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Dorsal Root Ganglion Stimulation as a Salvage Therapy Following Failed Spinal Cord Stimulation

Open AccessPublished:June 25, 2022DOI:https://doi.org/10.1016/j.neurom.2022.04.050

      Abstract

      Introduction

      Spinal cord stimulation (SCS) can provide long-term pain relief for various chronic pain conditions, but some patients have no relief with trial stimulation or lose efficacy over time. To “salvage” relief in patients who do not respond or have lost efficacy, alternative stimulation paradigms or anatomical targets can be considered. Dorsal root ganglion stimulation (DRG-S) has a different mechanism of action and anatomical target than SCS.

      Objectives

      We assessed DRG-S salvage therapy outcomes in patients who did not respond to SCS or had lost SCS efficacy.

      Materials and Methods

      We retrospectively included consecutive patients from 2016 to 2020 who were salvaged with DRG-S after failed SCS trials (<50% pain reduction) or who had lost efficacy after permanent SCS. We compared numerical rating scale (NRS) pain, Oswestry disability index (ODI), health-related quality of life (EuroQol five-dimensions five-level), and oral morphine equivalent (OME) opioid requirements before DRG-S salvage and at patients’ last follow-up.

      Results

      A total of 60 patients who had failed SCS were salvaged with DRG-S. The mean age was 56 ± 12 years, and the most common diagnoses were complex regional pain syndrome (n = 24) and failed back surgery syndrome (n = 24). The most common failed modalities included tonic (n = 32), Burst (n = 18), and high-frequency (n = 10) SCS. The median follow-up duration of salvage DRG-S was 34 months. With DRG-S, NRS decreased (8.7 ± 1.2 to 3.8 ± 2.1), and OME declined (median 23 mg to median 15 mg), whereas EuroQol 5D scores increased (0.40 ± 0.15 to 0.71 ± 0.15), and ODI improved (64 ± 14% to 31 ± 18%) (all p < 0.05).

      Conclusions

      DRG-S can be used in patients with chronic pain who have previously failed to receive persistent benefit from SCS.

