Spinal Cord Stimulation
Number: 0194
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses spinal cord stimulation.
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Medical Necessity
Aetna considers the following interventions medically necessary:
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A trial of percutaneous dorsal column stimulation to predict whether a dorsal column stimulator will induce significant pain relief in members with chronic pain due to any of the following indications (1 through 4) when the criteria (5) listed below are met:
- Failed back surgery syndrome (FBSS, also known as post-spinal surgery syndrome; defined as lumbar spinal pain of unknown origin either persisting despite surgical intervention or appearing after surgical intervention for spinal pain originally in the same topographical location) with low back pain and significant radicular pain; or
- Complex regional pain syndrome (CRPS) (also known as reflex sympathetic dystrophy [RSD]) Note: For clinical diagnostic criteria, see Appendix for the Budapest Criteria for Complex Regional Pain Syndrome; or
- Inoperable chronic ischemic limb pain secondary to peripheral vascular disease; or
- Last resort treatment of moderate to severe (5 or more on a 10-point VAS scale) chronic neuropathic pain of certain origins (i.e., lumbosacral arachnoiditis, phantom limb/stump pain, peripheral neuropathy (including diabetic peripheral neuropathy), post-herpetic neuralgia, intercostal neuralgia, cauda equina injury, incomplete spinal cord injury, or plexopathy) that has been present for 12 or more months; and
- The member must meet all of the following criteria:
- Member has undergone careful screening, evaluation and diagnosis by a multidisciplinary team prior to implantation (Note: screening must include psychological as well as physical evaluations); and
- Member does not have any untreated existing substance use disorder(s) (per American Society of Addiction Medicine (ASAM) guidelines), and
- Member has obtained clearance from a psychiatrist, psychologist, or other qualified mental health professional (e.g., Master of Social Work in behavioral health); and
- Other more conservative methods of pain management have been tried and failed for a minimum of 6 months (including non-steroidal anti-inflammatory drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants) and physical therapy (formal in-person (not virtual) physical therapy with a licensed physical therapist for a minimum of 6 weeks within the past year) and psychological therapies; and
- If the member has had spinal surgery, they are at least 6 months post-operative; and
- Member’s functional disability assessed using the Oswestry Disability Index (ODI); member has received an ODI score greater than or equal to 21%. Note: The ODI is available here;
- Implantation of a dorsal column stimulator (DCS) for members who meet the above-listed criteria who have experienced significant pain reduction (50 % or more) with a 3- to 7-day trial of percutaneous spinal stimulation;
- The use of cervical dorsal column stimulation for the treatment of members with complex regional pain syndrome when criteria in section A are met and the member has experienced significant pain reduction (50 % or more) with a 3- to 7-day trial of percutaneous spinal stimulation;
- DCS as DME for the management of intractable angina in members who are not surgical candidates and whose pain is unresponsive to all standard therapies when all of the following criteria are met:
- Member experienced significant pain reduction (50 % or more) with a 3- to 7-day trial of percutaneous spinal stimulation. (A trial of percutaneous spinal stimulation is considered medically necessary for members who meet the above-listed criteria, in order to predict whether a dorsal column stimulator will induce significant pain relief); and
- Member has angiographically documented significant coronary artery disease and is not a suitable candidate for revascularization procedures such as coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA); and
- Member has had optimal pharmacotherapy for at least one month. Optimal pharmacotherapy includes the maximal tolerated dosages of at least 2 of the following anti-anginal medications: long-acting nitrates, beta-adrenergic blockers, or calcium channel antagonists; and
- Member’s angina pectoris is New York Heart Association (NYHA) Functional Class III (patients are comfortable at rest; less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain) or Class IV (symptoms of cardiac insufficiency or angina are present at rest; symptoms are increased with physical activity); and
- Reversible ischemia is documented by symptom-limited treadmill exercise test.
Note: Contraindications to dorsal column stimulation for intractable angina are presented in an Appendix to the Background section of this CPB.
- Dorsal column stimulators using high-frequency spinal cord stimulation (Senza), burst stimulation (BurstDR)) or differential target multiplexed stimulation (Medtronic DTM) are considered equally effective alternatives to standard dorsal column stimulators for the indications listed above. Replacement of a functioning standard dorsal column stimulator with a high-frequency, burst dorsal column or DTM stimulator is considered not medically necessary;
- Replacement of a cervical, lumbar or thoracic dorsal column stimulator or battery/generator for individuals who have had a positive pain relief response from the existing DCS and the existing stimulator or battery/generator are no longer under warranty and cannot be repaired. A change in battery for spinal cord stimulator because of paresthesia is considered not medically necessary;
- If a spinal cord stimulation trial fails, a repeat trial is not medically necessary unless there are extenuating circumstances that lead to trial failure;
Note: Lead and electrode replacement are not generally required at the time of generator replacement due to end of battery life. - Removal of dorsal column stimulator even where installation would not have been indicated;
- A spinal cord stimulator patient programmer for members who meet criteria for a dorsal column stimulator;
- Up to 16 electrodes/contacts, 2 percutaneous leads, or 1 paddle lead for a trial of a dorsal column stimulator;
Note: An additional 16 electrodes/contacts, 2 percutaneous leads, or 1 paddle lead are considered not medically necessary for implantation of a dorsal column stimulator. Spinal cord stimulation using more than 16 electrodes/contacts or more than 2 percutaneous leads has not been proven more effective than standard spinal cord stimulation using up to 16 electrodes/contacts or 2 percutaneous leads.
- Dorsal root ganglion stimulators (e.g., Axium Neurostimulator System) for moderate-to-severe chronic intractable pain of the lower limbs in persons with complex regional pain syndrome (CRPS) types I and II, when general medical necessity criteria for spinal cord stimulators in Section A are met;
- Revision/replacement of a previously implanted stimulator for any of the following:
- Lead malfunction (e.g., fracture or migration); or
- Prior device removal for infection with consult from an infectious disease specialist to confirm infection has been eradicated; or
- If member has a documented need for an MRI-compatible device due to contraindications to CT/myelography;
- Closed-loop spinal cord stimulation system is considered equivalent to a standard spinal cord stimulation system;
- If a dorsal root ganglion stimulation trial fails, a repeat trial is not medically necessary unless there are extenuating circumstances that lead to trial failure.
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Experimental, Investigational, or Unproven
The following interventions are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- The use of cervical dorsal column stimulation for the treatment of members with cervical trauma, disc herniation, essential tremor, failed cervical spine surgery syndrome presenting with arm pain, neck pain, cervicogenic headache, gliomas, migraine, radiation-induced brain injury, stroke, trigeminal neuropathy, or any other indication (other than CRPS);
- Dorsal column stimulation for all other indications not mentioned above including the following (not an all-inclusive list):
- Management of pain associated with chronic pancreatitis
- Treatment of persons in a chronic vegetative or minimally conscious state
- Abdominal pain related to celiac artery compression syndrome
- Chest wall/sternal pain
- Chronic abdominal pain
- Chronic malignant pain
- Chronic pelvic pain
- Chronic visceral pain
- Coccydynia
- Disorders of consciousness
- Gait and balance disorders (including multi-system atrophy, Parkinson’s disease, progressive supranuclear palsy, and spinocerebellar ataxia)
- Gastroparesis
- Guillain Barre syndrome
- Irritable bowel syndrome
- Meralgia paresthetica
- Neurodegenerative ataxia
- Neuropathic pain associated with multiple sclerosis
- Orthostatic tremor
- Parkinson's disease
- Peri-rectal pain
- Sleep disorders
- Sphincter of Odi dysfunction
- Types of chronic non-malignant non-neuropathic pain not mentioned above
- Ventricular fibrillation
- Ventricular tachycardia;
- The Nalu micro-IPG for spinal cord stimulation;
- The use of intra-operative motor evoked potentials (MEP) and somatosensory evoked potentials (SSEP) for implantation of spinal cord stimulators;
- Dorsal root ganglion stimulators for all other indications (e.g., treatment of chronic pelvic pain (meralgia paresthetica) and failed back surgery syndrome).;
- The concurrent use of 2 dorsal column stimulators for the treatment of complex regional pain syndrome or any other indications;
- The combined use of dorsal column stimulation and dorsal root ganglion stimulation for the treatment of complex regional pain syndrome or any other indications;
- Transcutaneous spinal cord stimulation for motor rehabilitation in individuals with spinal cord injury.
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Related CMS Coverage Guidance
This Clinical Policy Bulletin (CPB) supplements but does not replace, modify, or supersede existing Medicare Regulations or applicable National Coverage Determinations (NCDs) or Local Coverage Determinations (LCDs). The supplemental medical necessity criteria in this CPB further define those indications for services that are proven safe and effective where those indications are not fully established in applicable NCDs and LCDs. These supplemental medical necessity criteria are based upon evidence-based guidelines and clinical studies in the peer-reviewed published medical literature. The background section of this CPB includes an explanation of the rationale that supports adoption of the medical necessity criteria and a summary of evidence that was considered during the development of the CPB; the reference section includes a list of the sources of such evidence. While there is a possible risk of reduced or delayed care with any coverage criteria, Aetna believes that the benefits of these criteria – ensuring patients receive services that are appropriate, safe, and effective – substantially outweigh any clinical harms.
This CPB is being used to supplement Medicare LCDs on spinal cord stimulators (LCD L36204, Spinal Cord Stimulators for Chronic Pain; LCD L37632, Spinal Cord Stimulators for Chronic Pain). This CPB is used to define indications for which spinal cord stimulators are proven to be safe and effective (see, e.g., de Vos, et al., 2014; Eldabe, et al., 2010; Horsch, et al., 1994; Kemler, et al., 2000; Kemler, et al., 2004; Lamer, et al., 2019; Mingoli, et al., 1993; North, et al., 2005; Petersen, et al., 2021; Ubbink, et al., 2013). This will better ensure that beneficiaries avoid the risks of this invasive procedure for indications that are not proven safe and effective (see, e.g., Bendel, et al., 2017; Hussain, et al., 2022; Hussain, et al., 2023; Levy, et al., 2011; Meyer, et al., 2007; Petraglia, et al., 2016; Simopoulos, et al., 2021). We believe the clinical benefits of avoiding unnecessary and potentially harmful care outweighs any potential risks in delayed or reduced access to care.Code of Federal Regulations (CFR):
42 CFR 417; 42 CFR 422; 42 CFR 423.
Internet-Only Manual (IOM) Citations:
CMS IOM Publication 100-02, Medicare Benefit Policy Manual; CMS IOM Publication 100-03 Medicare National Coverage Determination Manual.
Medicare Coverage Determinations:
Centers for Medicare & Medicaid Services (CMS), Medicare Coverage Database [Internet]. Baltimore, MD: CMS; updated periodically. Available at: Medicare Coverage Center. Accessed November 7, 2023.
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Related Policies
Background
Dorsal Column Stimulation for Chronic Pain
- other more conservative methods of pain management have been tried and failed;
- the patient has exhausted all surgical options;
- the patient has predominantly radiating extremity pain; and
- the patient experienced significant pain reduction with trial percutaneous spinal stimulation.
Examples of DCS include, but may not be limited to, Eon, EonC, Eon Mini, Genesis IPG System, Itrel4, Precision Plus SCS System, Precision Spectra, PrimeAdvanced Neurostimulator, Protégé, RestoreAdvanced, RestorePrime, Restore Sensor and RestoreUltra. The Restore Sensor SureScan is an example of the first DCS that is approved by the US Food and Drug Administration (FDA) for use in a magnetic resonance imaging (MRI). The Senza HF-10 DCS is a bit different than the previously mentioned devices, as it utilizes high frequency stimulation, the first device to receive FDA approval to treat chronic pain without creating/causing paresthesia.
Cardiac pacemakers’ and internal cardiac defibrillators’ compatibility with SCS should be established before spinal cord stimulator trial.
Spinal cord stimulation requires a surgical procedure, conducted in two phases, to place an electrode into the epidural space of the spinal column. The electrode is then connected to a pulse generator (which contains the battery) that is surgically implanted. An electrical impulse generated by the device travels to the electrodes where it creates a "tingling" sensation (paresthesia) which is thought to alter the perception of pain by the patient.
In the first phase, a local anesthetic is given and an electrode is inserted with the assistance of fluoroscopy to guide the electrodes to the desired level in the spinal column. Over the next two to three days extensive testing with the temporary electrode is performed as an outpatient to measure the effectiveness and determine adequate positioning. If at least a 50% reduction in pain is reported, the patient returns for permanent electrodes and a generator device.
In the second phase, the patient is kept awake, though sedated, during the procedure to help guide electrode placement and ensure that the SCS provides adequate parasthetic sensation over the affected area. Permanent electrodes are placed; a connector wire is tunneled under the skin and connected to an implantable pulse generator which is inserted into a surgically prepared pocket in the abdomen.
Dorsal column stimulation is a therapy for chronic pain with organic origins and has not been shown to benefit problems which are largely behavioral or psychiatric. There is evidence that outcomes of DCS are improved if candidates are subject to psychological clearance to exclude from surgery persons with serious mental disabilities, psychiatric disturbances, or poor personality factors that are associated with poor outcomes. The literature supporting pre-surgical psychological clearance for DCS has been reviewed by a number of authors (Heckler et al, 2007; van Dorsten, 2006).
There is sufficient evidence of the effectiveness of dorsal column stimulation in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS). North et al (1991b) reviewed the long-term results of 50 patients with FBSS who had received implantable DCS. Successful outcome, as judged by at least 50 % sustained analgesia and patient satisfaction with the result, was recorded in 53 % of patients at 2.2 years and 47 % of patients at 5.0 years. Eighty three percent of the subjects continued to use their stimulators at the 5-year follow-up. At the time of follow-up, only 12 % of patients were using analgesic medications with half of them at reduced dosage, compared with 74 % before the commencement of DCS therapy. Moreover, most patients reported an improvement in ability to perform daily activities. In another report that examined 5-year follow-up in 102 patients with FBSS undergoing repeated operation, North et al (1991a) found that most of these patients reported no change in their abilities to carry out activities of daily living.
Bell et al (1997) as well as Devulder et al (1997) reported that spinal cord stimulation is cost-effective in treating patients with chronic FBSS.
Turner et al (2004) conducted a systematic review on the effectiveness of DCS in relieving pain and improving functioning for patients with FBSS and CRPS. These authors concluded with suggestions for methodologically stronger studies to provide more definitive data regarding the effectiveness of DCS in relieving pain and improving functioning, short-term and long-term, among patients with chronic pain syndromes. Taylor et al (2005) assessed the safety and effectiveness of DCS for the treatment of chronic back and leg pain and FBSS and concluded that there is moderate evidence for the effectiveness of DSC for these indications. Furthermore, a recent Cochrane review (Mailis-Gagnon et al, 2004) concluded that although there is limited evidence in favor of DCS for FBSS and CRPS, more research is needed to confirm whether DCS is an effective treatment for certain types of chronic pain. This is in agreement with the findings of a recent assessment on spinal cord stimulation for the management of neuropathic pain by the Ontario Ministry of Health and Long Term Care (2005). This report stated that FBSS and CRPS are the 2 most common indications for DCS. North et al (2005) also reported that DCS provided adequate pain relief in patients with FBSS with predominant LBP and secondary radicular pain. Harney et al (2005) stated that there is now a significant body of evidence to support the utilization of DCS in the management of CRPS.
The National Institute for Health and Clinical Excellence (NICE)'s guideline on spinal cord stimulation for chronic neuropathic or ischemic pain (2008) recommended DCS for patients who continue to experience chronic neuropathic pain (e.g. FBSS after lumbar spine surgery and CRPS) for at least 6 months despite trying conventional approaches to pain management. Patients should have had a successful trial of the therapy before a spinal cord stimulator is implanted.
