±0.8 years. They experienced significant baseline pain, despite being managed by prescription opioid therapy. Over a third (39.3%) of subjects were taking > 90 MME of opioids at baseline. 10 kHz SCS therapy was successful in reducing the mean opioid dose and patient reported pain at 12 months. Figure 2 shows following 10 kHz SCS therapy, the mean dose was reduced below 90 MME to 61.4 MME in the combined dataset. Despite a substantial reduction in the mean opioid dose, 10 kHz SCS therapy significantly improved patient-reported back and leg pain at the 12-month follow-up.
Not only was 10 kHz SCS therapy able to reduce the overall dose of opioids used by subjects with CLBP and leg pain, it reduced the proportion of subjects requiring high-risk doses >90 MME per day at the same time. Figure 3 shows in both studies fewer subjects remained on >90 MME per day, and more subjects were able to withdraw their opioid altogether following 10 kHz SCS therapy. In the combined dataset, nearly 80% of the subjects were now on dosing range associated with a reduced risk doses of opioids, with over 20% shifting from >90 MME to <90 MME at follow-up. The dose reduction was observed across individual subjects, as shown in Fig. 4, with most of them demonstrating a reduction in dose at 12 months. A reduction in pain with a reduction in opioid dose is a clinically important finding, demonstrating 10 kHz SCS therapy is not only an alternative to opioid therapy, regardless of high-or low-dose, it is able to provide more effective pain relief than baseline opioid therapy.
Interestingly, compared to SENZA-RCT, higher reductions in opioid dose and higher proportion of subjects taking lower doses of opioids at 12 months were observed in the SENZA-EU study. There may be multiple factors contributing to these observed differences. While SENZA-EU was a prospective, single-arm study designed to assess the efficacy of 10 kHz SCS system, SENZA-RCT was a randomized controlled trial designed to compare 10 kHz SCS with traditional SCS in order to support regulatory approval. Thus, the SENZA-RCT was highly focused on pain management rather than opioid reduction, whereas more emphasis was placed on weaning SENZA-EU subjects off of opioids. In SENZA-RCT, subjects were allowed to continue on stable doses of opioids but were considered as treatment failures regardless of pain scores (VAS) if they increased opioid dose. Related, there were also differences in pain management practice between study centers in SENZA-EU

SENZA-EU Europe Combined
Completely  www.nature.com/scientificreports www.nature.com/scientificreports/ and SENZA-RCT. Investigators from SENZA-EU study actively encouraged the subjects to titrate and taper their opioid dose, whereas investigators from SENZA-RCT did not actively encourage opioid reduction. Lastly, chronic pain patients who are on long term opioids but still have high pain scores underscores the observation that opioids seem to have little benefit in improving chronic pain, especially as measured by VAS, yet are difficult to discontinue. Over the past decade, especially in the US, patients remained on opioids despite their dubious clinical benefit. This may have translated into clinical management changes that were not part of the goals of the RCT or EU studies.
In the past few years, several studies have documented lack of clinically relevant efficacy with the use of opioids for chronic non-cancer pain and highlighted the harmful side effects of using opioids [61][62][63][64][65][66][67] . The CDC guidelines published in 2016, recommended caution when increasing the opioid doses above 50 MME and avoiding opioid doses above 90 MME 29 . To prescribe safe doses of opioids and to wean the chronic pain patients off opioids, pain management specialists need durable alternatives for management of chronic pain. The current findings indicate that 10 kHz SCS can be considered as an alternative to opioids. A case-controlled retrospective study by researchers from Boston, USA showed that opioid usage was reduced or eliminated in 71% (n = 15/21) of patients treated with 10 kHz SCS for back and/or leg pain 68 . Another retrospective study by pain management specialist from Perth, Australia showed that percentage of patients not taking opioids increased nearly 2-fold www.nature.com/scientificreports www.nature.com/scientificreports/ in patients treated with 10 kHz SCS therapy and 70% of patients either eliminated or reduced their opioid dose at last follow-up. More importantly, average opioid dose in patients taking high dose opioids at baseline was reduced by 47% at last follow-up 69 . Current study further confirms the findings from the retrospective studies and shows that 10 kHz SCS can provide long-lasting pain relief and allow reduction or elimination of opioids even in patients who were prescribed high-risk doses. Pain physicians need to take note of the findings from the studies and encourage patients treated with 10 kHz SCS to discontinue opioids. They need to include reduction or elimination of opioid use as part of treatment plan when contemplating 10 kHz SCS. Establishing opioid reduction as part of the treatment goal even prior to the trial could help in setting up expectations and result in meaningful improvement in quality of life.