      Keywords

      Introduction

      Since its initial use in 1967, indications for spinal cord stimulation (SCS) have expanded and patient-related outcomes improved. Material and software refinements have provided smaller batteries, Bluetooth-enabled wireless trials, remote programming, magnetic resonance imaging compatibility, and closed-loop feedback systems. Nonetheless, a portion of patients treated with tonic SCS (t-SCS) applied to the dorsal columns eventually undergo device explant, most commonly owing to the loss of therapeutic effect, with rates as high as 43% to 73%
      • Pope J.E.
      • Deer T.R.
      • Falowski S.
      • et al.
      Multicenter retrospective study of neurostimulation with exit of therapy by explant.
      ,
      • Dupré D.A.
      • Tomycz N.
      • Whiting D.
      • Oh M.
      Spinal cord stimulator explantation: motives for removal of surgically placed paddle systems.
      at long-term follow-up.
      Newer paresthesia-free waveforms for SCS were demonstrated to be superior to t-SCS.
      • Deer T.
      • Slavin K.V.
      • Amirdelfan K.
      • et al.
      Success using neuromodulation with BURST (SUNBURST) study: results from a prospective, randomized controlled trial using a novel burst waveform.
      ,
      • Kapural L.
      • Yu C.
      • Doust M.W.
      • et al.
      Novel 10-kHz high-frequency therapy (HF10 therapy) is superior to traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: the SENZA-RCT randomized controlled trial.
      The introduction of new waveforms and neural targets provided an opportunity to recapture therapeutic efficacy for those who lost benefit with t-SCS, a term coined “salvage” therapy. Before new waveform technology, salvage outcomes were poor—a 2015 Marketscan review of 21,672 patients demonstrated that only 27% of second-time trials and 14% of third-time trials proceeded to implantation.
      • Huang K.T.
      • Martin J.
      • Marky A.
      • et al.
      A national survey of spinal cord stimulation trial-to-permanent conversion rates.
      Newer SCS modalities including high-frequency SCS (Hf-SCS), Burst-SCS, and high-density SCS used as salvage therapies have demonstrated significantly improved results.
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      • De Jaeger M.
      • Goudman L.
      • Brouns R.
      • et al.
      The long-term response to high-dose spinal cord stimulation in patients with failed back surgery syndrome after conversion from standard spinal cord stimulation: an effectiveness and prediction study.
      • Hunter C.W.
      • Carlson J.
      • Yang A.
      • et al.
      BURST(able): a retrospective, multicenter study examining the impact of spinal cord stimulation with burst on pain and opioid consumption in the setting of salvage treatment and “upgrade”.
      Dorsal root ganglion stimulation (DRG-S) is a targeted form of the stimulation paradigm that applies an electrical field to the somata of afferent nerve fibers. DRG-S has demonstrated efficacy in the treatment of complex regional pain syndrome (CRPS) in its lone randomized controlled trial.
      • Deer T.R.
      • Levy R.M.
      • Kramer J.
      • et al.
      Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.
      Results from smaller studies treating likely mixed nociceptive/neuropathic pain conditions such as postsurgical joint pain or low back pain also have reported promising results.
      • Chapman K.B.
      • Groenen P.S.
      • Patel K.V.
      • Vissers K.C.
      • van Helmond N.
      T12 dorsal root ganglion stimulation to treat chronic low back pain: a case series.
      • Morgalla M.H.
      • Fortunato M.
      • Lepski G.
      • Chander B.S.
      Dorsal root ganglion stimulation (DRGS) for the treatment of chronic neuropathic pain: a single-center study with long-term prospective results in 62 cases.
      • Kallewaard J.W.
      • Edelbroek C.
      • Terheggen M.
      • Raza A.
      • Geurts J.W.
      A prospective study of dorsal root ganglion stimulation for non-operated discogenic low back pain.
      As the experience with DRG-S grows, the understanding of mechanistic and therapeutic differences between DRG-S and SCS also is increasing. Compared with SCS, DRG-S has non–γ-aminobutyric acid–mediated inhibitory mechanisms,
      • Koetsier E.
      • Franken G.
      • Debets J.
      • et al.
      Mechanism of dorsal root ganglion stimulation for pain relief in painful diabetic polyneuropathy is not dependent on GABA release in the dorsal horn of the spinal cord.
      lower energy requirements for efficacy,
      • Chapman K.B.
      • Yousef T.A.
      • Vissers K.C.
      • van Helmond N.
      • D Stanton-Hicks M.
      Very low frequencies maintain pain relief from dorsal root ganglion stimulation: an evaluation of dorsal root ganglion neurostimulation frequency tapering.
      the potential for delayed washout,
      • Koetsier E.
      • Franken G.
      • Debets J.
      • et al.
      Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy.
      potentially less habituation,
      • Levy R.M.
      • Mekhail N.
      • Kramer J.
      • et al.
      Therapy habituation at 12 months: spinal cord stimulation versus dorsal root ganglion stimulation for complex regional pain syndrome type I and II.
      and more targeted dermatomal coverage.
      • Deer T.R.
      • Levy R.M.
      • Kramer J.
      • et al.
      Comparison of paresthesia coverage of patient’s pain: dorsal root ganglion vs. spinal cord stimulation. An ACCURATE study sub-analysis.
      DRG-S uses a very low-frequency, tonic waveform delivered at subthreshold and paresthesia-free levels.
      • Verrills P.
      • Mitchell B.
      • Vivian D.
      • Cusack W.
      • Kramer J.
      Dorsal root ganglion stimulation is paresthesia-independent: a retrospective study.
      These parameters are not efficacious when applied on the dorsal columns.
      • Wolter T.
      • Kiemen A.
      • Porzelius C.
      • Kaube H.
      Effects of sub-perception threshold spinal cord stimulation in neuropathic pain: a randomized controlled double-blind crossover study.
      When considering DRG-S as a salvage therapy for SCS, DRG-S not only allows for a new anatomical target but also uses underlying mechanisms unlikely to be maladapted from previous exposure to a neuromodulatory system.
      Data on DRG-S as a salvage therapy for SCS have been limited to case reports.
      • Yang A.
      • Hunter C.W.
      Dorsal root ganglion stimulation as a salvage treatment for complex regional pain syndrome refractory to dorsal column spinal cord stimulation: a case series.
      ,
      • Goebel A.
      • Lewis S.
      • Phillip R.
      • Sharma M.
      Dorsal root ganglion stimulation for complex regional pain syndrome (CRPS) recurrence after amputation for CRPS, and failure of conventional spinal cord stimulation.
      The aim of this study was to determine if DRG-S is an option for patients who do not respond to SCS trial stimulation or who have lost SCS efficacy over time.