Kumar and co-workers (2008) reported that after randomizing 100 FBSS patients to receive DCS plus conventional medical management (CMM) or CMM alone, the results of the 6-month Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation (i.e., PROCESS) showed that DCS offered superior pain relief, health-related quality of life (HRQoL), and functional capacity. Because the rate of cross-over favoring DCS beyond 6 months would bias a long-term randomized group comparison, these investigators presented all outcomes in patients who continued DCS from randomization to 24 months and, for illustrative purposes, the primary outcome (greater than 50 % leg pain relief) per randomization and final treatment. Patients provided data on pain, quality of life, function, pain medication use, treatment satisfaction, and employment status. Investigators documented adverse events. Data analysis included inferential comparisons and multi-variate regression analyses. The 42 patients continuing DCS (of 52 randomized to DCS) reported significantly improved leg pain relief (p < 0.0001), quality of life (p < or = 0.01), and functional capacity (p = 0.0002); and 13 patients (31 %) required a device-related surgical revision. At 24 months, of 46 of 52 patients randomized to DCS and 41 of 48 randomized to CMM who were available, the primary outcome was achieved by 17 (37 %) randomized to DCS versus 1 (2 %) to CMM (p = 0.003) and by 34 (47 %) of 72 patients who received DCS as final treatment versus 1 (7 %) of 15 for CMM (p = 0.02). The authors concluded that at 24 months of DCS treatment, selected FBSS patients reported sustained pain relief, clinically important improvements in functional capacity and HRQoL, and satisfaction with treatment.
Manca and associates (2008) assessed HRQoL as well as cost implications of DCS plus non-surgical CMM (DCS group) versus non-surgical CMM alone (CMM group) in the management of neuropathic pain in patients with FBSS. A total of 100 patients were randomized to either the DCS or CMM group. Healthcare resource consumption data relating to screening, the use of the implantable generator in DCS patients, hospital stay, and drug and non-drug pain-related treatment were collected prospectively. Resource consumption was costed using UK and Canadian 2005 to 2006 national figures. Health-related quality of life was assessed using the EuroQol-5D (EQ-5D) questionnaire. Costs and outcomes were assessed for each patient over their first 6-months of the trial. The 6-month mean total healthcare cost in the DCS group (CAN$19,486; 12,653 Euros) was significantly higher than in the CMM group (CAN$3,994; 2,594 Euros), with a mean adjusted difference of CAN$15,395 (9,997 Euros) (p < 0.001). However, the gain in HRQoL with DCS over the same period of time was markedly greater in the DCS group, with a mean EQ-5D score difference of 0.25 [p < 0.001] and 0.21 [p < 0.001], respectively at 3- and 6-months after adjusting for baseline variables. The authors concluded that the addition of DCS to CMM in patients with neuropathic leg and back pain results in higher costs to health systems but also generates important improvements in patients' EQ-5D over the same period.
In a randomized controlled study, Kemler et al (2008) evaluated the effectiveness of DCS in reducing pain due to CRPS-I at the 5-year follow-up. These researchers carried out a randomized trial in a 2:1 ratio in which 36 patients with CRPS-I were allocated to receive DCS and physical therapy (PT) and 18 patients to receive PT alone. Twenty-four patients who received DCS+PT also underwent placement of a permanent spinal cord stimulator after successful test stimulation; the remaining 12 patients did not receive a permanent stimulator. These investigators assessed pain intensity, global perceived effect, treatment satisfaction, and health-related quality of life. Patients were examined before randomization, before implantation, and every year until 5 years thereafter. A total of 10 patients were excluded from the final analysis. At 5 years post-treatment, DCS+PT produced results similar to those following PT for pain relief and all other measured variables. In a sub-group analysis, the results with regard to global perceived effect (p = 0.02) and pain relief (p = 0.06) in 20 patients with an implant exceeded those in 13 patients who received PT. The authors concluded that despite the diminishing effectiveness of DCS over time, 95 % of patients with an implant would repeat the treatment for the same result.
Ohnmeiss et al (1996) concluded that spinal cord stimulation can result in improved physical function and reduced pain in selected patients with intractable leg pain. Shatin et al (1986) published the findings of a multi-center clinical study of DCS for treatment of chronic, intractable pain of the low back and/or legs. Ninety patients were available for follow-up which averaged 14.5 months. Seventy percent of the subjects experienced excellent (75 to 100 %) or good (50 to 74 %) analgesia. In addition, 28 % of all subjects at last follow-up used opioid medications, compared to 40 % of all subjects before implantation of the DCS.
In a review of the evidence for non-surgical interventional therapies for LBP for the American Pain Society, Chou and colleagues (2009) concluded that there is fair evidence that spinal cord stimulation (SCS) is moderately effective for FBSS with persistent radiculopathy though device-related complications are common.
Simpson et al (2009) examined the clinical and cost-effectiveness of SCS in the management of chronic neuropathic or ischemic pain. A total of 13 electronic databases including MEDLINE (1950 to 2007), EMBASE (1980 to 2007) and the Cochrane Library (1991 to 2007) were searched from inception; relevant journals were hand-searched; and appropriate websites for specific conditions causing chronic neuropathic/ischemic pain were browsed. Literature searches were conducted from August 2007 to September 2007. A systematic review of the literature sought clinical and cost-effectiveness data for SCS in adults with chronic neuropathic or ischemic pain with inadequate response to medical or surgical treatment other than SCS. Economic analyses were performed to model the cost-effectiveness and cost-utility of SCS in patients with neuropathic or ischemic pain. From approximately 6,000 citations identified, 11 randomized controlled trials (RCTs) were included in the clinical effectiveness review: 3 of neuropathic pain and 8 of ischemic pain. Trials were available for the neuropathic conditions FBSS and CRPS type I, and they suggested that SCS was more effective than conventional medical management (CMM) or re-operation in reducing pain. The ischemic pain trials had small sample sizes, meaning that most may not have been adequately powered to detect clinically meaningful differences. Trial evidence failed to demonstrate that pain relief in critical limb ischemia (CLI) was better for SCS than for CMM; however, it suggested that SCS was effective in delaying refractory angina pain onset during exercise at short-term follow-up, although not more so than coronary artery bypass grafting (CABG) for those patients eligible for that surgery. The results for the neuropathic pain model suggested that the cost-effectiveness estimates for SCS in patients with FBSS who had inadequate responses to medical or surgical treatment were below 20,000 pounds per quality-adjusted life-year (QALY) gained. In patients with CRPS who had had an inadequate response to medical treatment the incremental cost-effectiveness ratio (ICER) was 25,095 pounds per QALY gained. When the SCS device costs varied from 5,000 pounds to 15,000 pounds, the ICERs ranged from 2,563 pounds per QALY to 22,356 pounds per QALY for FBSS when compared with CMM and from 2,283 pounds per QALY to 19,624 pounds per QALY for FBSS compared with re-operation. For CRPS the ICERs ranged from 9,374 pounds per QALY to 66,646 pounds per QALY. If device longevity (1 to 14 years) and device average price (5,000 pounds to 15,000 pounds) were varied simultaneously, ICERs were below or very close to 30,000 pounds per QALY when device longevity was 3 years and below or very close to 20,000 pounds per QALY when device longevity was 4 years. Sensitivity analyses were performed varying the costs of CMM, device longevity and average device cost, showing that ICERs for CRPS were higher. In the ischemic model, it was difficult to determine whether SCS represented value for money when there was insufficient evidence to demonstrate its comparative efficacy. The threshold analysis suggested that the most favorable economic profiles for treatment with SCS were when compared to CABG in patients eligible for percutaneous coronary intervention (PCI), and in patients eligible for CABG and PCI. In these 2 cases, SCS dominated (it cost less and accrued more survival benefits) over CABG. The authors concluded that the evidence suggested that SCS was effective in reducing the chronic neuropathic pain of FBSS and CRPS type I. For ischemic pain, there may need to be selection criteria developed for CLI, and SCS may have clinical benefit for refractory angina short-term. They stated that further trials of other types of neuropathic pain or subgroups of ischemic pain, may be useful.
The review by Simpson et al (2009) did not address chronic painful diabetic neuropathy (CPDN), and there is inadequate evidence to support the use of SCS for this indication.
Daousi and colleagues (2005) assessed the efficacy and complication rate of SCS at least 7 years previously in 8 patients. After a trial period of percutaneous stimulation, 8 male patients had been implanted with a permanent system. Mean age at implantation was 53.5 years and all patients were insulin-treated with stage 3 severe disabling CPDN of at least 1 year's duration. The stimulator was removed from 1 patient at 4 months because of system failure and 1 patient died 2 months after implantation from a myocardial infarction. Thus, a total of 6 patients were reviewed a mean of 3.3 years post-implantation. With the stimulator off, McGill pain questionnaire (MPQ) scores (a measure of the quality and severity of pain) were similar to MPQ scores prior to insertion of the stimulator. Visual analog scale (VAS) were measured with the stimulator off and on, respectively: background pain [74.5 (63 to 79) mm versus 25 (17 to 33) mm, median (inter-quartile range), p = 0.03), peak pain (85 (80 to 92) mm versus 19 (11 to 47) mm, p = 0.03]. There were 2 further cardiovascular deaths (these patients had continued pain relief) and the 4 surviving patients were re-assessed at 7.5 (range of 7 to 8.5) years: background pain [73 (65 to 77) mm versus 33 (28 to 36) mm, median (inter-quartile range)], peak pain [86 (81 to 94) mm versus 42 (31 to 53) mm]. Late complications (greater than 6 months post-insertion) occurred in 2 patients; electrode damage secondary to trauma requiring replacement (n = 1), and skin peeling under the transmitter site (n = 1). One patient had a second electrode implanted in the cervical region which relieved typical neuropathic hand pains. The authors concluded that SCS can continue to provide significant pain relief over a prolonged period of time with little associated morbidity.
In a prospective, open-label study, de Vos et al (2009) evaluated the safety and effectiveness of SCS for the treatment of pain and the effects on microcirculatory blood flow in the affected areas in patients with refractory peripheral diabetic neuropathy. Data were collected during screening, at implant and at regular intervals, after initiation of therapy. A total of 11 diabetic patients with chronic pain in their lower limbs and no response to conventional treatment were studied. The SCS electrode was implanted in the thoracic epidural space. Neuropathic pain relief was assessed by VAS and microcirculatory skin perfusion was measured with laser Doppler flowmetry. Nine subjects had significant pain relief with the percutaneous electrical stimulator. Average pain score for all 9 patients was 77 at baseline and 34 at 6 months after implantation. At the end of the study, 8 of 9 patients continued to experience significant pain relief and have been able to significantly reduce their pain medication. For 6 of them, the stimulator was the sole treatment for their neuropathic pain. No significant changes in microcirculatory perfusion were recorded.
Findings from the studies by Daousi et al (2005) as well as de Vos et al (2009) need to be validated by well-designed RCTs.
Kapural and colleagues (2010) noted that a few recent reports suggested that SCS effectively suppresses chronic abdominal pain. However, there is no consensus on patient selection or technical aspects of SCS for such pain. Thus, these researchers conducted national survey and collected 76 case reports. There were 6 incompletely filled reports, so 70 cases were analyzed. There were 43 female and 27 male patients. Spinal cord stimulation was trialed in an average of 4.7 days (median of 4 days). In most patients, the leads were positioned for the SCS trial with their tips at the level of the T5 vertebral body (n = 26) or T6 vertebral body (n = 15). Four patients failed SCS trial: their average baseline VAS pain score was 7 +/- 2.4 cm and did not improve at the conclusion of the trial (6.5 +/- 1.9 cm; p = 0.759). Pain relief exceeded 50 % in 66 of 70 patients reported. Among those, VAS pain score before the trial averaged 7.9 +/- 1.8 cm. During the trial VAS pain scores decreased to 2.45 +/- 1.45 cm (p < 0.001). The opioid use decreased from 128 +/- 159 mg of morphine sulfate equivalents a day to 79 +/- 112 mg (p < 0.017). During permanent implantation most of the physicians used 2 octrode leads and were positioned mid-line at T5 to T6 levels. The average patient follow-up was 84 weeks. Pain scores (VAS) before an implant were 8 +/- 1.9 cm, while after the implant 2.49 +/- 1.9 cm. The opioid use before an implant was 158 +/- 160 mg and at the last office visit after the implant 36 +/- 49 mg. The authors concluded that it seems that the SCS for the treatment of the abdominal visceral pain may provide a positive patient long-term experience, significant improvements in pain scores and a decrease in opioid use. The findings of this study needs to be validated by well-designed studies (RCTs).
In an evidence-based guideline on “Neuropathic pain interventional treatments”, Mailis and Taenzer (2012) provided the following recommendations:
- Failed back surgery syndrome and complex regional pain syndrome: In patients with FBSS and CRPS I or II, who are not candidates for corrective surgery and have failed more conservative evidence-based treatment, clinicians should consider offering a trial of SCS. Evidence quality: Good; Certainty: Moderate; Strength of recommendation: Grade B (Recommend: High certainty with moderate effect or moderate certainty with moderate to substantial effect.
- Traumatic neuropathy and brachial plexopathy: In patients with traumatic neuropathy and brachial plexopathy, who are not candidates for corrective surgery and who have failed more conservative evidence-based treatment, clinicians may consider offering a trial of SCS. Evidence quality: Fair; Certainty: Moderate; Strength of recommendation: Grade C (May recommend depending on circumstances. At least moderate certainty with small net benefit).
- Other neuropathic pain syndromes: In patients with other (than the above) neuropathic pain syndromes, there is insufficient evidence to recommend a trial of SCS. Evidence quality: Poor; Certainty: Low; Strength of recommendation: Grade I (Current evidence is insufficient to make a recommendation for or against using the intervention (poor quality of evidence, conflicting evidence, or benefits and harms cannot be determined).
Duarte et al (2020) stated that the recent availability of paraesthesia-/sensation-free SCS modalities allow the design of clinical trials of SCS using placebo/sham controls and blinding of patients, clinicians, and researchers. In a systematic review, these investigators examined the current evidence base of RCTs of SCS placebo/sham trials; and undertook a methodological critique of their methods. Based on this critique, these researchers developed a checklist for the design and reporting of future RCTs of SCS. They searched electronic data bases from inception until January 2019 for RCTs of SCS using a placebo/sham control. RCTs with only an active comparator arm were excluded. The results were presented as a narrative synthesis. Searches identified 12 eligible RCTs. SCS modalities included paraesthesia stimulation, sub-threshold, burst, and HF SCS and were mainly carried out in patients with FBSS, CRPS, and refractory angina. The quality and transparency of reporting of the methods of placebo stimulation, blinding of patients, clinicians, and researchers varied markedly across studies. The authors concluded that to-date the methods of placebo/sham control and blinding in RCTs have been poorly reported, leading to concerns regarding the validity and replicability of the findings. Important aspects that need to be clearly reported in the design of placebo-/sham-controlled RCTs of SCS include the transparent reporting of stimulation programming parameters, patient position during perception threshold measurement, management of the patient hand-held programmer, frequency of re-charging, and assessment of the fidelity of blinding.
Dorsal Column Stimulation for Angina Pectoris
Dorsal column stimulators have also been shown to be effective in the treatment of patients with angina pectoris patients who fail to respond to standard pharmacotherapies and are not candidates for surgical interventions. Patients should undergo a screening trial of percutaneous DCS of 3 to 7 days. If they achieve significant pain reduction (more than 50 %), the system is then implanted permanently. For this procedure, epidural electrodes are generally placed at an upper thoracic or lower cervical spinal level. Although the exact mode of action of DCS in alleviating anginal pain is unclear, it has been suggested that its beneficial effects are achieved through an increase in oxygen supply to the myocardium in addition to its analgesic effect.
