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Randomized Controlled Trial
. 2023 Sep:203:110865.
doi: 10.1016/j.diabres.2023.110865. Epub 2023 Aug 1.

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial

Erika A Petersen  1 , Thomas G Stauss  2 , James A Scowcroft  3 , Michael J Jaasma  4 , Elizabeth S Brooks  4 , Deborah R Edgar  5 , Judith L White  6 , Shawn M Sills  7 , Kasra Amirdelfan  8 , Maged N Guirguis  9 , Jijun Xu  10 , Cong Yu  11 , Ali Nairizi  12 , Denis G Patterson  12 , Kostandinos C Tsoulfas  2 , Michael J Creamer  13 , Vincent Galan  14 , Richard H Bundschu  15 , Neel D Mehta  16 , Dawood Sayed  17 , Shivanand P Lad  18 , David J DiBenedetto  19 , Khalid A Sethi  20 , Johnathan H Goree  21 , Matthew T Bennett  20 , Nathan J Harrison  9 , Atef F Israel  3 , Paul Chang  14 , Paul W Wu  22 , Charles E Argoff  23 , Christian E Nasr  24 , Rod S Taylor  25 , David L Caraway  4 , Nagy A Mekhail  26
Affiliations
Randomized Controlled Trial

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial

Erika A Petersen et al. Diabetes Res Clin Pract. 2023 Sep.

Abstract

Aims: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN).

Methods: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding.

Results: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection.

Conclusions: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN.

Trial registration: ClincalTrials.gov Identifier, NCT03228420.

Keywords: Diabetes mellitus; Neuropathy; Painful diabetic neuropathy; Sensory function; Spinal cord stimulation.

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Conflict of interest statement

Declaration of competing interest Author Erika A. Petersen has received consulting fees from Abbott Laboratories, Biotronik, Boston Scientific, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, Presidio Medical, Saluda, and Vertos Medical, research support from Mainstay, Medtronic Neuromodulation, Nalu Medical, Neuros Medical, Nevro Corp, ReNeuron, Saluda, and SPR, and stock options from neuro42 and SynerFuse. Author Thomas G. Stauss has received research support from Nevro Corp. Author James A. Scowcroft has received research support from Boston Scientific, Nevro Corp, Saluda Medical, and Vertiflex. Author Michael J. Jaasma is an employee of Nevro Corp. Author Elizabeth S. Brooks was an employee of Nevro Corp during her contributions to the work associated with this manuscript. Author Deborah R. Edgar received consulting fees from Nevro in her capacity as an independent medical writer. Author Judith L. White has received consulting fees from California Institute for Biomedical Research and Eli Lilly and research support from Nevro Corp. Author Shawn M. Sills has received research support from Nevro Corp. Author Kasra Amirdelfan has received consulting fees from Biotronik, Medtronic, Nalu Medical, Nevro Corp, and Saluda Medical, as well as research support from Biotronik, IPM Medical Group, Nevro Corp, Saluda Medical, SPR Therapeutics, and Vivex Biologics. Author Maged N. Guirguis has received consulting fees from Abbott Laboratories, Avanos Medical, Avertis Pharmacy, Boston Scientific, Nevro Corp, and Saluda Medical, as well as research support from Abbott Laboratories, Avanos Medical, Boston Scientific, Nalu Medical, Neuros Medical, Nevro Corp, and Saluda Medical. Author Jijun Xu has received research support from the Cleveland Clinic Velosano Program, the National Institutes of Health, the Steve and Melody Golding Foundation, and Nevro Corp. Author Cong Yu has received research support from Nevro Corp. Author Ali Nairizi has received consulting fees from Aurora Spine, Flowonix, and Nevro Corp as well as research support from Nevro Corp. Author Denis G. Patterson has received consulting fees from Abbott Laboratories, AIS Healthcare, Allergan, Amgen, Aurora Spine, CornerLoc, Flowonix, Lundbeck, Pajunk Medical, Saluda Medical, Spark Biomedical, and Vertos Medical, research support from Abbott Laboratories, Aurora Spine, Flowonix, Nevro Corp, and Saluda Medical, speakers’ bureau or honoraria from Abbott Laboratories, Allergan, Amgen, CornerLoc, Lundbeck, Saluda Medical, and Vertos Medical, and stock options from CornerLoc. Author Michael J. Creamer has received research support from Nevro Corp. Author Vincent Galan has received research support from Biotronik, Medtronic, Nevro Corp, PainTEQ, SPR Therapeutics, and St. Jude. Author Richard H. Bundschu has received research support from Nevro Corp. Author Neel D. Mehta has received consulting fees from Averitas, Nevro Corp, and Salix Pharmaceuticals, as well as research support from Boston Scientific and Nevro Corp. Author Dawood Sayed has received consulting fees from Abbott Laboratories, Boston Scientific, Flowonix, Medtronic, Nevro Corp, Vertiflex, and Vertos Medical, as well as research support from Abbott Laboratories, Biotronic, Nevro Corp, Vertiflex, and Vertos Medical. Author Shivanand P. Lad has received consulting fees from Nevro Corp and research support from Nevro Corp. Author David J. DiBenedetto has received research support from Nevro Corp, as well as funding for serving as principal investigator of a study supported by SPR Therapeutics paid to his institution. Author Khalid A. Sethi has received research support from Nevro Corp. Author Johnathan H. Goree has received consulting fees from Abbott Laboratories and Stratus Medical. Author Paul W. Wu has received research support from Nevro Corp. Author Charles E. Argoff has received consulting fees from AbbVie, Amgen, Biohaven, Clexio Biosciences, Collegium, Eli Lilly, Elsevier, Flowonix, Gene Pharma, Lundbeck, Nevro Corp, Novartis, Pfizer, SK Life Science, Teva Pharmaceutical, and Vertex as well as research support from AbbVie, Allergan, Amgen, Daiichi Sankyo, Eli Lilly, Novartis, Teva Pharmaceutical, and Vertex Pharmaceuticals. Author Christian E. Nasr has received consulting fees from Exelixis, Neurogastrx, and Nevro Corp as well as research support from Nevro Corp. Author Rod S. Taylor has received consulting fees from Nevro Corp, Medtronic, and Saluda Medical. Author David L. Caraway is an employee of Nevro Corp. Author Nagy A. Mekhail has received consulting fees from Nevro Corp, Relievant Medsystems, Saluda Medical, Sollis Therapeutics, and Vertos Medical, as well as research support from Avanos Medical, Mesoblast, Neuros Medical, and Nevro Corp.