      Materials and Methods

      This was a multicenter retrospective review, and institutional review board approval or waiver from each participating institution was obtained before commencing the retrospective chart review. All patients’ data were deidentified before placement in a central database for analysis after an institutional review board exemption was acquired for data sharing. This report adheres to the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.
      • Vandenbroucke J.P.
      • Von Elm E.
      • Altman D.G.
      • et al.
      Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.

      Patients

      We included consecutive patients (age >18 years) who had experienced failed SCS trials (<50% pain reduction) or who had lost SCS efficacy after permanent implantation regardless of SCS waveform, and who were found to be appropriate candidates for DRG-S therapy. Eligibility for DRG-S was established after excluding internal pulse generator or lead malfunction, and standard-of-care measures to mitigate SCS failure were taken, including lead placement optimization and reprogramming. Patients who underwent a subsequent DRG-S trial between April 1, 2016, and September 30, 2020, were included. We did not include patients who underwent DRG-S implantation because their underlying pain condition had changed to a different anatomical area or who had developed a new pain condition in a different anatomical area.

      DRG-S Implantation

      The implanters used the contemporary implant technique for lead placement.
      • Verrills P.
      Dorsal root ganglion stimulation for pain control.
      ,
      • Vancamp T.
      • Levy R.M.
      • Peña I.
      • Pajuelo A.
      Relevant anatomy, morphology, and implantation techniques of the dorsal root ganglia at the lumbar levels.
      For levels above the sacrum, this approach starts with needle puncture at the lateral aspect of the pedicle two levels below the target foramen, using a contralateral approach. Epidural strain relief loops were placed in an “S” configuration, with multiple loops in the inferior and superior aspects of the “S.” Sacral leads were placed through a retrograde approach, with strain relief loops placed in the sacral canal and/or extracanalicular, depending on implanter preference. The implantable pulse generator was placed in the gluteal region. Figure 1 shows exemplar implantations.
      Figure thumbnail gr1
      Figure 1DRG-S lead placement. a. DRG-S salvage of a t-SCS paddle lead for foot pain. L4, L5, and S1 leads were placed to cover the foot, and a T12 lead was placed for right-sided low back pain. b and c. A right-sided T12 and S1 DRG-S trial over existing failed SCS. Of note, our authors trial with unilateral lead placement.

      Data Collection

      Data collected included demographics, diagnoses, medications, pain sites, previous SCS system manufacturer and waveform, date of DRG-S trial, date of DRG-S implantation, and lead location(s). Patient-reported outcomes of numeric rating scale (NRS) pain, Oswestry disability index (ODI), and EuroQol five-dimensions five-level (EQ-5D-5L) health-related quality of life were retrieved. Data were gathered from before the DRG-S trial and at patients’ last visits. Any DRG-S complications, revision, or explantation procedures were retrieved from the medical records as well.

      Outcomes

      Primary outcomes were NRS pain, ODI, and EQ-5D-5L measured at the last follow-up. For NRS scores, at least 30% improvement from baseline to last follow-up was considered to constitute a minimal clinically important difference (MCID).
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      ,
      • Farrar J.T.
      • Portenoy R.K.
      • Berlin J.A.
      • Kinman J.L.
      • Strom B.L.
      Defining the clinically important difference in pain outcome measures.
      Patients were divided into three distinct groups, based on their responder status to DRG-S permanent implantation: poor responders (<30% pain relief from baseline), moderate responders (30%–49% pain relief), and excellent responders (≥50% pain relief). ODI scores were stratified into minimal disability (0%–20%), moderate disability (21%–40%), severe disability (41%–60%), and bed bound (81%–100%), as previously described.
      • Yates M.
      • Shastri-Hurst N.
      The Oswestry disability index.
      Secondary endpoints included opioid requirement in oral morphine equivalent (OME) in milligram and DRG-S complications at the last follow-up. Oral morphine equivalents were calculated using the United States Centers for Disease Control and Prevention opioid conversion guidelines.
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain — United States, 2016.

      Statistical Analysis

      Descriptive statistics of mean with SD, median with interquartile range, and n (%) were used, dependent on the type of variable and its distribution. Normality of data was assessed using the Shapiro-Wilk test. Comparisons between pre–DRG-S baseline and last follow-up were made using paired t-tests or Wilcoxon signed-rank tests. We compared baseline and last follow-up measurements from all patients who underwent a DRG-S trial (including patients who failed the trial or who had their DRG-S system eventually explanted) to provide an analysis of the real-world results of DRG-S as a salvage therapy when the clinical intention was to treat a patient with DRG-S. We performed separate secondary analyses on clinical outcomes in patients treated for the classical Food and Drug Administration–approved indication of CRPS and patients without CRPS. Kaplan Meier estimation was used to assess DRG-S system explantation rates. Significance was defined as a two-sided p < 0.05. All statistical analyses were performed using SPSS (version 27, IBM, Armonk, NY).

