Poster Number-39 - Treatment of Painful Diabetic Neuropathy (PDN): High-Frequency (10 kHz) Spinal Cord Stimulation (SCS) Provides Significant, Durable Pain Relief for PDN Patients

Treatment of Painful Diabetic Neuropathy (PDN: High-Frequency (10 kHz) Spinal Cord Stimulation (SCS) Provides Significant, Durable Pain Relief for PDN Patients

Purpose:

Approximately 37 million Americans have diabetes, and 25-30% of these patients will experience painful diabetic neuropathy (PDN).^1-2 PDN is characterized by chronic sensory loss, neuropathic pain, and dysesthesias that gradually progress proximally from the feet and hands in a glove-and-stocking pattern.² PDN often results in poor quality of life, depression, anxiety, and impaired sleep.^2,3 Unfortunately, conventional medical management (CMM), which includes several classes of pharmacotherapies, is ineffective or intolerable for many PDN patients.^3,4 Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic lower extremity pain, and several recent studies have shown that SCS can also be effective for reducing pain associated with PDN.^5-7 While low-frequency SCS (typically 40-60 Hz) has demonstrated moderate pain relief for PDN patients (responder rate of 53-68% at 6 months),^5,6 it requires the use of stimulation-induced paresthesia, which may negatively affect patient comfort⁸ and limit therapy acceptability and success in a population that often has underlying disease-induced paresthesia symptoms.³ In contrast, high-frequency (10 kHz) SCS provides paresthesia-free treatment, and results at 12 months⁷ indicate that 10 kHz SCS provides greater pain relief (responder rate of 86%) than low-frequency SCS. In addition, 10 kHz SCS has been shown to provide improved neurological function and improved quality of life metrics at 12 months.⁷ Because PDN is a chronic condition, the long-term effectiveness of any treatment should be considered. Here we report on the durability of outcomes to 24 months for 10 kHz SCS treatment of PDN.

Methods:

We conducted a prospective, multicenter, randomized, controlled trial (RCT) to evaluate 10 kHz SCS in PDN patients. Key inclusion criteria were: PDN symptoms ≥12 months refractory to at least two classes of medications, lower limb pain intensity ≥5cm (0-10cm visual analog scale [VAS]), hemoglobin A1c (HbA1c) ≤10%, and BMI ≤45 kg/m². Patients were randomized 1:1 to 10 kHz SCS plus CMM (10 kHz SCS arm) or CMM alone (CMM arm), with optional crossover to the other treatment arm at 6 months (6M). Temporary trial SCS was used to evaluate eligibility (≥50% pain relief from baseline) for a permanent SCS device implant. To date, patients assigned to the 10 kHz SCS arm have been followed for 24M after receiving a permanent implant, and CMM-to-SCS crossover patients have been followed for 18 months post-implantation. To evaluate safety, study-related adverse events were tabulated. To evaluate effectiveness for pain-associated outcomes, results for each patient were compared to baseline values for lower limb pain (100-mm VAS), pain-associated sleep disturbance (Pain and Sleep Questionnaire three-item index, PSQ-3), and pain interference with mood and daily activities (Brief Pain Inventory, BPI-DPN). A repeated measures ANOVA was used to assess percent change (from baseline) for each outcome. To evaluate neurological function, neurologists trained investigators to perform comprehensive neurological examinations assessing lower limb motor strength, reflexes, and sensation (pin-prick, 10-g monofilament, and light-touch at 10 locations per foot). At each neurological exam, the investigator assessed if there was improvement, maintenance, or deficit in each functional category (motor strength, reflex, and sensory) relative to the baseline exam. Overall neurological improvement was noted if a patient was assessed to have improvement in at least one category without deficit in any category.

Results:

We randomized 216 patients (10 kHz SCS arm: n=113; CMM arm: n=103). Treatment groups were well-matched for baseline characteristics. Among participants assigned to the 10 kHz SCS arm, 104 proceeded to temporary trial and 90 received a permanent device implant.

At 6M, patients randomized to 10 kHz SCS experienced average pain relief of 76% (95%CI: 71%–82%; n=88; p< 0.001 vs. baseline, p< 0.001 vs. CMM). In contrast, patients randomized to CMM experienced average pain increase of 2% (95%CI: 6% decrease to 10% increase; n=95). After 6M, 93% of eligible CMM patients elected to cross over to 10 kHz SCS, while zero 10 kHz SCS patients crossed over to CMM. The CMM-to-SCS crossover patients experienced significant pain relief after receiving 10 kHz SCS, with average pain relief of 71% (95%CI: 64%–78%; n=59; p< 0.001 vs. baseline) after 6M of 10 kHz SCS. Patients receiving 10 kHz SCS continued to experience significant pain relief after 6M, with average pain relief of 82% (95%CI: 77–87%; n=84; p< 0.001 vs. baseline) at 24M. HbA1c remained unchanged in both groups throughout the study, supporting that SCS vs. CMM treatment effects were not due to group differences in HbA1c. 

Neurological improvements were also observed with 10 kHz SCS. At 6M, neurological improvements were observed in 62% and 3% of patients in the 10 kHz SCS and CMM arms, respectively. Then, for CMM-to-SCS crossover patients, improvements were observed in 62% of patients after 6M of 10 kHz SCS. Neurological improvements were also durable as 72% of patients receiving 10 kHz SCS were assessed to have improvement at 24M.

Reductions in pain-associated sleep disturbance and pain interference with mood and daily activities were consistent with pain relief. At 6M, 10 kHz SCS provided significant reductions in these outcomes vs. CMM (p< 0.001), and the 10 kHz SCS-associated reductions were durable through 24M. At 24M, patients receiving 10 kHz SCS experienced a decrease of 70% (95%CI: 61–80%; n=83; p< 0.001 vs. baseline) in pain-associated sleep disturbance and a decrease of 70% (95%CI: 63–77%; n=84; p< 0.001 vs. baseline) in pain interference with mood and daily activities.

There were no stimulation-related neurological deficits, and no device explants due to lack of efficacy. Of the 154 patients who received an SCS implant (including 10 kHz SCS arm and CMM-to-SCS crossover patients), there were eight (5.2%) study-related infections, three of which resolved with treatment. Five devices were explanted due to infection (3.2%).

Conclusion:

This is the largest RCT to date for SCS management of PDN. The 24M results demonstrate that 10 kHz SCS provides significant, durable reductions in pain and pain-associated effects on sleep and quality of life. In addition, the observed improvements in neurological function highlight the unique disease-modifying potential of 10 kHz SCS for PDN. Infection risk can be a concern for diabetic patients. However, the infection rate of 5.2% observed in this study is within the range reported for SCS in non-diabetic patients (2.5-10%)⁹, indicating that SCS can be a safe treatment option for PDN patients. Taken together, the results from this study support that 10 kHz SCS can provide safe, durable pain and symptom relief for PDN patients, while offering the potential for neurological improvements.

References: 1. CDC. National Diabetes Statistics Report; Accessed May 2022
2. Pop-Busui et al. ADA Clinical Compendia Series 2022
3. Feldman et al. Nat Rev Dis Primers 2019; 5(1):41
4. Finnerup et al. Lancet Neurol 2015; 14(2):162
5. Slangen et al. Diabetes Care 2014; 37(11):3016
6. de Vos et al. Pain 2014; 155(11):2426
7. Petersen et al. Diabetes Care 2022; 45(1):e3
8. Kapural et al. Neurosurgery 2016; 79(5):667
9. Eldabe et al. Pain Med 2016; 17(2):325