Gonzalez-Dader et al (1991) reported their findings of DCS on 12 patients with established angina at rest or with minimum effort, who are unresponsive to the maximum tolerable pharmacotherapies, and there was a contraindication for re-vascularization surgery or intraluminal angioplasty. After a mean follow-up of 9.8 months, there was a significant decrease in the number of angina attacks (30.9 to 9.6 attacks per week) and a significant improvement in the treadmill ergometric test. The authors concluded that DCS is a very low-risk technique that significantly enhances the quality of life of patients with unstable angina. Similarly, Sanderson et al (1992) noted that in 14 patients with severe intractable angina pectoris unresponsive to conventional therapies including bypass grafting, DCS resulted in a significant improvement of symptoms and a marked decrease in glycerol trinitrate consumption. These benefits persisted in some patients for over 2 years without any apparent adverse sequelae. It was concluded that DCS is a useful technique for patients with severe intractable angina who have failed to respond to standard therapies.
In a RCT with a 1-year follow-up (n = 22), de Jongste and Staal (1993) found that DCS improved both the quality of life and cardiac parameters of patients with refractory angina pectoris. Mannheimer et al (1993) examined the effects of DCS on myocardial ischemia, coronary blood flow, and myocardial oxygen consumption in angina pectoris induced by atrial pacing (n = 20). Fifteen subjects had recurrent angina following a previous coronary bypass procedure and 5 subjects were considered unsuitable for bypass surgery. It was concluded that DCS has an anti-anginal and an anti-ischemic effect in severe coronary artery disease. Moreover, myocardial ischemia during treatment (SCS) results in anginal pain. Thus, DCS does not deprive these patients of a warning signal. This observation was supported by the findings of Anderson et al (1994) as well as Eliasson et al (1994). In a prospective study (n = 50), Anderson and co-workers investigated whether DCS employed for relief of refractory angina can mask acute myocardial infarction. These investigators found no evidence that DCS concealed acute myocardial infarction. Eliasson and colleagues evaluated the safety aspects of DCS in patients (n = 19) with severe angina pectoris by means of repeated long-term electrocardiograph recordings. There were no increases in the frequency of ischemic attacks, the total ischemic burden, or the number of arrhythmic episodes during treatment with DCS.
- angiographically documented significant coronary artery disease not suitable for revascularization procedures such as CABG or PTCA,
- New York Heart Association Functional Class III or IV angina pectoris,
- reversible ischemia documented at least by a symptom-limited treadmill exercise test, and
- pharmacologically optimal drug treatment for at least 1 month.
Optimal pharmacotherapy included the maximal tolerated dosages of at least 2 of the following anti-anginal medications -- long-acting nitrates, beta-adrenergic blockers, or calcium channel antagonists. Exclusion criteria included myocardial infarction or unstable angina in the last 3 months; significant valve abnormalities as demonstrated by echocardiography; and somatic disorders of the spine leading to insurmountable technical problems in treatment. Seventeen patients were randomly assigned to one of the two groups:
- treatment (implantation within 2 weeks, n = 8), and
- control (implantation after 8 weeks, n = 9).
Quality of life was assessed by daily and social activity scores and recording sublingual glyceryl trinitrate consumption and angina pectoris episodes in a diary. Exercise capacity was evaluated by means of treadmill exercise testing. All subjects were followed up for 1 year. The authors found that DCS significantly improved quality of life and exercise capacity in these patients and that the beneficial effects of DCS may be mediated via an improvement of oxygen supply to the heart in addition to an analgesic effect.
Sanderson et al (1994) reported the long-term clinical outcome of 23 patients with intractable angina treated with DCS. They were followed-up for 21 to 62 months. Three patients died during the course of the study. None of the deaths was sudden or unexplained; and this mortality rate was acceptable for such patients. Two subjects had a myocardial infarction which was associated with typical pain, and not concealed by DCS. The authors concluded that DCS is an effective and safe treatment for patients whose angina is unresponsive to conventional therapies.
Dorsal Column Stimulation for Cancer Pain
An AHRQ evidence-based guideline on management of cancer pain concluded that dorsal column stimulators have not been shown to be effective for treatment of refractory cancer pain. The assessment states: "Percutaneous electrical stimulation for the relief of otherwise refractory cancer pain has likewise not yet been evaluated in controlled trials. Case reports -- limited essentially to the percutaneous insertion of spinal cord electrodes for dorsal column stimulation -- tend to focus on details of the method, to use non-uniform patient selection criteria, and to use heterogeneous pain assessment methods and follow-up duration. Not all experience is favorable. Hence, as Miles and colleagues wrote nearly 20 years ago, ‘At this stage it seems sensible to concentrate effort on evaluating the method rather than on encouraging widespread and possibly indiscriminate use of what is an expensive use and relatively unproven technique.’"
In a Cochrane review, Lihua and colleagues (2013) evaluated the effectiveness of SCS for cancer-related pain compared with standard care using conventional analgesic medication. These investigators also appraised risk and potential adverse events associated with the use of SCS. They searched the following bibliographic databases in order to identify relevant studies: the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (from inception to 2012, Issue 6); MEDLINE; EMBASE; and CBM (Chinese Biomedical Database) (from inception to July, 2012); they also hand-searched relevant journals. These researchers planned to include RCTs that directly compared SCS with other interventions with regards to the effectiveness of pain management. They also planned to include cross-over trials that compared SCS with another treatment. They planned to identify non-RCTs but these would only be included if no RCTs could be found. The initial search strategy yielded 430 articles. By scrutinizing titles and abstracts, these investigators found 412 articles irrelevant to the analytical purpose of this systematic review due to different scopes of diseases or different methods of intervention (intra-thecal infusion system; oral medication) or aims other than pain control (spinal cord function monitoring, bladder function restoration or amelioration of organ metabolism). The remaining 18 trials were reviewed as full manuscripts. No RCTs were identified; 14 sporadic case reports and review articles were excluded and 4 before-and-after case-series studies (92 participants) were included. Two review authors independently selected the studies to be included in the review according to the pre-specified eligibility criteria. A check-list for methodological quality of non-RCTs was used (STROBE check-list) and all review authors discussed and agreed on the inclusion of trials and the results of the quality assessment. Four before-and-after case-series studies (a total of 92 participants) met inclusion criteria. All included trials adopted a VAS to evaluate pain relief. Heterogeneity existed in terms of baseline characteristics, electrode and stimulator parameters, level of implantation and route of implantation; data reporting was different among all trials. In 2 trials, pain relief was achieved in 76 % (48/63) of patients at the end of the follow-up period. In the 3rd trial, pre-procedure VAS was 6 to 9 (mean of 7.43 ); the 1-month post-implant VAS was 2 to 4 (mean of 3.07); the 12-month post-implant VAS was 1 to 3 (mean of 2.67). In the 4th trial, the pre-procedure VAS was 6 to 9 (mean of 7.07); 1 to 4 (mean of 2.67) at 1-month; 1 to 4 (mean of 1.87) at 12 months. Analgesic use was largely reduced. The main adverse events were infection of sites of implantation, cerebrospinal fluid (CSF) leakage, pain at the sites of electrodes, dislodgement of the electrodes and system failure, however, the incidence in patients with cancer could not be calculated. Since all trials were non-RCTs, they carried risk of all types of bias. The authors concluded that current evidence is insufficient to establish the role of SCS in treating refractory cancer-related pain. Moreover, they stated that future randomized studies should focus on the implantation of SCS in patients with cancer-related pain.
Cervical Spinal Cord Stimulation
Cervical SCS has been used to treat patients with cervical trauma/disc herniation presenting with arm pain, neck pain, and/or cervicogenic headache. However, there is insufficient evidence that cervical SCS is effective for these indications.
Garcia-March et al (1987) reported the use of SCS in 6 patients with total or partial brachial plexus avulsion. Two patients had had amputation of the arm and suffered from phantom limb and stump pain. After a mean follow-up of 14 months, 2 patients were pain-free, 1 had partial relief and required analgesics, and in 3 patients there was no effect. Robaina et al (1989) studied the use of SCS for relief of chronic pain in vasospastic disorders of the upper limbs. A total of 11 patients with chronic pain due to severe vasospastic disorders in the upper limbs were treated with cervical SCS. In 8 patients the pain was due to reflex sympathetic dystrophy (RSD) in the late stage of the disease, and 3 patients had severe idiopathic Raynaud's disease. The mean follow-up for both groups was 27 months. A total of 10 patients (91 %) had good or excellent results. In the RSD group, the amount of pain relief achieved enabled most patients to undergo subsequent physiotherapy and rehabilitation. These investigators concluded that in severe cases of RSD and idiopathic Raynaud's disease, SCS is an alternative treatment that can be used as primary therapy or as secondary therapy after unsuccessful sympathectomy or sympathetic blocks.
Forouzanfar et al (2004) noted that SCS has been used since 1967 for the treatment of patients with chronic pain. However, long-term effects of this treatment have not been reported. The present study investigated the long-term effects of cervical and lumbar SCS in patients with CRPS type I (CRPS I). A total of 36 patients with a definitive implant were included in this study. A pain diary was obtained from all patients before treatment and 6 months and 1 and 2 years after implantation. All patients were asked to complete a seven-point Global Perceived Effect (GPE) scale and the Euroqol-5D (EQ-5D) at each post-implant assessment point. The pain intensity was reduced at 6 months, 1 and 2 years after implantation (p < 0.05). However, the repeated measures ANOVA showed a statistically significant, linear increase in the visual analog scale (VAS) score (p = 0.03). According to the GPE, at least 42 % of the cervical SCS patients and 47 % of the lumbar SCS patients reported at least "much improvement". The health status of the patients, as measured on the EQ-5D, was improved after treatment (p < 0.05). This improvement was noted both from the social and from the patients' perspective. Complications and adverse effects occurred in 64 % of the patients and consisted mainly of technical defects. There were no differences between cervical and lumbar groups with regard to outcome measures. The authors concluded that SCS reduced the pain intensity and improves health status in the majority of the CRPS I patients in this study. There was no difference in pain relief and complications between cervical and lumbar SCS.
De Andres et al (2007) stated that SCS is used in the treatment of chronic pain, ischemia because of obstructive arterial disease, and anginal pain. Recently, a number of studies have described the effects of the high cervical SCS, including increased cerebral blood flow, although the underlying mechanisms are unknown. The authors presented the case of a patient with a severe complex ischemic condition affecting both cerebral and upper limb blood flow with an associated CRPS in upper limb. While all previous clinical treatments proved ineffective, cervical SCS afforded satisfactory results.
Canlas et al (2010) reported a case of a severe form of a rapidly progressive CRPS I developing after a right shoulder injury managed with SCS. After failed conservative treatments, a rechargeable SCS system was implanted in the cervical spine. Allodynia and dystonia improved but the patient subsequently developed similar symptoms in lower right extremity followed by her lower left extremity. The patient became wheelchair bound. A second rechargeable SCS with a paddle electrode was implanted for the lower extremity coverage. The patient's allodynia and skin lesions improved significantly. However, over time, her initial symptoms re-appeared which included skin breakdown. Due to the need for frequent recharging, the system was removed. During explantation of the surgical paddle lead, it was noted by the neurosurgeon that the contacts of the paddle lead were detached from the lead. After successful implantation of another SCS system, the patient was able to reduce her medications and is now able to ambulate with the use of a left elbow crutch.
Simpson et al (2003) reported on the use of cervical SCS for the management of patients with chronic pain syndromes affecting the upper limb and face (n = 41). Follow-up ranged from 5 months to 11 years and 3 months (median of 4 years and 7 months). Overall, 68 % obtained sustained pain relief, rated as significant in 51 % of total. Patients with facial pain did not respond, while those with ischemic syndromes responded well. The major drawback of this study was that it was a retrospective uncontrolled study.
In a review on the treatment of cervicogenic headache (Martelletti and van SuijlekomIn, 2004), cervical SCS was not listed as one of the therapeutic approaches that include drug-based therapies (e.g., paracetamol and non-steroidal anti-inflammatory drugs), manual modalities, transcutaneous electrical nerve stimulation, local injection of anesthetic or corticosteroids, and invasive surgical therapies. In addition, in a review on the safety and effectiveness of SCS for the treatment of chronic pain, Cameron (2004) stated that SCS had a positive, symptomatic, long-term effect in cases of refractory angina pain, severe ischemic limb pain secondary to peripheral vascular disease, peripheral neuropathic pain, and chronic low-back pain. Spinal cord stimulation for the treatment of cervical trauma with disc herniation presenting with arm pain, neck pain, and/or cervicogenic headache was not discussed in the review. The clinical value of cervical SCS for these indications needs to be investigated by well-designed RCTs.
Clavo and colleagues (2008) stated that syndromes resulting from decreased cerebral blood flow and metabolic activity have significant clinical and social repercussion. However, treatment options are limited. These investigators examined the effect of cervical SCS on cerebral glucose metabolism. Between April 2000 and December 2005, a total of 16 patients with brain tumors were assessed. Before and during SCS, they had cerebral glucose metabolism evaluated using 18fluoro-2-deoxyglucose positron emission tomography (18FDG-PET) in the healthy cerebral hemisphere contralateral to the lesion area. Following cervical SCS, there was a significant (p < 0.001) increase in glucose metabolism in healthy cerebral hemisphere. The measured increase was 37.7 %, with an estimated potential maximal contribution of the first 18FDG injection to the quantification of the second PET study (carry-over effect) less than or equal to 16.6 %. The authors concluded that cervical SCS can increase cerebral glucose metabolism. This result supports the potential usefulness of this neurosurgical technique as an adjuvant treatment in stroke and brain disorders that result from decreased blood flow and metabolism.
In a preliminary study, Clavo et al (2009) examined the effect of cervical SCS on radiation-induced brain injury (RBI)-tissue metabolism, as indexed by FDG-PET. Devices for cervical SCS were inserted in 8 patients with diagnosis of potential RBI in previously irradiated areas. While the SCS device was de-activated, each patient underwent an initial FDG-PET study to evaluate the clinical status. A second FDG-PET study was performed later the same day while the SCS device was activated in order to evaluate the effect of cervical SCS on glucose metabolism. Basal glucose metabolism in RBI areas was 31 % lower than peri-RBI areas (p = 0.009) and 32 % lower than healthy contra-lateral areas (p = 0.020). There was a significant increase in glucose uptake during SCS in both the RBI (p = 0.005) and the peri-RBI (p = 0.004) areas, with measured increases of 38 % and 42 %, respectively. The estimated potential maximal residual activity of the first FDG dose's contribution to the activity on the second scan was less than or equal to 14.3 +/- 4.6 %. The authors concluded that in this study using PET, SCS increased glucose metabolism in RBI and peri-RBI areas. They stated that these findings warrant further clinical investigation to elucidate more fully the clinical usefulness of SCS in these patients.