      Results

      A total of 60 patients who had failed SCS and who were salvaged with DRG-S were included. Trials lasted five to seven days, with a 50% pain reduction used as the threshold for proceeding to implant (Fig. 2). Five patients underwent an “on table” trial and were implanted upon a successful intraoperative response. There were four patients who did not undergo device implantation despite a successful trial; one halted treatment owing to a malignancy; one died of unrelated causes while awaiting implant; and two were denied coverage for permanent implantation by their health insurance. Two patients salvaged with DRG-S ultimately underwent device explantation for lack of long-term efficacy at 21 and 28 months after implantation. The median time to last follow-ups for all patients was 34 months (interquartile range 21–42 months).
      Figure thumbnail gr2
      Figure 2Flowchart of patients included in the study.

      Demographic and Clinical Characteristics

      The patients who underwent trials included 34 women (57%) and 26 men (43%) (Table 1). The mean age was 56 ± 12 years. The most common primary pain diagnoses were CRPS (n = 24, 40%), followed by failed back surgery syndrome (n = 24, 40%). The remaining 12 patients had pelvic pain, radicular pain, nonsurgical low back pain, peripheral neuropathy, and mechanical knee pain.
      Table 1Demographic and Clinical Characteristics of Patients Who Had Failed SCS Who Underwent Attempted Salvage With DRG-S.
      Demographic and clinical characteristicsPatients, N = 60
       Sex, women/men, n/n (%/%)34/26 (57/43)
       Age, y, mean ± SD56 ± 12
      Clinical characteristics
       Primary diagnosis, n (%)
      CRPS24 (40)
      Failed back surgery syndrome24 (40)
      Pelvic pain3 (5)
      Radicular pain3 (5)
      Nonsurgical low back pain4 (7)
      Peripheral neuropathy1 (2)
      Mechanical knee pain1 (2)
       Previously failed type of SCS, n (%)
      t-SCS32 (53)
      Burst-SCS17 (28)
      Hf-SCS10 (17)
      Both t-SCS and Hf-SCS1 (2)
      DRG-S treatment characteristics
       DRG-S lead location, n (%)
      Percentage summate to >100% owing to placement of multiple leads in patients.
      T1232 (53)
      L15 (8)
      L25 (8)
      L36 (10)
      L411 (18)
      L512 (20)
      S146 (77)
      S24 (7)
      S31 (2)
      Percentage summate to >100% owing to placement of multiple leads in patients.
      The most common SCS stimulation types that patients had used before they underwent DRG-S were t-SCS (n = 32, 53%), followed by Burst-SCS (n = 17, 28%), and Hf-SCS (n = 10, 17%). One patient had both failed t-SCS and failed Hf-SCS.

      DRG-S Salvage Trials

      On average, 3.1 DRG-S leads were placed per patient; the most common lead level was S1 (n = 77 leads; Table 1). In 31 patients, an S1 lead was placed bilaterally, and in 15 patients, an S1 lead was placed unilaterally. Leads at T12 (n = 57 leads) also were commonly placed; in 25 patients, a T12 lead was placed bilaterally, and in seven patients, a T12 lead was placed unilaterally.

