IMPORTANCE Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments.OBJECTIVE To determine whether 10-kHz spinal cord stimulation (SCS) improves outcomes for patients with refractory painful diabetic neuropathy (PDN). DESIGN, SETTING, AND PARTICIPANTSThe prospective, multicenter, open-label SENZA-PDN randomized clinical trial compared conventional medical management (CMM) with 10-kHz SCS plus CMM. Participants with PDN for 1 year or more refractory to gabapentinoids and at least 1 other analgesic class, lower limb pain intensity of 5 cm or more on a 10-cm visual analogue scale (VAS), body mass index (calculated as weight in kilograms divided by height in meters squared) of 45 or less, hemoglobin A 1c (HbA 1c ) of 10% or less, daily morphine equivalents of 120 mg or less, and medically appropriate for the procedure were recruited from clinic patient populations and digital advertising. Participants were enrolled from multiple sites across the US, including academic centers and community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional crossover at 6 months. Screening 430 patients resulted in 214 who were excluded or declined participation and 216 who were randomized. At 6-month follow-up, 187 patients were evaluated.INTERVENTIONS Implanted medical device delivering 10-kHz SCS. MAIN OUTCOMES AND MEASURESThe prespecified primary end point was percentage of participants with 50% pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary end points were tested hierarchically, as prespecified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA 1c over 6 months. RESULTSOf 216 randomized patients, 136 (63.0%) were male, and the mean (SD) age was 60.8 (10.7) years. Additionally, the median (interquartile range) duration of diabetes and peripheral neuropathy were 10.9 (6.3-16.4) years and 5.6 (3.0-10.1) years, respectively. The primary end point assessed in the intention-to-treat population was met by 5 of 94 patients in the CMM group (5%) and 75 of 95 patients in the 10-kHz SCS plus CMM group (79%; difference, 73.6%; 95% CI, 64.2-83.0; P < .001). Infections requiring device explant occurred in 2 patients in the 10-kHz SCS plus CMM group (2%). For the CMM group, the mean pain VAS score was 7.0 cm (95% CI, 6.7-7.3) at baseline and 6.9 cm (95% CI, 6.5-7.3) at 6 months. For the 10-kHz SCS plus CMM group, the mean pain VAS score was 7.6 cm (95% CI, 7.3-7.9) at baseline and 1.7 cm (95% CI, 1.3-2.1) at 6 months. Investigators observed neurological examination improvements for 3 of 92 patients in the CMM group (3%) and 52 of 84 in the 10-kHz SCS plus CMM group (62%) at 6 months (difference, 58.6%; 95% CI, 47.6-69.6; P < .001).CONCLUSIONS AND RELEVANCE Substantial pain relief and improved health-related quality of life sustained over 6 months demonstrates 10-kHz SCS can s...

ObjectiveTo evaluate clinical outcomes and health care utilization at 12 months post spinal cord stimulator (SCS) implantation compared with baseline and a matched sample of patients receiving conventional medical management (CMM) for the treatment of low back and lower extremity pain.PatientsA retrospective study of patients with at least 24 months of active treatment at an interdisciplinary community pain center between December 1, 2014 and December 31, 2017. Thirty-two patients receiving implantation of a high-frequency (10 kHz) SCS and 64 patients receiving CMM were identified through propensity matching at a ratio of 2:1.MethodsData were extracted from medical records, including pain severity, prescribed opioid dose in morphine milligram equivalents, patient perception of disability, and volume of interventional pain procedures and total office visits to the pain center.ResultsReductions in opioid dose were significantly greater for the SCS group than the CMM group. The 26.2 mg morphine equivalent dose reduction represents a 28% reduction from baseline, with 71.4% of those prescribed opioids in the SCS group reducing their dose at 12 months post-implant. Among those with SCS, there were significant within-group reductions in numerical pain score for low back and lower extremity pain, reducing by 46.2% and 50.9% from baseline, respectively. Change in functional pain score was not significant for either SCS group or CMM. Both groups had significant within-group reduction in disability. Reduction of interventional procedure volume was significant for both groups with a greater reduction observed in the SCS group. Office visit volume reduction was significant for the CMM group, but this was not a significant difference from the SCS group.ConclusionsResults support the efficacy of 10 kHz SCS for analgesia, reduction of opioid utilization, reduction of interventional pain procedures, and patient perception of disability.

Stimulation of murine resident peritoneal cells (RPCs) by encapsulated strain 52 and acapsular strain 602 of Cryptococcus neoformans was compared. Fresh serum was required for fungistasis of both strains. Encapsulated organisms were killed only if the RPCs were activated with gamma interferon (IFN-y) or if the organisms were opsonized with anticapsular immunoglobulin G (IgG). In contrast, acapsular organisms were killed by unactivated RPCs, with enhanced killing seen if the cells were activated with IFN-y. Except for unopsonized strain 52, all organisms of both strains were phagocytosed. The respiratory burst was stimulated in unactivated and IFN-y-activated RPCs by encapsulated strain 52 only if organisms were opsonized with both IgG and serum. In contrast, the burst was stimulated by acapsular strain 602, with or without opsonization. Only unopsonized strain 602 stimulated significant lysosomal enzyme release. Nitrite synthesis by unactivated RPCs was seen only if strain 52 was opsonized with anticapsular IgG or if strain 602 was opsonized with serum. If RPCs were activated with IFN-y, then serum-opsonized strain 52 was also able to stimulate nitrite synthesis. Thus, RPC killing, phagocytosis, respiratory burst, lysosomal enzyme release, and nitrite synthesis following challenge by both unopsonized and opsonized with serum or anticapsular IgG strains 52 and 602 varied according to the surface properties of the organisms, the state of activation of the RPCs, and the particular RPC event studied. However, stimulation of nitrite synthesis was the only RPC event which correlated with killing of both strains.