Deer and colleagues (2014) analyzed data from an international registry to support the use of cervical SCS. The following outcomes were collected as part of an institutional review board (IRB)-approved, prospective, multi-center, international registry: pain relief, Pain Disability Index (PDI) score, QOL, and satisfaction at 3, 6, and 12 months post-implantation. Descriptive statistics were provided for all measures. Changes from baseline in PDI scores were analyzed using Tukey's pairwise comparisons. A total of 38 patients underwent implantation of SCS leads in the cervical spine at 16 study sites in the United States and 3 international study sites. Direct patient report of percentage of pain relief was 54.2 %, 60.2 %, and 66.8 % at 3, 6, and 12 months post-implantation, respectively. Pain relief was categorized as excellent/good by 61.6 % of patients at 3 months, with similar results observed at 6 and 12 months; PDI scores were significantly reduced at all time-points. At 3 months post-implantation, 92.4 % of patients indicated they were very satisfied/satisfied with the SCS device. No patients indicated that they were dissatisfied. Overall QOL was reported as improved/greatly improved by 73.1 % of patients at 3 months. Similar results for QOL and satisfaction were reported at 6 and 12 months. The authors concluded that these findings suggested that the use of SCS in the cervical spine was a medically effective method of pain management that satisfied and improved the QOL of most patients. They noted that the use of SCS could reduce the high cost of direct medical treatment of pain, as well as increasing the productivity of patients, and therefore should be reimbursed in appropriately selected patients.
The authors stated that although this study provided preliminary support for the effectiveness of cervical SCS for treatment of certain specific indications such as CRPS, failed back/neck surgery syndrome, cervical radicular pain, ischemic pain, and injury or disease of the peripheral nerves, additional studies are needed. These studies should ideally include a randomized controlled study; however, placebo-controlled studies of SCS are plagued with design issues related to the paresthesia induced by stimulation. Thus, a randomized, matched cohort study may be more appropriate, though not without methodologic limitations.
Russo and colleagues (2018) reported the findings of a patient with refractory essential tremor (ET) of the hands and head/neck, and who refused deep brain stimulation (DBS) and requested consideration for SCS. Trial of a cervical SCS system using a basic tonic waveform produced positive outcomes in hand tremor, head-nodding and daily functioning. The patient proceeded to implant and received regular programming sessions. Outcomes were recorded at follow-ups (1, 3, 6, 12, 23 months post-implant) and included patient self-reported changes, clinical observations, hand-writing assessments and The Essential Tremor Rating Assessment Scale scores. Trial of a paraesthesia-free burst waveform program produced a small improvement in head-nodding, without uncomfortable paraesthesia. The authors concluded that with continued programming, the patient reported further improvements to tremor and functionality, with minimal tremor remaining at 12 to 23 months; no major AEs were reported. This was a single-case study; these preliminary findings need to be validated by well-designed studies.
Furthermore, an UpToDate review on “Essential tremor: Treatment and prognosis” (Tarsy, 2018) does not mention spinal cord stimulation as a therapeutic option.
In a consecutive, single-center series, Velasquez and colleagues (2018) described the indications and outcomes of upper cervical cord stimulation in trigeminal neuropathy; patients were retrospectively reviewed. This trial included 12 patients with trigeminal neuropathy treated with upper cervical spinal cord stimulation. Clinical features, complications, and outcomes were reviewed. All patients had a successful trial before the definitive implantation of a SCS at the level of the cranio-cervical junction. The mean follow-up period was 4.4 years (range of 0.3 to 21.1 years). The average coverage in the pain zone was 72 % and the median baseline, trial, and post-operative numeric rating scale (NRS) was 7, 3, and 3, respectively. When compared with the baseline, the mean reduction achieved in the post-operative average NRS was 4 points, accounting for a 57.1 % pain reduction; the long-term failure rate was 25 %. The authors concluded that despite there being enough evidence to consider upper cervical spinal cord stimulation as an effective treatment for patients with neuropathic trigeminal pain, a RCT is needed to fully evaluate its indications and outcomes and compare it with other therapeutic approaches.
Elahi and Reddy (2014) noted that headache following head injuries has been reported for centuries. The majority of post-traumatic headache (PTH) patients will report resolution of their complaints within a few months from the time of the initial injury. PTHs can contribute to disability, lost productivity, and health care costs. These investigators discussed a 40-year-old man with a history of motor vehicle accident and basal skull fracture. The patient had no headache history prior to the accident. He presented with more than 3 years persistent daily headache. The patient described constant throbbing and stabbing quality headaches predominantly on the left hemi-cranium with constant facial pain. He denied having aura, nausea, or vomiting, but reported occasional neck tightness. An extensive work-up was carried out under the direction of the patient's primary neurologist. Secondary to persistent intractable pain, the patient was referred to the pain clinic for further evaluation. As his headaches were resistant to all trialed strategies, these researchers decided to turn their therapeutic focus toward electrical neuromodulation along with continuing multi-modal medications and multi-disciplinary approach. During 7 days of high cervical dorsal column electrical nerve stimulation trial, he reported almost 90 % pain reduction and significant improvement on his quality of life (QOL). On 12 months follow-up after he underwent a permanent implant of high cervical dorsal column electrical nerve stimulation, he reported the same level of pain reduction along with 100 % satisfaction rate. The authors concluded that to the best of their knowledge, there have been no publications to-date concerning the application of high cervical nerve stimulation for PTH.
Hunter et al (2018) noted that SCS is an accepted, cost-effective therapeutic option for a variety of chronic pain syndromes, including failed back surgery syndrome (FBSS). The application of SCS in the cervical spine, particularly for pain after cervical spine surgery, has been drawn into question in recent years by payers due to a purported lack of clinical evidence. To challenge this claim, these researchers analyzed data from a prospective registry to support the use of SCS in the cervical spine for pain after spine surgery. Data from the EMPOWER and PAIN registries were analyzed on patients diagnosed with pain after neck surgery (C-FBSS) for the following outcomes: patient reported percent pain relief (PRPR), PDI, QOL, and satisfaction at 3-, 6-, and 12-month post-implantation; statistical analysis was provided for all measures. A total of 15 patients with C-FBSS were successfully implanted with SCS leads in the cervical spine. PRPR was 65.2 %, 62.4 %, and 71.9 % at 3-, 6-, and 12-month post-implantation, respectively. PDI scores were significantly reduced from baseline (51.21 to 23.70 at 12 months, p = 0.001). At 1-year post-implantation, the average overall QOL was reported to be improved/greatly improved and patient satisfaction was rated satisfied/greatly satisfied. The authors concluded that for many, the application of SCS in the neck for pain after surgery was based on the obvious similarities to FBSS or anecdotal experience rather than published data. The data contained herein suggested SCS for C-FBSS was an effective therapy that improves QOL and patient satisfaction, as well as decreasing pain and PDI. These researchers stated that the use of successful application of neuro-stimulation as a therapy has largely been predicated on the principles of patient selection, implantation technique, and stimulation parameters. As such, SCS would appear to be an appropriate and valid treatment for C-FBSS that requires further study and investigation to make additional recommendations.
Baird and Karas (2019) stated that dorsal column spinal cord stimulation is used for the treatment of chronic neuropathic pain of the axial spine and extremities. Recently, high-dose (HD) thoracic dorsal column stimulation for paresthesias has been successful. These researchers examined the utility of HD stimulation in the cervical spine for managing upper neck and upper extremity pain and paresthesias. A total of 3 patients suffering from cervical and upper extremity chronic pain were assessed. Each underwent a 2-stage process that included a trial period, followed by permanent stimulator implantation. Therapy included the latest HD stimulation settings including a pulse width of 90 μs, a frequency setting of 1,000-Hz, and an amplitude range of 1.5 amps to 2.0 amps. Pain relief was measured utilizing relative percent pain improvement as self-reported by each patient before and after surgery. After permanent implantation, (range of 15 to 21 months), all 3 patients continued to experience persistent pain and paresthesia relief (70 % to 90 %). The authors concluded that in 3 patients, HD cervical spinal cord stimulation successfully controlled upper extremity chronic pain/paresthesias. Moreover, these researchers stated that the significant risks and complications of these procedures must be carefully taken into account when choosing to use this treatment modality for pain alone. In the future, more extensive studies should be conducted to determine the long-term effects of HD cervical spinal cord stimulation.
Furthermore, an UpToDate review on “Cervical spondylotic myelopathy” (Levin, 2019) does not mention cervical / spinal cord stimulation as a therapeutic option.
El Majdoub et al (2019) noted that SCS overlaps painful areas with paresthesia to alleviate pain; 10-kHz HF SCS (HF10 cSCS) constitutes a therapeutic option that could provide pain relief without inducing paresthesia. In a retrospective, open-label, single-center study, these researchers examined the efficacy of HF10 cSCS in chronic neck and/or upper limb pain. Between May 2015 and August 2017, a total of 24 consecutive patients with neck and/or upper limb pain were treated with HF10 cSCS. The patients' mean age was 61.4 years (range of 40.1 to 82.6 years). The mean neck and upper limb pain at baseline was 8.8 (range of 7.0 to 10) and 7.5 (range of 6.0 to 9.0) according to the VAS. Functionality was evaluated using the Oswestry Disability Index (ODI). To assess health-related psychological impairment, these investigators used the Global Assessment of Functioning questionnaire. A total of 23 patients responded to treatment. Pain intensity reduced significantly to a mean VAS score of 2.5 (range of 2.0 to 4.0) for neck and 2.0 (range of 1.0 to 3.0) for upper limb pain after 6 months. At 12 months, VAS scores for neck and upper limb pain reduced to 2.2 (range of 1.0 to 3.0) and 1.7 (range of 1.0 to 3.0), respectively. Mean ODI scores decreased from 31 (range of 21 to 42) at baseline to 19.9 (range of 8 to 26) after 12 months. In 3 patients, infection of the IPG pocket occurred r and 8.7 months after surgery; 1 patient has had lead migration resulting in a surgical revision. The authors concluded that these preliminary results of HF10 cSCS in reducing neck and upper limb pain were encouraging. Moreover, these researchers stated that these findings warrant further studies with larger patient series and longer follow-ups since this study was a retrospective, single-center study with a short follow-up time of only 1 year and lack of a control group.
Amirdelfan et al (2020) noted that intractable neck and upper limb pain has historically been challenging to treat with conventional SCS being limited by obtaining effective paresthesia coverage. These researchers examined the safety and effectiveness of the high-frequency (HF; 10-kHz) SCS system, a paresthesia-independent therapy, in the treatment of neck and upper limb pain. Subjects with chronic, intractable neck and/or upper limb pain of greater than or equal to 5 cm (on a 0 to 10 cm visual analog scale [VAS]) were enrolled in 6 U.S. centers following an investigational device exemption (IDE) from the Food and Drug Administration (FDA) and IRB approval. Each subject was implanted with 2 epidural leads spanning C2 to C6 vertebral bodies. Subjects with successful trial stimulation were implanted with a Senza® system (Nevro Corp) and included in the evaluation of the primary safety and effectiveness end-points. In the per protocol population, the primary end-point (greater than or equal; to 50 % pain relief at 3 months) was achieved in 86.7 % (n = 39/45) subjects. Compared to baseline, subjects reported a significant reduction (p < 0.001) in their mean (± standard error of the mean) VAS scores at 12-month assessment for neck pain (7.6 ± 0.2 cm, n = 42 versus 1.5 ± 0.3 cm, n = 37) and upper limb pain (7.1 ± 0.3 cm, n = 24 versus 1.0 ± 0.2 cm, n = 20). At 12-month assessment, 89.2 % of subjects with neck pain and 95.0 % with upper limb pain had greater than or equal to 50 % pain relief from baseline, 95.0 % reported to be "satisfied/very satisfied" and 30.0 % either eliminated or reduced their opioid intake. The authors concluded that 10-kHz SCS could treat intractable neck and upper limb pain with stable long-term outcomes. This was a relatively small (n = 45) study with relatively short-term follow-up (primary end-point evaluated at 3 months).
Finnern et al (2022) noted that chronic headache remains a major cause of disability and pain worldwide. Although the literature has extensively described pharmacologic options for headache treatment and prophylaxis, there remains a paucity of data on the effectiveness of neuromodulation interventions for the treatment of headache unresponsive to conventional pharmacotherapies. In a systematic review, these investigators examined the available evidence on the effectiveness of cervical SCS (cSCS) in treating any intractable chronic headache, including migraine headaches (with or without aura), cluster headache, tension headache, and other types of headaches. In accordance with the PRISMA guidelines, these researchers carried out a systematic review by identifying studies in PubMed, Embase (Scopus), Web of Science, and Cochrane Central Register of Controlled Trials that evaluated cSCS in the treatment of chronic headache. Data were synthesized qualitatively, with primary outcomes of headache intensity and frequency; and the secondary endpoint was AEs. A total of 16 studies comprising 107 patients met the inclusion criteria. Findings were presented based on type of headache, which included migraine headache with or without aura, cluster headache, trigeminal neuropathy, occipital neuralgia, post-traumatic headache, cervicogenic headache, short-lasting unilateral neuralgiform headache with autonomic symptoms, and post-stroke facial pain. Per the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria, there was very low-quality evidence that cSCS was associated with a decrease in migraine headache frequency, migraine headache intensity, and trigeminal neuropathy intensity. Placement for cSCS leads ranged from C1 to C4. The authors concluded that the findings of this review suggested promising data from observational studies that cSCS may be helpful in decreasing frequency and intensity of chronic intractable headache. Moreover, these investigators stated that future well-powered RCTs are needed.
Dorsal Column Stimulation for Other Conditions
Georgiopoulos and colleagues (2010) performed a systematic review of the proposed medical or surgical treatments in patients in chronic vegetative state (VS) or minimally conscious state (MCS), as well as of their mechanisms of action and limitations. These investigators have agreed to include patients in VS or MCS having persisted for over 6 months in post-traumatic cases, and over 3 months in non-traumatic cases, before the time of intervention. Searches were independently conducted by 2 investigators between May 2009 and September 2009 in the following databases: Medline, Web of Science and the Cochrane Library. The electronic search was complemented by cross-checking the references of all relevant articles. Overall, 16 papers were eligible for this systematic review. According to the 16 eligible studies, medical management by dopaminergic agents (levodopa, amantadine), zolpidem and median nerve stimulation, or surgical management by deep brain stimulation, extra-dural cortical stimulation, SCS and intra-thecal baclofen have shown to improve the level of consciousness in certain cases. The authors concluded that treatments proposed for disorders of consciousness have not yet gained the level of "evidence-based treatments"; moreover, the studies to date have led to inconclusiveness. The published therapeutic responses must be substantiated by further clinical studies of sound methodology.
In a case report, Rana and Knezevic (2013) described the use of transverse tripolar DCS in a patient with a history of irritable bowel syndrome (IBS) associated with abdominal pain resistant to conservative treatments. These researchers reported a 36-year old man who presented to the pain clinic with an 8-year history of IBS (constipation predominant with occasional diarrheal episodes), with "crampy and sharp" abdominal pain. He also had non-radicular thoracic spine pain due to thoracic scoliosis. Both pains were affecting his ability to function as an attorney. Prior conservative therapy, including psychologic treatment, anti-depressants, and opioids, was without any benefits. The use of a SCS was discussed with the patient. The procedure was performed after Institutional Review Board approval. A tripolar SCS was implanted at the T8 level using one-eight contact and two-four contact percutaneous leads based on paresthesia reproduction of patient's areas of discomfort. This tripolar SCS provided relief of abdominal and thoracic pain, and better management of gastro-intestinal symptoms. The patient was followed-up for 1 year, and his quality of life also was improved via the IBS-Severity Scoring System quality of life tool. The authors concluded that the use of the tripolar SCS in this patient provided relief of abdominal and thoracic spine pain, regulated bowel habits, and improved the patient's quality of life. They believe that the use of SCS should be considered as a treatment option in patients with IBS when all conservative treatments failed. The findings of this case study need to be validated by well-designed randomized, controlled trials.