      Primary Outcome—Long-term Follow-up, Patient-Reported Outcomes

      All patient-reported outcome indices improved with DRG-S as salvage therapy. In particular, the NRS pain scores decreased from a baseline of 8.7 ± 1.2 before DRG-S trial to 3.8 ± 2.1 (p < 0.0001) at patients’ last follow-up (Fig. 3a). This represents a 56% reduction in NRS for the cohort of the study. When analyzed individually, 49 patients (82%) had a ≥30% improvement (MCID defined as ≥30% improvement), whereas 41 patients (68%) were excellent responders and reported a ≥50% improvement in their pain (Fig. 4).
      Figure thumbnail gr3
      Figure 3(a) Pain, (b) disability, and (c) health-related quality of life at baseline and at last follow-up after attempted salvage with DRG-S in patients who previously had failed SCS. Bars represent means with SD. Lines represent individual patients. ∗∗∗∗p < 0.0001 based on paired t-test between baseline and last follow-up.
      Figure thumbnail gr4
      Figure 4Individual patient percent change in NRS pain score from preoperative baseline and at last follow-up after attempted salvage with DRG-S. The MCID pain relief boundary, defined as a 30% decrease, is depicted.
      The mean ODI scores improved from 64 ± 14% to 31 ± 18% (p < 0.0001; Fig. 3b), signifying an on average improvement from mostly crippled to moderate disability. Figure 5 displays the proportions of disability categories at baseline and at last follow-up after attempted salvage with DRG-S, when all patients were analyzed individually. Like the improvement in disability, the mean EQ-5D-5L scores improved from 0.40 ± 0.15 at baseline to 0.71 ± 0.15 (p < 0.0001) at the last follow-up, which is a 77% improvement (Fig. 3c).
      Figure thumbnail gr5
      Figure 5Proportions of disability categories at baseline and at last follow-up after attempted salvage with DRG-S in patients who previously had failed SCS. Disability was measured using the ODI and stratified based on the categories minimal disability (0%–20%), moderate disability (21%–40%), severe disability (41%–60%), and bed bound (81%–100%).
      When clinical outcomes were analyzed separately in patients with CRPS (Fig. 6) and without CRPS (Fig. 7), comparable results were encountered. In patients with CRPS and without CRPS, respectively, the mean NRS pain scores (8.5 ± 1.3 to 3.8 ± 2.7 and 8.8 ± 1.2 to 3.9 ± 1.8), ODI scores (57 ± 16% to 30 ± 23% and 70 ± 13% to 34 ± 15%), and EQ-5D-5L scores (0.48 ± 0.13 to 0.73 ± 0.17 and 0.33 ± 0.16 to 0.68 ± 0.16) improved similarly and statistically significantly from baseline to the last follow-up (all p < 0.001).
      Figure thumbnail gr6
      Figure 6(a) Pain, (b) disability, and (c) health-related quality of life at baseline and at last follow-up after attempted salvage with DRG-S in patients with CRPS who previously had failed SCS. Bars represent means with SD. Lines represent individual patients. ∗∗∗∗p < 0.0001 based on paired t-test between baseline and last follow-up. ∗∗∗p < 0.001 based on paired t-test between baseline and last follow-up.
      Figure thumbnail gr7
      Figure 7(a) Pain, (b) disability, and (c) health-related quality of life at baseline and at last follow-up after attempted salvage with DRG-S in patients without CRPS who previously had failed SCS. Bars represent means with SD. Lines represent individual patients. ∗∗∗∗p < 0.0001 based on paired t-test between baseline and last follow-up.

      Opioid Analgesia Requirements

      The median opioid analgesia requirement before DRG-S salvage was 23 mg OME (interquartile range 0–52.5 mg OME), and this was reduced to a median of 15 mg OME (interquartile range 0–45 mg OME) at long-term follow-up (p = 0.015).

      Adverse Events

      Adverse events with DRG-S included two lead migrations and three lead fractures. One patient experienced a lead migration followed by a lead fracture. All migrations occurred in unanchored leads. All but one patient with complications underwent revision surgery with a restoration of therapy efficacy, although two patients eventually had the DRG-S device explanted at over a year after revision. One patient who had a lead fracture continued to have good pain coverage and did not have her system revised. In addition, two patients required an additional lead placed for better pain coverage. The estimated explantation rate at one-year, two-year, and three-year follow-up was 0%, 2.6%, and 4.7%, respectively.

      Discussion

      The development of SCS habituation is a poorly understood process that leads to the loss of efficacy and, in some clinical settings, to device explantation. This retrospective review assessed DRG-S for its ability to salvage failed or habituated t-SCS, Burst-SCS, and Hf-SCS. By targeting a distinct anatomical location and using a neurochemically based mechanism of action, the cohort salvaged with DRG-S demonstrated improvement in pain, disability, and quality of life at long-term follow-up.

      Trial Success

      DRG-S as salvage therapy in this study demonstrated a 90% (n = 56/60) trial-to-implantation rate for patients who had failed SCS, regardless of previous SCS waveform. The four patients who underwent trials and did not undergo implantation had successful trials in terms of improvement in pain and quality of life but were not implanted for reasons unrelated to the trial success. This result indicates that patients who responded to SCS and subsequently lost efficacy are likely to respond to DRG-S.