Figures

Fig. 1.
Fig. 1.
Disposition of All Screened Participants.
Fig. 2.
Fig. 2.
Lower Limb Pain Relief. Mean lower limb pain VAS scores (0–10 cm scale) during (A) the 6-month randomized phase and (B) the 24-month postimplantation phase. (C) Individual percentage pain reduction from preimplantation for all implanted participants who completed 24 months of follow-up: 90.1% (95% CI, 84.1%–94.0%; 128 of 142) were responders (≥50% pain reduction from preimplantation). Error bars indicate 95% CI; *P <.001 vs baseline or preimplantation; #P <.001 vs CMM alone; $P =.023 vs baseline; ^P =.003 vs baseline.
Fig. 3.
Fig. 3.
Patient-Reported Neuropathic Pain. The Douleur Neuropathique 4 Questions (DN4) scale is a validated neuropathic pain measure, with a score of ≥4 consistent with a clinical diagnosis of PDN. (A) Mean DN4 scores and (B) proportion of participants with DN4 <4 during the 6-month randomization phase. (C) Mean DN4 scores and (D) proportion of participants with DN4 <4 during the 24-month postimplantation phase. Error bars indicate 95% CI; *P <.001 vs baseline or preimplantation; #P <.001 vs CMM alone.
Fig. 4.
Fig. 4.
Neurological Outcomes. Standardized neurological assessments were performed at baseline and follow-up visits, including motor, sensory, and reflex tests. (A) Proportion of participants with a clinically meaningful improvement in sensory, motor, or reflex function from study baseline (without deficit in any category) during the 6-month randomized phase. (B) Proportion of participants with a clinically meaningful improvement in sensory function from study baseline during the 6-month randomized phase. (C) Proportion of participants with a clinically meaningful improvement in sensory, motor, or reflex function from study baseline (without deficit in any category) during the 24-month postimplantation phase. (D) Proportion of participants with a clinically meaningful improvement in sensory function from study baseline during the 24-month postimplantation phase. Error bars indicate 95% CI; #P <.001 vs CMM alone; ^P =.048 vs CMM crossover to 10 kHz SCS+CMM; &P =.021 vs CMM crossover to 10 kHz SCS+CMM.
Fig. 5.
Fig. 5.
Health-Related Quality of Life (HRQoL) and Pain Interference with Sleep. The EuroQol 5-Dimensional 5-Level Questionnaire (EQ-5D-5L) measures HRQoL. The Pain and Sleep Questionnaire Three-Item Index (PSQ-3) assesses how often pain interferes with sleep (0-never; 10-always). Mean EQ-5D-5L index values during (A) the 6-month randomized phase and (B) the 24-month postimplantation phase. Mean PSQ-3 scores during (C) the 6-month randomized phase and (D) the 24-month postimplantation phase. Error bars indicate 95% CI; *P <.001 vs baseline or preimplantation; #P <.001 vs CMM alone; ^P =.006 vs CMM crossover to 10 kHz SCS+CMM; $P =.012 vs CMM crossover to 10 kHz SCS+CMM; &P =.020 vs CMM crossover to 10 kHz SCS+CMM.
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