Hunter et al (2013) stated that chronic pelvic pain (CPP) is complex and often resistant to treatment. While the exact pathophysiology is unknown, the pain states resultant from conditions such as interstitial cystitis and the like yield patients with a presentation that bears a striking similarity to neuropathic syndromes that are known to respond to neuromodulation. In this study, 5 cases of CPP were presented. All 5 cases were different in presentation (vulvar, rectal, low abdominal pain) and required different “sweet spots” with a broad stimulation field; in 4 of 5 cases, 2 octapolar leads were used. The optimal positioning of the electrode is of major importance to the success of the treatment, but there is limited information available to-date regarding neuromodulation in visceral pain syndromes generally. While there has been past success using the sacral region as a target for SCS to treat these patients, there remains to be a consensus on the optimal location for lead placement. In an editorial that accompanied the afore-mentioned article, Puylaert (2013) noted that SCS is a potential treatment option for refractory visceral pain syndromes. In the era of evidence-based medicine, RCTs should be performed, but as visceral pain syndromes are so different in nature and expression, it is very difficult to select patient groups properly.
The American College of Obstetricians and Gynecologists’ clinical practice guideline on "Chronic pelvic pain" (ACOG, 2008) and the Royal College of Obstetricians and Gynecologists’ clinical practice guideline on “The initial management of chronic pelvic pain” (RCOG, 2012) did not mention SCS as a management tool. Also, the European Association of Urology’s clinical guideline on “General treatment of chronic pelvic pain” (Engeler et al, 2012) rendered a “C” grade (made despite the absence of directly applicable clinical studies of good quality) of recommendation on the use of neuromodulation for chronic pelvic pain. The guideline noted that the role of neuromodulation is developing with increasing research.
Furthermore, an UpToDate review on “Treatment of chronic pelvic pain in women” (Howard, 2013) states that “In general, neuromodulation for CPP has not been well-studied. Sacral nerve root neuromodulation for bladder related symptoms and pain is the best studied technique, but all trials are observational. A review of published case series suggests a 40 to 60 percent rate of improvement in pelvic pain symptoms after placement of either unilateral or bilateral lead placement. Follow-up has been up to three years in some series”. This review discusses sacral nerve stimulation; but it does not mention the use of SCS as a therapeutic option.
Baranidharan et al (2014) described a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with SCS were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. There was significant reduction in VAS from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. The authors concluded that there is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multi-center trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies.
Clavo et al (2014) noted that relapsed high-grade gliomas (HGGs) have poor prognoses and there is no standard treatment. High-grade gliomas have ischemia/hypoxia associated and, as such, drugs and oxygen have low access, with increased resistance to chemotherapy and radiotherapy. Tumor hypoxia modification can improve outcomes and overall survival in some patients with these tumors. In previous works, these researchers have described that cervical SCS can modify tumor microenvironment in HGG by increasing tumor blood flow, oxygenation, and metabolism. The aim of this preliminary, non-randomized, study was to assess the clinical effect of SCS during brain re-irradiation and chemotherapy deployed for the treatment of recurrent HGG; the hypothesis being that an improvement in oxygenated blood supply would facilitate enhanced delivery of the scheduled therapy. A total of 7 patients had SCS applied during the scheduled re-irradiation and chemotherapy for the treatment of recurrent HGG (6 anaplastic gliomas and 1 glioblastoma). Median dose of previous irradiation was 60 Gy (range of 56 to 72 Gy) and median dose of re-irradiation was 46 Gy (range of 40 to 46 Gy). Primary end-point of the study was overall survival (OS) following confirmation of HGG relapse. From the time of diagnosis of last tumor relapse before re-irradiation, median OS was 39 months (95 % confidence intervals [CI]: 0 to 93) for the overall study group: 39 months (95 % CI: 9 to 69) for those with anaplastic gliomas and 16 months for the patient with glioblastoma. Post-treatment, doses of corticosteroids was significantly decreased (p = 0.026) and performance status significantly improved (p = 0.046). The authors concluded that SCS during re-irradiation and chemotherapy is feasible and well-tolerated. In this study, SCS was associated with clinical improvement and longer survival than previously reported in recurrent anaplastic gliomas. They stated that SCS as adjuvant during chemotherapy and re-irradiation in relapsed HGGs merits further research.
De Agostino et al (2015) stated that high-cervical SCS is a promising neuro-stimulation method for the control of chronic pain, including chronic cluster headache. The effects of high-cervical SCS in patients with intractable chronic migraine pain are unknown. This study was a retrospective survey of a cohort of 17 consecutive patients with medically intractable chronic migraine pain implanted with a high-cervical SCS device between 2007 and 2011. After a median of 15 months (range of 2 to 48) since implantation, mean pain intensity was significantly reduced by 60 % (p < 0.0001), with 71 % of the patients experiencing a decrease of 50 % or more. The median number of days with migraine decreased from 28 (range of 12 to 28) to 9.0 (range of 0 to 28) days (p = 0.0313). Quality of life was significantly improved (p = 0.0006), and the proportion of patients not requiring pain medication increased from 0.0 % to 37.5 % (p = 0.0313). Use of pharmacological and non-pharmacological treatments of migraine was decreased. Working capacity was not significantly improved. Complications were infrequent: 3 infections (13.0 % of all implanted) and 3 lead dislocations (17.6 % of all included). The authors concluded that in patients with intractable chronic migraine treated with high-cervical SCS, pain and quality of life significantly improved, warranting further research.
Sidiropoulos et al (2014) reported on the clinical effectiveness of epidural thoracic SCS on gait and balance in a 39-year old man with genetically confirmed spinocerebellar ataxia 7. A RESUME Medtronic electrode was placed at the epidural T-11 level. Spatiotemporal gait assessment using an electronic walkway and static posturography were obtained and analyzed in a blinded manner with and without stimulation. The Tinetti Mobility Test was also performed in the 2 conditions. At 11 months after surgery, there was a 3-point improvement in the Tinetti Mobility Test in the on stimulation condition, although there was no statistically significant difference in spatiotemporal gait parameters. Static posturography did not demonstrate a significant improvement in stability measures between the 2 conditions in a stochastic way. The authors concluded that thoracic epidural SCS had a mild but clinically meaningful beneficial effect in improving gait and balance in a patient with SCA-7. They stated that the underlying pathophysiologic mechanisms remain to be elucidated; further experience with SCS in refractory gait disorders is needed.
Walega and Rosenow (2015) observed the effect of thoracic SCS with dual octi-polar epidural electrodes on episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) in a patient with non-ischemic familial cardiomyopathy and severe electrical storm refractory to conventional medical treatment. Following implantation of temporary bilateral octi-polar thoracic epidural electrodes and constant low-grade stimulation, episodes of VT and VF were eradicated, and a permanent system was surgically implanted uneventfully. Electrical storm ceased thereafter, though ventricular function from progressive cardiomyopathy worsened, requiring heart transplantation several months later. The authors concluded that SCS may play an important therapeutic role in the treatment of refractory electrical storm when conventional medical treatments have failed. The mechanism by which stimulation of the spinal cord confers a therapeutic effect is not completely understood, although direct modulation of sympathetic and parasympathetic tone in the cardiac conduction system is most likely, based on animal models of ischemia-induced VT.
Obuchi et al (2015) stated that although sleep disorder is one of the most serious co-morbidities of refractory chronic pain, it is usually assessed only from the patients' subjective point of view. These investigators evaluated the sleep efficiency of patients with chronic pain. Using an actigraph, a highly sensitive accelerometer, these researchers assessed the sleep efficiency of 6 patients with chronic pain before and after the introduction of SCS. While pain improved in only 5 out of 6 patients after SCS, sleep efficiency improved in all cases. Interestingly, in 1 case, sleep efficiency improved even though pain intensity remained unchanged. The authors concluded that with the use of an actigraph, improvements in sleep of patients with chronic pain undergoing SCS were demonstrated. One case showing improvement in sleep despite pain palliation may suggest that SCS might have independently affected the sleep system, although further studies are needed.
In a randomized, double-blind, sham-controlled, cross-over trial, Benussi and colleagues (2018) examined if a 2-week treatment with cerebellar anodal and spinal cathodal transcranial direct current stimulation (tDCS) could reduce symptoms in patients with neurodegenerative ataxia and could modulate cerebello-motor connectivity at the short- and long-term. These investigators performed a study with cerebello-spinal tDCS (5 days/week for 2 weeks) in 20 patients with neurodegenerative ataxia. Each patient underwent a clinical evaluation before and after real tDCS or sham stimulation. A follow-up evaluation was performed at 1 and 3 months with a cross-over washout period of 3 months. Cerebello-motor connectivity was evaluated with transcranial magnetic stimulation at baseline and at each follow-up. Cerebello-spinal tDCS showed a significant improvement in all performance scores (Scale for the Assessment and Rating of Ataxia, International Cooperative Ataxia Rating Scale, 9-Hole Peg Test, 8-meter walking time), in motor cortex excitability, and in cerebellar brain inhibition compared to sham stimulation. The authors concluded that in light of limited pharmacologic and non-pharmacologic therapeutic options for patients with neurodegenerative ataxia, and on the basis of the results of this study, a 2-week treatment with cerebello-spinal tDCS could be considered a potentially promising tool for future rehabilitative approaches.
The authors stated that this study had several drawbacks. Neurodegenerative cerebellar ataxias are considerably uncommon, and this group of patients was relatively small (n = 20) and heterogeneous, so clear-cut associations need to be made with caution. Studies on repetition rate, session duration, and number of sessions have not been performed for cerebellar tDCS,41 and the optimal repetition rate and inter-stimulus interval still have to be determined. Finally, the effect of tDCS on cognitive functions was not objectively assessed in this study. Another important aspect that was not evaluated in this study was the effect of tDCS on orthostatic hypotension, particularly in patients with cerebellar variant of multiple system atrophy, considering the prominent involvement of autonomic pathways in this disease, bearing in mind the possible effects of spinal tDCS on the intermedio-lateral gray columns of the spinal cord. Furthermore, Unified Parkinson's Disease Rating Scale (UPDRS) scores should be assessed in future clinical trials in patients with extra-pyramidal syndromes treated with cerebellar tDCS.
Dorsal Column Stimulation for Orthostatic Tremor
Boogers et al (2022) stated that orthostatic tremor is a rare and debilitating movement disorder; its 1st-line treatment is pharmacological. For pharmacotherapy-refractory patients, surgical therapeutic options such as DBS and SCS have been examined recently. In a systematic review, these investigators examined safety and outcome data on DBS and SCS for patients with orthostatic tremor. They searched PubMed and Embase for studies examining orthostatic tremor patients treated with DBS or SCS. These researchers collected all available safety and outcome data and the primary endpoint was the change in unsupported stance duration 1 year post-operatively (± 6 months). The search identified 15 studies, reporting on 32 orthostatic tremor patients who underwent DBS, 4 patients SCS and 2 both. The ventral intermediate nucleus (VIN) and the zona incerta were targeted in 25/34 and 9/34 DBS cases, respectively. The median stance time at 1 year follow-up was 240 s compared to 30 s pre-operatively (p < 0.001). Stimulation-induced side effects occurred in the majority of patients; however, they were often transient. Bilateral stimulation appeared more effective than unilateral and stimulation settings were comparable to thalamic DBS for ET. There were insufficient data available to draw meaningful conclusions regarding the long-term effects of DBS. Due to insufficient data, no conclusions could be drawn on the effects of SCS on orthostatic tremor. The authors concluded that DBS may be effective to increase stance time in orthostatic tremor patients in the 1st year; however, further investigation is needed to examine the long-term effects and the role of SCS.
Limb Ischemia
A Cochrane review (Ubbink and Vermeulen, 2003) stated that there is evidence to favor DCS over standard conservative treatment to improve limb salvage and clinical situation in patients with inoperable chronic critical leg ischemia. This is in agreement with the findings of Carter (2004) who noted that though limited in quantity and quality, better evidence exists for the use of DCS in neuropathic pain, CRPS, angina pectoris and critical limb ischemia, as well as Cameron (2004) who stated that DCS had a positive, symptomatic, long-term effect in cases of refractory angina pain, severe ischemic limb pain secondary to peripheral vascular disease, peripheral neuropathic pain, and chronic LBP.
Naoumm and Arbid (2013) states that the "treatment of chronic limb ischemia [CLI] involves the restoration of pulsatile blood flow to the distal extremity. Some patients cannot be treated with endovascular means or with open surgery; some may have medical comorbidities that render them unfit for surgery, while others may have persistent ischemia or pain even in the face of previous attempts at reperfusion. In spinal cord stimulation (SCS), a device with electrodes is implanted in the epidural space to stimulate sensory fibers. This activates cell-signaling molecules that in turn cause the release of vasodilatory molecules, a decrease in vascular resistance, and relaxation of smooth muscle cells. SCS also suppresses sympathetic vasoconstriction and pain transmission. When patient selection is based on microcirculatory parameters, SCS therapy can significantly improve pain relief, halt the progression of ulcers, and potentially achieve limb salvage". Thus, patients who are candidates for SCS therapy are those with CLI who have exhausted both open and endovascular options, those whom are unfit for surgery, or those who continue to experience ischemic-related pain following revascularization.
Abu Dabrh et al (2015) reviewed the existing evidence about various non-revascularization-based therapies used to treat patients with severe or critical limb ischemia (CLI) who are not candidates for surgical revascularization. These investigators searched multiple databases through November 2014 for controlled randomized and non-randomized studies comparing the effect of medical therapies (prostaglandin E1 and angiogenic growth factors) and devices (pumps and spinal cord stimulators). They reported odds ratios (ORs) and 95 % CIs of the outcomes of interest pooling data across studies using the random effects model. These researchers included 19 studies that enrolled 2,779 patients. None of the non-revascularization-based treatments were associated with a significant effect on mortality. Intermittent pneumatic compression (OR, 0.14; 95 % CI: 0.04 to 0.55) and spinal cord stimulators (OR, 0.53; 95 % CI: 0.36 to 0.79) were associated with reduced risk of amputation. A priori established subgroup analyses (combined versus single therapy; randomized versus non-randomized) were not statistically significant. The authors concluded that very low-quality evidence, mainly due to imprecision and increased risk of bias, suggested that intermittent pneumatic compression and spinal cord stimulators may reduce the risk of amputations; evidence supporting other medical therapies is insufficient.
An UpToDate review on “Treatment of chronic limb-threatening ischemia” (Neschis and Golden, 2018) states that “Initial uncontrolled studies suggested that spinal cord stimulation was effective for pain relief and might prevent or delay amputation and improve limb survival. However, a controlled trial that randomly assigned 120 patients to spinal cord stimulation in addition to best medical therapy or to best medical therapy alone found that the rates of survival and amputation were the same in both groups. Pain scores were also similar, although the spinal cord stimulation group was able to reduce pain medications by approximately 50 %”. Spinal cord stimulation is not listed in the “Summary and Recommendations” of this review.
In a systematic review, Asimakidou and Matis (2022) studied the efficacy of SCS in non-reconstructable critical limb ischemia (CLI) compared with conservative treatment and re-appraise the existing literature of advances in neuromodulation. A total of 404 records were identified. Six randomized controlled trials (RCTs), a Cochrane review and a meta-analysis were included in their review. The studies assessed the efficacy of tonic SCS in the treatment of patients with non-reconstructable CLI compared with the conservative treatment. The authors found that there is moderate to high quality evidence suggesting, that tonic SCS has beneficial effects for patients suffering from non-reconstructable CLI in terms of limb salvage, pain relief, clinical improvement and quality of life. The contradictory conclusions of the two meta-analyses regarding the efficacy of SCS for limb salvage at 12 months refer rather to the magnitude of the beneficial effect than to the effect itself. Thus far, the literature provides evidence about the traditional tonic SCS; however, there is a lack of studies investigating the efficacy of new waveforms in the treatment of non-reconstructable CLI. The authors concluded that SCS represents an alternative for peripheral vascular disease (PVD) patients with non-reconstructable CLI. Further, the authors state that the existing literature provides encouraging clinical results, that should not be neglected. Instead, they should be re-appraised in light of the recent advances in neuromodulation with the emergence of novel waveform technologies and neuromodulation targets.