      Patient-Reported Outcomes With Salvage Therapy in Previous Studies

      With the inception of novel SCS waveforms, various paradigms have been retrospectively studied for their efficacy as a salvage therapy for t-SCS. Salvage outcomes with various new SCS modalities are summarized in Table 2. When combining the reported counts of patients who received a >50% relief from salvage Hf-SCS studies in Table 2, this summates to 69% of patients receiving >50% pain relief (n = 136/197 patients).
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      ,
      • Van Buyten J.P.
      • Al-Kaisy A.
      • Smet I.
      • Palmisani S.
      • Smith T.
      High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study.
      • Kapural L.
      • Sayed D.
      • Kim B.
      • Harstroem C.
      • Deering J.
      Retrospective assessment of salvage to 10 kHz spinal cord stimulation (SCS) in patients who failed traditional SCS therapy: RESCUE study.
      • Russo M.
      • Verrills P.
      • Mitchell B.
      • Salmon J.
      • Barnard A.
      • Santarelli D.
      High frequency spinal cord stimulation at 10 kHz for the treatment of chronic pain: 6-month Australian clinical experience.
      This study differed from these previous efforts in that DRG-S was used to salvage not only t-SCS but also Burst-SCS and Hf-SCS waveforms. In the present salvage cohort, 68% of patients sustained a ≥50% pain relief with DRG-S at a median 34-month follow-up, and our follow-up was thus substantially longer than previous studies. This stability is important, considering that habituation to neuromodulation therapies develops over time.
      Table 2Comparison of Findings From Current Salvage Study With Previous Studies on Salvage Treatment of Patients Who Had Failed SCS.
      Study authorsYearNo. of patients enrolledSalvage modalityTrial responsePain reliefOther endpointsFollow-up duration
      De Jaeger et al
      • De Jaeger M.
      • Goudman L.
      • Brouns R.
      • et al.
      The long-term response to high-dose spinal cord stimulation in patients with failed back surgery syndrome after conversion from standard spinal cord stimulation: an effectiveness and prediction study.
      202078HD-SCS51% were nonresponder (n = 16) or lost to follow-up (n = 22)68% of patients reported a ≥2 decrease on 0–10 VASN/A12 mo
      Ghosh et al
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      202031Hf-SCSn = 28/31 (90%) trial to implantation ratio46% of patients reported a ≥50% pain reliefODI improved from 58 ± 4 at baseline to 39 ± 5 at last follow-up21 mo
      Hunter et al
      • Hunter C.W.
      • Carlson J.
      • Yang A.
      • et al.
      BURST(able): a retrospective, multicenter study examining the impact of spinal cord stimulation with burst on pain and opioid consumption in the setting of salvage treatment and “upgrade”.
      2020307Burst-SCSN/A (direct conversion)Average 18%–35% improvement in NRS89 patients on opioids before salvage therapy, 76 patients on opioids after salvage therapy12 mo
      Kapural et al
      • Kapural L.
      • Sayed D.
      • Kim B.
      • Harstroem C.
      • Deering J.
      Retrospective assessment of salvage to 10 kHz spinal cord stimulation (SCS) in patients who failed traditional SCS therapy: RESCUE study.
      2020105Hf-SCSN/A (direct conversion)

      1 explantation owing to infection
      81% of patients reported a ≥50% relief.

      90% reported a >30% relief
      47% in average opioid use at last follow-up12 mo
      Russo et al
      • Russo M.
      • Verrills P.
      • Mitchell B.
      • Salmon J.
      • Barnard A.
      • Santarelli D.
      High frequency spinal cord stimulation at 10 kHz for the treatment of chronic pain: 6-month Australian clinical experience.
      201676Hf-SCSn = 52/76 (68%) trial to implantation ratio55% of patients reported a ≥50% relief.

      Average reduction of 49% on VAS
      ODI improved from 41 at baseline to 33 at last follow-up6 mo
      Van Buyten et al
      • Van Buyten J.P.
      • Al-Kaisy A.
      • Smet I.
      • Palmisani S.
      • Smith T.
      High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study.
      201314Hf-SCSn = 11/14 (79%) trial successAverage 76% reduction in VAS62% of patients reduced opioid use at last follow up6 mo
      Current study202260DRG-Sn = 56/60 (90%) trial to implantation ratio69% of patients reported a ≥50% pain reliefEQ-5D-5L scores improved from 0.40 ± 0.15 at baseline to 0.71 ± 0.15 at last follow-up