The main limitation of this study is that it involved post hoc analysis of the dataset and there was no prospectively defined statistical analysis plan (SAP) for predetermined outcomes. Although the combined dataset in the study included 129 subjects with opioid dose information, there were differences between the two studies and the number of subjects taking > 90 MME was relatively small. Additional prospective studies and real-world studies may be needed to validate the findings of this analysis. Nevertheless, current analysis shows that despite the differences between the two studies and the patient cohorts, 10 kHz SCS therapy resulted in significant reduction in opioid dosage while maintaining pain relief when the data was analysed individually and when combined. www.nature.com/scientificreports www.nature.com/scientificreports/ Based on the results of this study, 10 kHz SCS therapy has the potential to assist physicians and patients in the wake of the opioid crisis, offering a non-pharmacological alternative to the suite of pain management tools for patients on high-risk doses of opioids (>90 MME). Methods SENZA-EU. As described previously, SENZA-EU was a prospective, multicentre, open-label study in 83 subjects conducted at two European centers including AZ Nikolaas Pain Centre, St Niklaas Belgium and Guy's and St Thomas' Pain and Neuromodulation Centre, London, United Kingdom 50 . The study protocol and informed consent forms were approved by each study site's ethic committee (Commissie voor Medische Ethiek AZ Nikolaas, Belgium and NRES Northern & Yorkshire REC, UK respectively). Local clinical research and data protection regulations, good clinical practice guidelines (ISO 14155), and the Declaration of Helsinki were followed during the study. Selection bias in the study was minimized by the involvement of independent medical monitors, which assured high level diligence for the recruitment of subjects. Inclusion and exclusion criteria for enrollment of patients has been previously reported 50 . Briefly, patients who signed informed consent forms, with chronic back pain (defined as lumbo-sacral pain) with or without leg pain with pain intensity of ≥5.0 cm (average score over the last 30 days) on the 0 to 10 cm, visual analog scale (VAS), who were ≥18 years of age and who were candidates for SCS were included in the study. Patients were evaluated at baseline and then received a trial 10 kHz SCS (Senza ® SCS system Nevro Corp., Redwood City, CA, USA) therapy for 14-30 days 50 . Patients who had at least 50% reduction in pain intensity received a permanent IPG implant and followed for 24 months with assessments at 1, 3, 6, 12, and 24 months 50 . Subjects were enrolled in the study between August 2009 and February 2011. The follow-up for the last implanted patient was completed in April 2013. The study design allowed adjustment of stimulation parameters and clinical judgement-based adjustment to pain medication dosage throughout the follow-up period 50 .
SENZA-RCT. SENZA-RCT was a prospective, randomized, controlled trial in 198 patients across 10 centers in the U.S., designed to assess 10 kHz SCS therapy as compared with traditional low frequency SCS 51 . The study was conducted in compliance with the U.S. Code of Federal Regulations and recommendations guiding physicians in biomedical research by the 18th World Medical Assembly, Helsinki, Finland. The study protocol and informed consent forms were approved by each study site's institutional review board (Western Institutional Review Board, Puyallup, Washington; Forsyth Medical Center Institutional Review Board, Winston-Salem, North Carolina). Selection bias in the study was addressed by the involvement of independent medical monitors for the recruitment of subjects and randomized assignment of subjects to the 10 kHz SCS group. Patients who signed informed consent forms and were candidates for SCS with chronic, intractable back and/or leg pain, refractory to conservative therapy for a minimum of 3 months with an average back pain intensity of 5 or greater out of 10 cm on the VAS, average leg pain intensity of 5 or greater out of 10 cm on the VAS, an Oswestry Disability Index (ODI) score of 41 to 80 out of 100 were randomized in a 1:1 ratio to receive stimulation with an investigational 10 kHz SCS therapy system (Senza ® System; Nevro Corp., Redwood City, USA) or a commercially available SCS system (Precision Plus System; Boston Scientific, USA) 51 . Patients underwent a percutaneous trial lasting up to 14 days 51 . Those with ≥40% back pain reduction from baseline proceeded to permanent implantation and subjects with at least 50% pain reduction were considered as 'responders' 51 . Subjects were enrolled between June 2012 and December 2012. Following randomization, subjects were implanted with 10 kHz SCS system and followed through 12 months, which concluded in February 2014. Oral analgesics were stabilized from 28 days before Figure 5. Overall reduction in mean opioid dose (mean ± SEM) in subjects with a baseline opioid dose >90 MME in the combined dataset (A) and change in patient-reported back and leg pain VAS scores (mean ± SEM; B) from baseline to 12 months following 10 kHz SCS therapy. ***p < 0.001, paired t-test.