Piedade and colleagues (2023) evaluated the therapeutic use of SCS as an option in patients with non-reconstructable critical limb ischemia (CLI). The authors report on a retrospective cohort of CLI patients who were implanted with SCS systems between July 2010 and December 2013 in a single center. The study included 72 CLI patients who underwent SCS implantation, with 35 of them classified as non-reconstructable and 37 with previous but failed or only partially successful vascular procedures. A total of 21 subjects were at Fontaine’s stage III (29.2%), and the remaining 51 were at stage IV (70.8%). In total, 26.4% of the patients had diabetes (n = 19), two of them at Fontaine’s stage III. The mean follow-up was 17.1 ± 10.5 months. At the last follow-up, 59.2% of all patients (42/71), 85.7% of Fontaine’s stage III (18/21), 48.0% of Fontaine’s stage IV (24/50), and 52.6% of diabetic patients (10/19) were alive without major amputation. The authors found the probability of limb survival at 12 months was 72% for all patients, 94% for Fontaine’s stage III, 62% for Fontaine’s stage IV, and 61% for diabetic patients. They noted the probability of survival at 12 months for patients who underwent major limb amputation (n = 25) was 86% with a mean survival time of 31.03 ± 4.63 months. The authors concluded that non-reconstructable CLI patients treated with SCS can achieve meaningful clinical outcomes with few procedure-related complications. Further, the therapy may be more beneficial in patients classified as Fontaine’s Stage III. The authors acknowledged that the interpretation of the outcomes is limited due to the study design was not controlled, and data were collected retrospectively. Their results were derived from a patient population of refractory patients which adds to the growing body of evidence that is broadly supportive of treating selected CLI patients with SCS therapy.
Parkinson's Disease
de Andrade et al (2016) stated that axial symptoms are a late-developing phenomenon in the course of Parkinson's disease (PD) and represent a therapeutic challenge given their poor response to levodopa therapy and deep brain stimulation. Spinal cord stimulation may be a new therapeutic approach for the alleviation of levodopa-resistant motor symptoms of PD. These investigators reviewed the effectiveness of SCS for the treatment of motor symptoms of PD and evaluated the technical and pathophysiological mechanisms that may influence the outcome efficacy of SCS. A comprehensive literature search was conducted using electronic databases for the period from January 1966 through April 2014. The methodology utilized in this work followed a review process derived from evidence-based systematic review and meta-analysis of randomized trials described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Reports examining SCS for the treatment of PD are limited. A total of 8 studies with 24 patients were included in this review. The overall motor score of the Unified Parkinson's Disease Rating Scale in the on/off-stimulation condition remained unchanged in 6 patients and improved in 18 patients after SCS. The authors concluded that SCS appeared to yield positive results for PD symptoms, especially for impairments in gait function and postural stability. However, they stated that the evidence is limited and long-term prospective studies are needed to identify the optimal candidates for SCS and the best parameters of stimulation and to fully characterize the effects of stimulation on motor and non-motor symptoms of PD.
Sphincter of Oddi Dysfunction
Lee and colleagues (2015) noted that sphincter of Oddi dysfunction (SOD) is a syndrome of chronic biliary pain or recurrent pancreatitis due to the functional obstruction of the pancreaticobiliary flow. These investigators reported a case of spinal cord stimulation (SCS) for chronic abdominal pain due to SOD. The patient had a history of cholecystectomy and had suffered from chronic right upper quadrant abdominal pain. The patient had been diagnosed as having SOD. The patient was treated with opioid analgesics and nerve blocks, including a splanchnic nerve block. However, 2 years later, the pain became intractable. These researchers implanted percutaneous SCS at the T5 to T7 level for this patient. Visual analog scale (VAS) scores for pain and the amount of opioid intake decreased. The patient was tracked for more than 6 months without significant complications. The authors concluded that from this clinical case, SCS is an effective and alternative treatment option for SOD. Moreover, they stated that further studies and long-term follow-up are needed to understand the effectiveness and the limitations of SCS on SOD.
Coccydynia
Hope and Gruber (2012) noted that only 1 case report was found that discussed SCS for treatment of coccygodynia after a coccygeal fracture …. The majority of pain that the sacral neuromodulation has previously treated has been chronic pelvic pain that is refractory to other therapies, which often coexists with urinary incontinence or refractory interstitial cystitis. For these 2 indications, it appears that the sacral neuromodulation has a significant improvement in pain. No citations were found that described the use of sacral neuromodulation in terms of coccygeal pain; only SCS has previously been used. The authors concluded that sacral neuromodulation has the potential for treatment of coccygeal pain.
Pain in Chronic Pancreatitis
In a systematic review, Ratnayake and colleagues (2019) examined the effectiveness and complications of SCS in the management of pain associated with chronic pancreatitis (CP). These researchers carried out an exploratory systematic review through a literature search of the PubMed, Medline, Embase, SCOPUS, and Cochrane databases. A total of 7 studies including 31 patients met the inclusion criteria. There was 1 observational cohort study, 2 case series, and 4 case reports. The estimated median age of the study group was 44 years (range of 21 to 87) in primarily non-alcoholic CP (74 %, 23/31). The SCS leads were typically placed at the level of T6 to T8 in the epidural space. All patients reported an improvement in pain. The estimated median reduction of VAS was 61 % (range of 50 % to 100 %) with an estimated median reduction of morphine equivalent opioid use of 69 % (range of 25 % to 100 %) at the end of follow-up (less than 1 year to greater than 2 years). Infection at the site of the lead occurred in 2 of the 31 (6 %) and lead migration in 2 of the 31 (6 %) patients. The authors concluded that the findings of this systematic review suggested that SCS has a potentially effective role in reducing pain and opioid use in patients with CP. These findings need to be validated by well-designed studies.
Meralgia Paresthetica
Barna et al (2005) stated that meralgia paresthetica is a clinical syndrome of pain, dysesthesia or both, in the antero-lateral thigh. It is associated with an entrapment mononeuropathy of the lateral femoral cutaneous nerve. Diagnosis of meralgia paresthetica is typically made clinically and is based on the characteristic location of pain or dysesthesia, sensory abnormality on exam, and absence of any other neurological abnormality in the leg. The majority of patients with meralgia paresthetica respond well to conservative treatment. These researchers presented a case of intractable meralgia paresthetica in which conservative therapeutic options failed but which was successfully treated with a spinal cord stimulator (SCS). This case entailed a 44-year old woman presented to the pain clinic with a 1-year history of bilateral antero-lateral thigh pain. History, physical examination, and diagnostic work-up were consistent with meralgia paresthetica. Multiple medications, physical therapy, and chiropractic therapy were not successful for this patient. In addition, local anesthetic / steroid injection of the lateral femoral cutaneous nerve provided only short-term relief. Ultimately, a SCS was implanted after a successful temporary percutaneous trial. Two months after the implantation, she continued to have 100 % pain relief, worked full-time, was physically active, and no longer required any pain medication including opioids. The authors concluded that an implanted SCS may be an ideal treatment for intractable meralgia paresthetica after conservative treatments have failed because it is not destructive and can always be explanted without significant permanent adverse effects.
Furthermore, an UpToDate review on “Meralgia paresthetica (lateral femoral cutaneous nerve entrapment)” (Anderson, 2019) does not mention spinal cord stimulation as a therapeutic option.
Abdominal Pain Related to Celiac Artery Compression Syndrome
An UpToDate review on “Celiac artery compression syndrome” (Scovell and Hamdan, 2020) does not mention dorsal column stimulation / spinal cord stimulation as a management / therapeutic option.
Neuropathic Pain Associated with Multiple Sclerosis
Barolat et al (1988) reported on the case of a 42-year old man who presented with advanced multiple sclerosis (MS) had severe left-sided trigeminal neuralgia (TN) in the maxillary and mandibular divisions that was extremely difficult to control with medications. Glycerol injection in the Gasserian cystern provided only temporary results. Two electrodes were implanted epidurally at the C1 to C2 level, 1 in the mid-line and the other to the left of mid-line. The authors stated that electrical stimulation (high cervical spinal cord stimulation [SCS]) produced complete relief from the painful paroxysms.
Lam and Monroe (2019) stated that non-paresthesia-free spinal cord stimulation (PF-SCS) has been successfully used in treating central pain syndromes in MS patients. However, the efficacy of PF-SCS in MS is unknown. These researchers presented the case of an MS patient (13-year history) with late-stage disease. Her concomitant central pain and spasticity failed multiple attempts of medical management despite escalating multi-modal pharmacological regimens. A trial and subsequent permanent placement of dorsal column spinal cord stimulator with paresthesia-free programming was successful in managing her central pain, illustrating a potential role of PF-SCS in treating patients with MS.
Furthermore, an UpToDate review on “Symptom management of multiple sclerosis in adults” (Olek et al, 2020) does not mention spinal cord stimulation as a management option.
In a systematic review, Rapisarda and colleagues (2021) examined the effectiveness of SCS in MS patients. They carried out a literature search through different databases (PubMed, Scopus, and Embase) using the following terms: "multiple sclerosis", "spinal cord stimulation", and "dorsal column stimulation" according to PRISMA guidelines. A total of 452 articles were reviewed, and 7 studies were included in the present analysis. A total of 373 MS patients were submitted to a stimulation trial, and 82 MS patients underwent a de-novo implantation; 285/373 (76.4 %) of cases submitted to the SCS trial were enrolled for permanent stimulation. These investigators found a long-lasting improvement in 193/346 (55.8 %) MS patients with motor disorders, in 90/134 (67.13 %) MS patients with urinary dysfunction, and in 28/34 (82.35 %) MS patients with neuropathic pain. The effectiveness of SCS was higher for urinary dysfunction (p = 0.0144) and neuropathic pain (p = 0.0030) compared with motor disorders. The authors concluded that this systematic review showed that SCS was effective in MS patients; urinary dysfunction and pain symptoms appeared to be most responsive to SCS. Moreover, these researchers stated that further studies with longer follow-up are needed to improve the patient selection, clarify the best timing to perform SCS in these patients, and better understand the potential loss of effectiveness of SCS over time. Moreover, these researchers stated that this study had several drawbacks due to the retrospective nature of data and the different evaluation scales used among the different articles. This did not allow further subgroup analyses (different MS types, different motor and urinary symptoms, and different pain locations).
High-Frequency Spinal Cord Stimulation
In a prospective, multi-center, open-label, pilot trial, Tiede et al (2013) examined the feasibility of novel high-frequency spinal cord stimulation therapy in a cohort of patients with chronic predominant back pain during a 4-day, percutaneous trial. A total of 24 patients with back pain greater than leg pain who were candidates for spinal cord stimulation (SCS) were trialed at 5 U.S. centers. Patients completed a percutaneous trial with a commercially available spinal cord stimulator. The implanted leads were then connected to the novel external stimulation device and patients were trialed for an additional 4 days. Outcome measures included pain intensity ratings, subjective descriptions, and patients' preference. There was significant improvement from baseline in overall pain scores (8.68 to 2.03, [p < 0.001]) and back pain scores (8.12 to 1.88, [p < 0.001]) with the investigational stimulation. The investigational stimulation was preferred to the commercially available systems in 21 of 24 patients (88 %). The authors concluded that patients with predominant back pain reported a substantial reduction in overall pain and back pain when trialed with high-frequency SCS therapy.
In a prospective, multi-center, observational study, Al-Kaisy et al (2014) examined the long-term safety and effectiveness of paresthesia-free high-frequency SCS (HF10 SCS) for the treatment of chronic, intractable pain of the low back and legs. Patients with significant chronic low back pain (LBP) underwent implantation of a spinal cord stimulator capable of HF10 SCS. Patients' pain ratings, disability, sleep disturbances, opioid use, satisfaction, and adverse events were assessed for 24 months. Eighty percent of subjects receiving a permanent implant had a diagnosis of failed back surgery syndrome. After a trial period, 88 % (72 of 82) of patients reported a significant improvement in pain scores and underwent the permanent implantation of the system; 90 % (65 of 72) of patients attended a 24-month follow-up visit. Mean back pain was reduced from 8.4 ± 0.1 at baseline to 3.3 ± 0.3 at 24 months (p < 0.001), and mean leg pain from 5.4 ± 0.4 to 2.3 ± 0.3 (p < 0.001). Concomitantly to the pain relief, there were significant decreases in opioid use, Oswestry Disability Index score, and sleep disturbances. Patients' satisfaction and recommendation ratings were high. Adverse Events were similar in type and frequency to those observed with traditional SCS systems.
In a randomized, parallel-arm, non-inferiority study, Kapural et al (2015) compared long-term safety and effectiveness of SCS therapies in patients with back and leg pain. A total of 198 subjects with both back and leg pain were randomized in a 1:1 ratio to a treatment group across 10 comprehensive pain treatment centers. Of these, 171 passed a temporary trial and were implanted with an SCS system. Responders (the primary outcome) were defined as having 50 % or greater back pain reduction with no stimulation-related neurological deficit. In this pivotal trial, about 90 percent of subjects had previous back surgery and 80 percent were categorized as having failed back syndrome. At 3 months, 84.5 % of implanted HF10 therapy subjects were responders for back pain and 83.1 % for leg pain, and 43.8 % of traditional SCS subjects were responders for back pain and 55.5 % for leg pain (p < 0.001 for both back and leg pain comparisons). The relative ratio for responders was 1.9 (95 % confidence interval [CI]: 1.4 to 2.5) for back pain and 1.5 (95 % CI: 1.2 to 1.9) for leg pain. The superiority of HF10 therapy over traditional SCS for leg and back pain was sustained through 12 months (p < 0.001). HF10 therapy subjects did not experience paresthesia. The authors concluded that HF10 therapy promised to substantially impact the management of back and leg pain.
Rapcan et al (2015) presented their clinical experience with HF-SCS for failed back surgery syndrome (FBSS) in patients with predominant LBP. After a trial period, 100 % (21 out of 21) of patients with FBSS with predominant LBP reported a significant improvement in visual analog scale (VAS) pain score and underwent permanent implantation of the HF-SCS system; SCS trials lasted 7 to 14 days (median of 9 days); SCS leads were mostly positioned at the T8 to T10 or T8 to T12 vertebral levels . These researchers used both single and dual lead placement; VAS, patient satisfaction, patient performance status, opioid consumption and complication rate were assessed for the period of 12 months. The mean VAS score before implantation (8.7) compared to VAS 12 months after implantation (4.0) was significantly lower (95 % CI: 3.9 to 5.4], p < 0.001). There was a significant improvement in performance status when comparing PS before implantation (3.0) and 12 months after implantation (1.8) (95 % CI: 0.9 to 1.6], p < 0.001). The mean patient satisfaction scores (PSS) did not differ throughout the whole 1-year follow-up period. The authors concluded that this group of 21 patients with implanted HF-SCS systems reported significant LBP and leg pain relief within the period of 12 months as well as significant improvement in their performance status. There was a special subgroup of 5 patients with regular change of frequencies between high frequency and conventional frequency (with paresthesia) also with significant leg and LBP relief.