      ODI improved from 64 ± 14% at baseline to 31 ± 18% at last follow-up
      34 mo
      HD-SCS, high-density SCS; N/A, not applicable; VAS, visual analogue scale.
      Regarding reports on disability in the existing salvage literature, Ghosh et al
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      documented an absolute improvement in ODI of 19 points (58%–39%) and Russo et al
      • Russo M.
      • Verrills P.
      • Mitchell B.
      • Salmon J.
      • Barnard A.
      • Santarelli D.
      High frequency spinal cord stimulation at 10 kHz for the treatment of chronic pain: 6-month Australian clinical experience.
      reported an absolute 8-point ODI improvement (41%–33%) in patients treated with Hf-SCS. In comparison, we observed a 33-point (64%–31%) reduction in disability, which represents an on average improvement across two disability classifications, from mostly crippled to moderate disability.
      Quality of life as measured by EQ-5D-5L improved 77% with DRG-S in this study (from 0.40 to 0.71). In addition, 100% of patients experienced at least an MCID (≥0.074) in EQ-5D-5L at last follow up.
      • Walters S.J.
      • Brazier J.E.
      Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D.
      These improvements are consistent with results from a pooled analysis of 90 patients with DRG-S implants who maintained an 82% (0.38–0.69) improvement at one year.
      • Huygen F.J.P.M.
      • Kallewaard J.W.
      • Nijhuis H.
      • et al.
      Effectiveness and safety of dorsal root ganglion stimulation for the treatment of chronic pain: a pooled analysis.
      In comparison, a recent study on closed-loop SCS (n = 50) with 24-month follow-up showed an improvement in EQ-5D scores from 0.404 at baseline to 0.633 (57% improvement) at one year and to 0.645 (60% improvement) at two years.
      • Brooker C.
      • Russo M.
      • Cousins M.J.
      • et al.
      ECAP-controlled closed-loop spinal cord stimulation efficacy and opioid reduction over 24-months: final results of the prospective, multicenter, open-label Avalon study.
      Lastly, the total decrease of opioid requirements in our cohort (35% reduction in median use) was similar to that in a study by Kapural et al,
      • Kapural L.
      • Sayed D.
      • Kim B.
      • Harstroem C.
      • Deering J.
      Retrospective assessment of salvage to 10 kHz spinal cord stimulation (SCS) in patients who failed traditional SCS therapy: RESCUE study.
      who reported a 47% reduction in mean opioid requirements in patients salvaged with Hf-SCS, although their result may have been skewed somewhat owing to reporting of means with large SDs rather than medians with interquartile ranges. In addition, opioid requirement data in all studies have an inherent bias of being influenced by physician decision making and favorable or unfavorable views of opioid therapies for chronic pain.

      Therapy Durability

      Our retrospective cohort of consecutive patients demonstrated sustained improvements in NRS, ODI, and EQ-5D-5L over a median follow-up time of 34 months; two patients underwent therapy exit through explantation over that period. These patients were explanted for lack of pain relief, at 21 and 28 months after implant. Both had successful trials; however, they reported a <30% relief with their permanent implant, despite multiple reprogramming efforts. Levy et al
      • Levy R.M.
      • Mekhail N.
      • Kramer J.
      • et al.
      Therapy habituation at 12 months: spinal cord stimulation versus dorsal root ganglion stimulation for complex regional pain syndrome type I and II.
      postulated that DRG-S may be less susceptible to habituation than SCS. Our cohort supports this conclusion because the estimated explantation rate at one-year, two-year, and three-year follow-up was 0%, 2.6%, and 4.7%, respectively. Another important factor in promoting therapy durability is to prevent device-related adverse events such as lead fracture or lead migration. Our group of authors has previously found that DRG-S lead anchoring may reduce these adverse events.
      • Chapman K.B.
      • Mogilner A.Y.
      • Yang A.H.
      • et al.
      Lead migration and fracture rate in dorsal root ganglion stimulation using anchoring and non-anchoring techniques: a multicenter pooled data analysis.
      Salvage device explant rates were unreported in some of the previously mentioned salvage studies; rates were not reported for a study in 105 patients salvaged with Hf-SCS followed over 12 months and for a study in 29 patients salvaged with Hf-SCS followed over 21 months.
      • Ghosh P.E.
      • Gill J.S.
      • Simopoulos T.
      The evolving role of high-frequency spinal cord stimulation as salvage therapy in neurostimulation.
      ,
      • Kapural L.
      • Sayed D.
      • Kim B.
      • Harstroem C.
      • Deering J.
      Retrospective assessment of salvage to 10 kHz spinal cord stimulation (SCS) in patients who failed traditional SCS therapy: RESCUE study.
      Outside the salvage specific context, the literature demonstrates a 12-month Hf-SCS explantation rate of 3% to 11% and a 24-month explantation rate of 8% to 22%.
      • Al-Kaisy A.
      • Royds J.
      • Al-Kaisy O.
      • et al.
      Explant rates of electrical neuromodulation devices in 1177 patients in a single center over an 11-year period.
      • Wang V.C.
      • Bounkousohn V.
      • Fields K.
      • Bernstein C.
      • Paicius R.M.
      • Gilligan C.
      Explantation rates of high frequency spinal cord stimulation in two outpatient clinics.
      • Van Buyten J.P.
      • Wille F.
      • Smet I.
      • et al.
      Therapy-related explants after spinal cord stimulation: results of an international retrospective chart review study.