Russo and Van Buyten (2015) stated that chronic pain remains a serious public health problem worldwide. A SCS therapy called HF10 SCS uses 10-kHz high-frequency stimulation to provide pain relief without paresthesia. These investigators described the therapy, device, and the methods of implant and then reviewed the safety and effectiveness data for this therapy. HF10 SCS uses a charge-balanced stimulation waveform that has been shown to be safe in both animal and human studies. Data from a multi-center, prospective clinical trial showed that the therapy provided substantial back and leg pain relief. Numerous additional reports suggested improved pain relief in other body areas and for complex pain patterns, even for patients who have previously failed other neuromodulation therapies. The authors concluded that the clinical experience reported in this article supported the effectiveness and pain relief provided by HF10 SCS therapy. Clinical studies have also concluded that HF10 SCS did not generate paresthesia nor was it necessary to provide adequate coverage for pain relief. As clinical evidence accumulates and technological innovation improves patient outcomes, neuro-modulatory techniques will be sought earlier in the treatment continuum to reduce the suffering for the many with otherwise intractable chronic pain.
De Andres and colleagues (2017) noted that SCS for patients with failed back surgery syndrome (FBSS) showed variable results and limited to moderate evidence. In the past several years, high frequency (HF) stimulation has been considered as a better alternative in this pathology for its supposed benefits compared to the stimulation with conventional frequency (CF). In a prospective, blinded, randomized trial, these researchers compared the 1-year follow-up, the efficacy of HF-SCS versus CF- SCS oi the patients with FBSS. A total of 78 patients with FBSS diagnosis based on internationally recognized criteria, and refractory to conservative therapy for at least 6 months, were initially recruited, and 60 subjects met the eligibility criteria and were randomized and scheduled for the trial phase. Subjects were randomly assigned in either 1 of the 2 groups: CF-SCS or HF-SCS. Within the study methods, special attention was paid to standardizing patient programming, so that these parameters would not impact the results. The trial period was considered successful if there was greater than or equal to 50 % reduction in the numeric rating scale (NRS) from baseline. A total of 55 subjects successfully completed all assessments during 1-year follow-up. Change patterns in scores did not differ based on HF versus CF, with significant global average reduction at 1 year similarly for both groups. Among all the items included in the Short Form-12 questionnaire (SF-12), only the variations in the social function score between the instants t1 and t2 were somewhat higher in the HF group. The authors concluded that the evolutionary pattern of the different parameters studied in these patients with FBSS did not differ according to their treatment by spinal stimulation, with CF or HF, in 1-year follow-up.
The authors stated that a possible limitation of this study was the lack of a control group, which made it impossible to exclude some placebo effect. The study conducted by Perruchoud et al (2013) included 40 patients who achieved stable pain relief with CF-SCS and who were randomized to receive either HF-SCS at 5-kHz or a sham control (no stimulation after achieving paresthesia-free stimulation). Complete data were available for 33 patients: the proportion of patients responding under HF-SCS was 42.4 % (14/33 patients) versus 30.3 % (10/33 patients) in the sham group. At the 2-week follow-up, the authors found no statistically significant difference between the 2 stimulation techniques in the PGIC scale, the NRS, and the EuroQoL 5-dimensional (EQ-5 D) index. The small sample and the short follow-up limited the interpretation of these data; however, they did suggest that different frequencies may have different effects.
In a retrospective, multi-center, real-world review, Chen et al (2022) evaluated pain relief and functional improvements for consecutive patients with diabetic neuropathy aged greater than or equal to 18 years of age who were permanently implanted with a high-frequency (10-kHz) SCS device. Available data were extracted from a commercial database. A total 89 patients consented to being included in the analysis; 61 % (54/89) of participants were men and the average age was 64.4 years (SD = 9.1). Most patients (78.7 %, 70/89) identified pain primarily in their feet or legs bilaterally. At the last assessment, 79.5 % (58/73) of patients were treatment-responders, defined as having at least 50 % patient-reported pain relief from baseline. The average time of follow-up was 21.8 months (range of 4.3 to 46.3 months); and a majority of patients reported improvements in sleep and overall function relative to their baseline. The authors concluded that this real-world study in typical clinical practices found 10-kHz SCS provided meaningful pain relief for a substantial proportion of patients who were refractory to current PDN management, similar to published literature. This patient population has tremendous unmet needs; and this study helped in demonstrating the potential for 10-kHz SCS to provide an alternative pain management approach.
The authors stated that this analysis had several drawbacks due to use of a commercial database. First, the retrospective nature of this study limited the systematic collection of patient data, including clinical characteristics, medication use, implantation details and QOL measures. Furthermore, given the last visit approach of the data analysis, patients were at varying time-points since permanent device implantation. Finally, analyses included in the study were limited to available data that were not collected uniformly for all patients. The lack of randomization plus need for insurance approval could also introduce selection bias for the patients who receive treatment and may not be representative of the broader population.
Strand and Burkey (2022) carried out a review to examine the evidence for SCS from published RCTs as well as prospective studies exploring the safety and effectiveness of treating PDN with neuromodulation. A total of 2 RCTs enrolling 60 and 36 participants with PDN showed treatment with conventional low-frequency SCS (LF-SCS) reduced daytime pain by 45 % to 55 % for up to 2 years. An RCT testing 10-kHz SCS versus CMM in 216 participants with PDN revealed 76 % mean pain relief after 6 months of stimulation. None of the studies revealed unexpected safety issues in the use of neuromodulation in this patient population. The authors concluded that there is currently a substantial unmet need for safe and effective treatments for PDN. Many patients with PDN do not benefit from pharmacotherapies in current use and are candidates for treatment with neuromodulation. Conventional LF-SCS and high-frequency 10-kHz SCS are supported by high-quality evidence from RCTs and prospective studies. High-frequency 10-kHz SCS offers several advantages over LF-SCS, including greater pain relief, a higher proportion of patients achieving treatment success, paresthesia-independence, and evidence of improved neurological function. Neuromodulation with SCS, especially with 10-kHz SCS, offers a pathway forward for improving the lives of PDN patients.
Burst Spinal Cord Stimulation
Burst waveform is a quick succession or “cluster” of five 1 millisecond pulses, separated by 1 ms (500 Hz). Deer, et al. (2017) conducted a multicenter, randomized, unblinded, crossover study (Success Using Neuromodulation with BURST (SUNBURST)) to determine the safety and efficacy of a device delivering both traditional tonic stimulation and burst stimulation to patients with chronic pain of the trunk and/or limbs. Following a successful tonic trial, 100 subjects were randomized to receive one stimulation mode for the first 12 weeks, and then the other stimulation mode for the next 12 weeks. The primary endpoint assessed the noninferiority of the within-subject difference between tonic and burst for the mean daily overall VAS score. An intention-to-treat analysis was conducted using data at the 12- and 24-week visits. Subjects then used the stimulation mode of their choice and were followed for one year. Descriptive statistics were used analyze additional endpoints and to characterize the safety profile of the device. The investigators reported that the SUNBURST study demonstrated that burst stimulation is non-inferior to tonic stimulation (p < 0.001). The investigators reported that superiority of burst was also achieved (p < 0.017). The investigators stated that significantly more subjects (70.8%) preferred burst stimulation over tonic stimulation (p < 0.001). Preference was sustained through one year: 68.2% of subjects preferred burst stimulation, 23.9% of subjects preferred tonic, and 8.0% of subjects had no preference. The investigators stated that no unanticipated adverse events were reported and the safety profile was similar to other spinal cord stimulation studies. The investigators concluded that the SUNBURST study demonstrated that burst spinal cord stimulation is safe and effective. The authors stated that burst stimulation was not only noninferior but also superior to tonic stimulation for the treatment of chronic pain. The investigators stated that a multimodal stimulation device has advantages.
Spinal Cord Stimulators with Extra Contacts/Leads
Standard spinal cord stimulators use up to 16 contacts/electrodes or up to 2 leads. Nuvectra Medical’s Algovita spinal cord stimulator has the capability for up to three leads with a lead portfolio of both 8 and 12 contact leads. Stimwave spinal cord stimulator has the ability for physicians to utilize a configuration of up to 64 contacts.
Boston Scientific is currently developing a 4-lead, 32 electrode spinal cord stimulator (the Precision Spectra System) to increase the effectiveness of dorsal column stimulation. In 2013, the manufacturer initiated the LUMINA study to test the hypothesis that the 4-lead, 32 contact Precision Spectrum System can provide effective low back pain relief. Preliminary results of this study have been presented in abstract form (Hayek, et al., 2015), and study results have been published.
In a multi-center, open-label, observational study with an observational arm and retrospective analysis of a matched cohort, Veizi and colleagues (2017) examined if SCS using 3D neural targeting provided sustained overall and LBP relief in a broad routine clinical practice population. After implantable pulse generator (IPG) implantation, programming was carried out using a patient-specific, model-based algorithm to adjust for lead position (3D neural targeting) or previous generation software (traditional). Demographics, medical histories, SCS parameters, pain locations, pain intensities, disabilities, and safety data were collected for all participants. A total of 213 patients using 3D neural targeting were included, with a trial-to-implant ratio of 86 %. Patients used 7 different lead configurations, with 62 % receiving 24 to 32 contacts, and a broad range of stimulation parameters utilizing a mean of 14.3 (± 6.1) contacts. At 24 months post-implant, pain intensity decreased significantly from baseline (ΔNRS = 4.2, n = 169, p < 0.0001) and even more in in the severe pain subgroup (ΔNRS = 5.3, n = 91, p < 0.0001). Axial LBP also decreased significantly from baseline to 24 months (ΔNRS = 4.1, n = 70, p < 0.0001, on the overall cohort and ΔNRS = 5.6, n = 38, on the severe subgroup). Matched cohort comparison with 213 patients treated with traditional SCS at the same centers showed overall pain responder rates of 51 % (traditional SCS) and 74 % (neural targeting SCS) and axial LBP responder rates of 41 % and 71 % in the traditional SCS and neural targeting SCS cohorts, respectively. Lastly, complications occurred in a total of 33 of the 213 patients, with a 1.6 % lead replacement rate and a 1.6 % explant rate. The authors concluded that these findings suggested that 3D neural targeting SCS and its associated hardware flexibility provided effective treatment for both chronic leg and chronic axial LBP that was significantly superior to traditional SCS.
The authors noted that this study had several drawbacks:
- the combination of an observational design with statistical cohort matching is a powerful way of achieving valid comparisons between the 2 treatment groups without compromising the pragmatic generalizability of the study results. However, it is important to recognize that unknown confounding variables may exist and this comparison method in this study did not incorporate prospective randomization,
- the measurement of LBP relied only on the axial LBP patients in this study, not patients with both LBP and leg pain. These researchers chose this approach because these patients provided the cleanest signal of LBP improvement, without the confounding matters of additional pain areas. Additionally, axial LBP patients have historically been the most challenging. Consequently, measuring LBP outcomes in these patients is conservative and may mark the minimal expected improvement with this 3D neural targeting for LBP,
- the study’s inclusion and exclusion criteria were purposefully left almost entirely open, with the exception of age and on-label treatment, in order to best mirror real world clinical practice. While the authors believed that this generalizability is critical to the objective of the study, it did inherently result in patient heterogeneity. In fact, it was precisely this heterogeneity that these researchers sought to capture,
- a limitation of the study was that the outcomes reflect mean improvements, some of which may be different among different patient subgroups and etiologies, and
- this study did not attempt to differentiate the pain types and the phenotype(s) that is (are) responsive to SCS (nature of chronic pain may be nociceptive, neuropathic, or mixed).
Dorsal Root Ganglion Stimulation
A technique with a different neural target than dorsal column stimulation is dorsal root ganglion stimulation (Thompson, 2016). Electrodes are placed through the intra-spinal epidural space in contact with the sensory dorsal root ganglia. Electrical fields are generated that can selectively stimulate different parts of the dorsal root ganglia. This is intended to allow focusing of stimulation onto specific nerve roots or parts of nerve roots.
In a pilot and feasibility 2-phase study, Weiner et al (2016) tested a miniaturized neurostimulator transforaminally placed at the dorsal root ganglion (DRG) and evaluated the device's safety and effectiveness in treating failed back surgery syndrome (FBSS) low back pain (LBP). A total of 11 subjects with chronic intractable neuropathic trunk and/or lower limbs pain were included. The system consisted of an implantable, miniaturized stimulator, provided by Stimwave Technologies (Freedom-4) and an external transmitter. Only 1 stimulator per subject was implanted unilaterally and transforaminally at L1 to L5 levels. During phase 1 of the study, the stimulators were not anchored. In phase 2, the stimulators were anchored. Subjects were treated during 45 days after which the stimulator was removed. Pain reduction, implant duration, and stimulator migration were registered. Overall pain reduction was 59.9 %, with only 1 device placed at 1 location, covering only a portion of the painful areas in the majority of the subjects. In phase 1, the non-anchored stimulators migrated a mean of 8.80 mm and in phase 2 a mean of 1.83 mm. Stimulator migration did not correlate with changes in pain relief. Mean time-to-implant duration was 10 minutes and no adverse events were reported during implant, follow-up period, or after explant. The authors concluded that the pain reduction results indicated that the Freedom-4 spinal cord stimulation (SCS) Wireless System is a viable treatment of LBP through stimulation of the DRG, and better overall pain reduction may be achieved by implanting multiple devices. They stated that with short percutaneous implant times and excellent safety profile, this new system may offer health cost savings. This was a small (n = 11) study with short duration ( 45 days). The findings of this pilot and feasibility study need to be validated by well-designed studies.
A commercially sponsored uncontrolled trial reported on outcomes of DRG stimulation in complex regional pain syndrome (Liem et al, 2015). Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to 4 percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. The investigators reported that, overall, pain was reduced by 56 % at 12 months post-implantation, and 60 % of subjects reported greater than 50 % improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42 %, 62 %, and 80 %, respectively. Measures of quality of life and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. Importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months.
Schu et al (2015) reported on a retrospective study of DRG in patients with groin pain of various etiologies. Data from 29 patients with neuropathic groin pain were reviewed. Patients underwent trial therapy where specifically designed leads were implanted at the target DRGs between T12 and L4. Patients who had a successful trial (> 50% improvement) received the fully implantable neuromodulation system. Pain scores were captured on a visual analog scale (VAS) at baseline and at regular follow-up visits. Twenty-five patients (86.2%) received fully implantable neurostimulators, and the average follow-up period was 27.8 ± 4.3 (standard error of the mean, SEM) weeks. The average pain reduction was 71.4 ± 5.6%, and 82.6% (19/23) of patients experienced a > 50% reduction in their pain at the latest follow-up. Individual cases showed improvement with a variety of etiologies and pain distributions; a sub-analysis of post-herniorrhaphy cohort also showed significant improvement.
Eldabe et al (2015) reported on outcomes of DRG in phantom limb pain (PLP). Patients trialed a DRG neuro-stimulation system for their PLP and were subsequently implanted if results were positive. Retrospective chart review was completed, including pain ratings on a 100-mm visual analogue scale (VAS) and patient-reported outcomes. Across eight patients, the average baseline pain rating was 85.5 mm. At follow-up (mean of 14.4 months), pain was rated at 43.5 mm. Subjective ratings of quality of life and functional capacity improved. Some patients reduced or eliminated pain medications. Patients reported precise concordance of the paresthesia with painful regions, including in their phantom limbs; in one case, stimulation eliminated PLP as well as nonpainful phantom sensations. Three patients experienced a diminution of pain relief, despite good initial outcomes.
van Buyten et al (2015) reported on a prospective case series of DRG in complex regional pain syndrome. Eleven subjects diagnosed with uni- or bilateral lower-extremity CRPS were recruited as part of a larger study involving chronic pain of heterogeneous etiologies. Quadripolar epidural leads of a neuro-stimulation system were placed near lumbar DRGs using conventional percutaneous techniques. The neurostimulators were trialed; 8 were successful and permanently implanted and programed to achieve optimal pain-paresthesia overlap. The investigators reported that all 8 subjects experienced some degree of pain relief and subjective improvement in function, as measured by multiple metrics. One month after implantation of the neurostimulator, there was significant reduction in average self-reported pain to 62% relative to baseline values. Pain relief persisted through 12 months in most subjects.