      Clinical Implications

      Patients who had failed SCS constitute a complex and heterogeneous population. Outside the salvage specific population, DRG-S is most clearly indicated for CRPS, given the landmark ACCURATE study was conducted in patients with CRPS.
      • Deer T.R.
      • Levy R.M.
      • Kramer J.
      • et al.
      Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.
      Approximately 20% of all patients who undergo SCS system explantation have CRPS.
      • Pope J.E.
      • Deer T.R.
      • Falowski S.
      • et al.
      Multicenter retrospective study of neurostimulation with exit of therapy by explant.
      ,
      • Dupré D.A.
      • Tomycz N.
      • Whiting D.
      • Oh M.
      Spinal cord stimulator explantation: motives for removal of surgically placed paddle systems.
      ,
      • Al-Kaisy A.
      • Royds J.
      • Al-Kaisy O.
      • et al.
      Explant rates of electrical neuromodulation devices in 1177 patients in a single center over an 11-year period.
      ,
      • Van Buyten J.P.
      • Wille F.
      • Smet I.
      • et al.
      Therapy-related explants after spinal cord stimulation: results of an international retrospective chart review study.
      • Hayek S.M.
      • Veizi E.
      • Hanes M.
      Treatment-limiting complications of percutaneous spinal cord stimulator implants: a review of eight years of experience from an academic center database.
      • Simopoulos T.
      • Aner M.
      • Sharma S.
      • Ghosh P.
      • Gill J.S.
      Explantation of percutaneous spinal cord stimulator devices: a retrospective descriptive analysis of a single-center 15-year experience.
      Consistently, 40% of the patients in this study had CRPS. We feel the maintained improvements in pain, function, and quality of life in the present cohort provide strong evidence to support the use of DRG-S for salvage of failed SCS for patients with CRPS, regardless of failed SCS waveform. This also would include those with causalgia or CRPS II, a condition where a named nerve is injured, resulting in continuing pain, allodynia, or hyperalgesia in combination with edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain.
      • Goebel A.
      • Birklein F.
      • Brunner F.
      • et al.
      The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria.
      In patients who do not fall into the diagnostic criteria of CRPS I or causalgia, this review may be helpful in considering those in other diagnostic categories. Treatment of these other conditions has become a common practice in both the USA and the international community and should be considered, based on the individual discretion of the physician.

      Limitations

      There are some limitations that pertain to this study. As a retrospective multicenter study, DRG-S lead implant techniques and follow-up care were not standardized between centers. In addition, we included patients who had both failed trials and failed implants. The underlying reasons for failure in these cases can fall into distinct categories that may be independent of each other. Furthermore, as with every retrospective study, the decision to offer treatment was not based on randomized allocation, and bias through appropriate patient selection may have influenced the results of this study.

      Conclusions

      DRG-S can be a salvage therapy for patients who failed to receive persistent benefit from SCS. The success of DRG-S as a salvage therapy might be explained by a unique, focused mechanism of action targeting a different anatomical structure than SCS. Prospective, large-scale, long-term data are necessary to confirm the efficacy of DRG-S as a salvage therapy for SCS.

      Authorship Statements

      Kenneth B. Chapman, Matthew A. Spiegel, and Noud van Helmond drafted the first version of the manuscript. Kenneth B. Chapman, Matthew A. Spiegel, Kiran V. Patel, Nataniel Mandelberg, Ajax Yang, Timothy Deer, and Alon Y. Mogilner collected the data. Kenneth B. Chapman, Matthew A. Spiegel, and Noud van Helmond analyzed the data. Kenneth B. Chapman, Matthew A. Spiegel, Noud van Helmond, Kiran V. Patel, Nataniel Mandelberg, Ajax Yang, Timothy Deer, and Alon Y. Mogilner edited the manuscript. All authors approved the final version of the manuscript.

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