Rowland et al (2016) reported the 1st case of successful implantation of a DRG stimulator at L1 and L2 for sustained improvement in chronic pelvic girdle pain. Additional case reports have been published on DRG in upper extremity complex regional pain syndrome (Garg and Danesh, 2015), and in complex regional pain syndrome of the knee (van Bussel, et al, 2015).
Deer and colleagues (2017) stated that animal and human studies indicated that electrical stimulation of DRG neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multi-center, randomized-comparative effectiveness trial, was conducted in 152 subjects diagnosed with CRPS or causalgia in the lower extremities. Subjects received neuro-stimulation of the DRG or DCS. The primary end-point was a composite of safety and effectiveness at 3 months and subjects were assessed through 12 months for long-term outcomes and adverse events (AEs). The pre-defined primary composite end-point of treatment success was met for subjects with a permanent implant who reported 50 % or greater decrease in VAS from pre-implant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving greater than or equal to 50 % pain relief and treatment success was greater in the DRG arm (81.2 %) versus the DCS arm (55.7 %, p < 0.001) at 3 months. Device-related and serious AEs were not different between the 2 groups; DRG stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (p < 0.001) and reduced extraneous stimulation in non-painful areas (p = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. The authors concluded that as the largest prospective, randomized comparative effectiveness trial to date, the results showed DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS. These encouraging findings need to be validated by well-designed RCTs.
This unblinded study had several drawbacks that may affect the interpretation of the results. The calculated success rate was contingent upon subjects not only achieving 50 % pain relief but also continuing in the study (drop-outs were counted as failures). Therefore, the success rate could be influenced by factors associated with the lack of blinded treatments (e.g., spinal cord stimulation (SCS) subjects were less motivated to stay in the trial, uncontrolled differences in health care provider interactions). In addition, subjects were required to maintain a stable regimen of pain medications through 3 months only, and the long-term results after 3 months may be affected by medication changes. The SCS device also had limitations placed on the programming of the device so that the comparison between the devices was not confounded by unique SCS device programming features. In particular, the accelerometer function in the SCS device was disabled. If the accelerometer was enabled, the SCS group may have had less postural changes in perceived paresthesia intensity. In addition, the analysis of subjects who did and did not experience paresthesia when stimulation was on was confounded by the fact that the SCS device instruction for use requires the device to be programmed for subjects to receive paresthesia. In addition, the number of subjects who did not have paresthesia was very small, and this end-point was not adequately powered to detect the difference in pain relief for subjects who reported feeling versus not feeling paresthesia.
Maino et al (2017) noted that small fiber neuropathy is a disorder of the peripheral nerves with typical symptoms of burning, sharp, and shooting pain and sensory disturbances in the feet. Pain treatment depends principally on the underlying etiology with concurrent administration of anti-depressants, anti-convulsants, opioids, and topical treatments like capsaicin and local anesthetics. However, treatments for pain relief in these patients frequently fail. These investigators described the first case of intractable painful small fiber neuropathy of the foot successfully treated with SCS of the left L5 DRG. A 74-year old man presented at the authors’ clinic with severe intractable pain, dysesthesia, and allodynia of the left foot caused by idiopathic small fiber neuropathy, confirmed by skin biopsy. His pain score was 8 on a standard 0 to 10 numeric rating scale. As the pain was not satisfactorily controlled by conventional therapy, DRG stimulation was proposed to the patient and, after informed consent, a specifically designed percutaneous stimulation lead was placed over the left L5 DRG and connected to an external neuro-stimulator. After a positive trial of 10 days, a permanent neuro-stimulator was implanted. Twenty months post-implantation the patient continued to experience stimulation-induced paresthesia covering the entire pain area and reported a pain rating of 4. The authors concluded that results from the case report demonstrated that the DRG is a promising neural stimulation target to treat neuropathic pain due to intractable small fiber neuropathy. Moreover, they stated that prospective controlled studies are needed to confirm the effectiveness of this treatment as an option for the afore-mentioned condition.
Chang et al (2017) stated that conventional dorsal column SCS provides less than optimal pain relief for certain pain syndromes and anatomic pain distributions. Practitioners have sought to treat these challenging therapeutic areas with stimulation of alternate intra-spinal targets. These investigators systematically reviewed the evidence for the value neuro-modulating specific neuronal targets within the spinal canal to achieve relief of chronic pain. They performed a systematic literature search using PubMed for clinical trials published from 1966 to March 1, 2015 to identify neuro-stimulation studies that employed non-dorsal column intra-spinal stimulation to achieve pain relief. Identified studies on such targeted intra-spinal stimulation were reviewed and graded using Evidence Based Interventional Pain Medicine criteria. These researchers found a total of 13 articles that satisfied the search criteria on targeted, non-dorsal column intra-spinal stimulation for pain. They identified 5 studies on neuro-stimulation of the cervico-medullary junction, 6 studies on neuro-stimulation of the DRG, 2 studies on the neuro-stimulation of the conus medullaris, unfortunately none was found on intra-spinal nerve root stimulation. The authors concluded that clinical use of intra-spinal neuro-stimulation is expanding at a very fast pace. Intra-spinal stimulation of non-dorsal column targets may well be the future of neuro-stimulation as it provides new clinically significant neuro-modulation of specific therapeutic targets that are not well or not easily addressed with conventional dorsal column SCS. In addition, they may avoid undesired stimulation-induced paresthesia, particularly in non-painful areas of the body. The limitations of this review included the relative paucity of well-designed prospective studies on targeted SCS.
Huygen et al (2018) noted that chronic low back pain (LBP) affects millions of people worldwide and can arise through a variety of clinical origins. In the case of failed back surgery syndrome (FBSS), previous surgical procedures can contribute to LBP that is often unresponsive to intervention. Although SCS can be an effective treatment modality, it does not provide sufficient pain relief for some intractable cases. Recently, alternative neuro-modulation options have been developed, including DRG stimulation. These researchers further examined these clinical observations. A total of 12 patients with significant chronic discogenic LBP due to FBSS were included. All subjects were implanted with DRG stimulation systems that had at least 1 lead placed at L2 or L3. Subjects' pain ratings, mood, and quality of life (QOL) was tracked prospectively for up to 12 months. More than 50 % of subjects reported 50 % or better pain relief in the low back, and the average LBP relief was 45.5 % at 12 months. Concomitant reductions in overall pain, leg pain, pain interference, mood, and QOL were also found. The authors concluded that for the studied population, DRG stimulation at the L2 to L3 levels was effective at relieving LBP. These reductions in pain were associated with improvements in QOL. Thus, DRG stimulation at these levels may be effective for LBP by recruiting both segmental and non-segmental neural pathways that are not otherwise accessible via traditional SCS. This was a small study (n = 12) with moderate follow-up (up to 12 months). These findings need to be validated by well-designed studies.
Vuka and colleagues (2018) stated that DRG has recently emerged as an attractive target for neuromodulation therapy since primary sensory neurons and their soma in DRGs are important sites for pathophysiologic changes that lead to neuropathic pain. These investigators created evidence synthesis regarding the effects of electrical stimulation of DRG in the context of pain from in-vitro and in-vivo animal models, analyzed methodology and quality of studies in the field. For conducting systematic review the researchers searched 3 data bases: Medline, Embase and Web of Science. The quality of included studies was assessed with the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool for animal studies. The study was registered in the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies data base. They included 6 in-vitro and 8 in-vivo animal studies. All included in-vitro studies combined neuro-stimulation with substances or drugs and reported an improvement in pain-related parameters due to neuro-stimulation. Among in-vivo studies, 6 used pulsed radiofrequency, while 2 used electrical field stimulation. All in-vivo studies reported improvement in pain-related behavior following stimulation. Meta-analysis was not possible because of heterogeneity and missing data. The quality of included studies was sub-optimal since all had an unclear risk of bias in multiple domains. The authors concluded that limited data from in-vitro and in-vivo animal studies indicated that electrical stimulation of DRG has a positive therapeutic effect in the context of pain-related outcomes. Moreover, they stated that further studies with a standardized methodological approach and outcomes will provide useful information about electrical stimulation of DRG in animal models.
Additional well-controlled clinical trials are necessary to assess the effectiveness of DRG in complex regional pain syndrome and in neuropathic pain of other etiologies.
Hunter and Yang (2019) stated that chronic pelvic pain (CPP) is an elusive and complex neuropathic condition that is notoriously recalcitrant to treatment. The term "CPP" encompasses a number of treatment-resistant conditions like pudendal neuralgia, interstitial cystitis, coccygodynia, vulvodynia. CPP has been presented neuromodulators attempting to utilize conventional SCS, with constant frustration and high explant rates. Contrary to SCS, DRG stimulation (DRGS) delivers targeted target to focal areas, does not rely on paresthesia, and is able to reliably capture body parts like the pelvis making it an ideal modality for the treatment of CPP. These researchers presented 7 patients with intractable CPP, resistant to conventional treatment methods, all successfully treated with DRGS. The case-series study included 7 patients with severe, CPP who failed to respond to a variety interventional treatments, and in some cases SCS. All 7 patients were successfully trialed with DRGS utilizing leads placed over the bilateral L1 and S2 DRG's -- to the authors’ knowledge, no publications describing either this particular lead configuration, or utilizing DRS on CPP, exist. Following treatment, all 7 patients experienced significant pain relief as well as reduction in opioid consumption and in some cases improvement with sexual function and urination; 4 of these patients have been implanted and continue to self-report sustained pain relief with high-satisfaction and functional improvement. To-date no explants or instances of loss of efficacy have occurred (greater than 1 year since implant). The authors concluded that like most neuropathic pain states, CPP was resilient, difficult to manage, and typically unresponsive to the traditional therapeutics and SCS. The findings of this case-series study demonstrated not only that DRGS is potentially an effective, long-term treatment modality for CPP, but that the L1/S2 lead placement is the configuration of choice despite distinct differences in etiologies of pain and location.
An UpToDate review on “Meralgia paresthetica (lateral femoral cutaneous nerve entrapment)” (Anderson, 2019) does not mention dorsal root ganglion stimulation as a therapeutic option.
Medical Necessity of Leads and Electrodes/Contacts
For spinal cord stimulation lead placement procedures, Medicare has established medically unlikely edits for both the physician and facility services. Medicare has established a MUE of 2 for "percutaneous implantation of neurostimulator electrode array, epidural" (CPT code 63650), an MUE of 1 for laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural" (CPT code 63655) and an MUE of 1 for "insertion and replacement of spinal neurostimulator pulse generator or receiver, direct or inductive coupling" (CPT code 63685).
Combined Use of Dorsal Column Stimulation and Dorsal Root Ganglion Stimulation
Yang and colleagues (2015) stated that electrical stimulation at the dorsal column (DC) and dorsal root (DR) may inhibit spinal wide-dynamic-range (WDR) neuronal activity in nerve-injured rats. These researchers examined if applying electrical conditioning stimulation (CS) at both sites provides additive or synergistic benefits. By conducting in-vivo extra-cellular recordings of WDR neurons in rats that had undergone L5 spinal nerve ligation, these investigators tested whether combining 50-Hz CS at the 2 sites in either a concurrent (2.5 mins) or alternate (5 mins) pattern inhibits WDR neuronal activity better than CS at DC alone (5 mins). The intensities of CS were determined by recording antidromic compound action potentials to graded stimulation at the DC and DR. These researchers measured the current thresholds that resulted in the first detectable Aα/β waveform (Ab0) and the peak Aα/β waveform (Ab1) to select CS intensity at each site. The same number of electrical pulses and amount of current were delivered in different patterns to allow comparison. At a moderate intensity of 50 % (Ab0+Ab1), different patterns of CS all attenuated the C-component of WDR neurons in response to graded intra-cutaneous electrical stimuli (0.1 to 10 mA, 2 ms), and inhibited windup in response to repetitive noxious stimuli (0.5-Hz). However, the inhibitory effects did not differ significantly between different patterns. At the lower intensity (Ab0), no CS inhibited WDR neurons. The authors concluded that the findings of this study suggested that combined stimulation of DC and DR may not be superior to DC stimulation alone for inhibition of WDR neurons.
Yang and Hunter (2017) stated that the efficacy of traditional SCS (t-SCS) tends to decay over time in patients with CRPS. While it has been shown that DRG stimulation is extremely effective in t-SCS-naïve patients with CRPS, its efficacy in patients who had previously failed t-SCS is unknown. Given that DRG-SCS and t-SCS target different spinal pathways, a failure with t-SCS should not automatically preclude a patient from attempting DRG-SCS. Two patients with lower extremity CRPS, previously implanted with t-SCS systems, experienced relapses in the pain despite exhaustive re-programming. Both patients were offered DRG stimulation as a means to salvage treatment. Patient 1 reported 90 % pain reduction with significant gait improvement during the DRG stimulation trial. The patient subsequently proceeded to implant and had the t-SCS implantable pulse generator explanted. Patient 2 was unable to undergo a trial with DRG-SCS because of health insurance constraints, so she elected to undergo a surgical revision of her existing system whereby a DRG-SCS system was added to the existing t-SCS to create a hybrid system with 2 implantable pulse generators. The patient reported an immediate improvement in pain because of the introduction of the DRG-SCS. Additionally, she was instructed to document her pain scores with each system on individually, as well as with both on -- her pain scores were at the lowest with the DRG-SCS on by itself. At 8-month follow-up, both patients reported sustained pain improvement and retained their functional gains. The authors concluded that this case series demonstrated that a failure of t-SCS is not necessarily a failure of neuro-stimulation as a whole. The efficacy of DRG-SCS was independent of prior t-SCS therapy outcomes in these 2 patients and a history of t-SCS failure served no predictive value in these 2 patients for future DRG stimulation success. Thus, the authors concluded that DRG-SCS could be considered as a reasonable next-step to salvage patients with CRPS who had failed other SCS treatments.
Goebel and co-workers (2018) noted that limb amputation is sometimes being performed in long-standing CRPS, although little evidence is available guiding management decisions, including how CRPS recurrence should be managed. This report detailed the management of a young soldier with CRPS recurrence 2 years after mid-tibial amputation for CRPS. Conventional SCS did not achieve paresthetic coverage, or pain relief in the stump, whereas L4 DRG stimulation achieved both coverage and initially modest pain relief, and over time, substantial pain relief. The authors concluded that current evidence does not support the use of amputation to improve either pain or function in CRPS. Before a decision is made, in exceptional cases, about referral for amputation, DRG stimulation should be considered as a potentially effective treatment, even where conventional SCS has failed to achieve reliable paresthetic cover. Furthermore, this treatment may provide pain relief in those patients with CRPS recurrence in the stump after amputation.
There is currently insufficient evidence to support the combined use of dorsal column stimulation and dorsal root ganglion stimulation for the treatment of CRPS or any other indications.
Dorsal Column Stimulation for the Treatment of Guillain Barre Syndrome
UpToDate reviews on “Guillain-Barré syndrome in adults: Treatment and prognosis” (Muley, 2021), and “Guillain-Barré syndrome in children: Treatment and prognosis” (Ryan, 2021) do not mention spinal cord stimulator/stimulation as a management / therapeutic option.
Medtronic’s DTM™ SCS for the Treatment of Chronic Pain
Medtronic’s DTM™ SCS is a spinal cord stimulation therapy delivered via the Intellis™ SCS platform to treat patients with chronic, intractable pain. It is a proprietary therapy supported by pre-clinical research and clinical research with level 1 evidence at 12-month follow-up from a RCT (Fishman et al, 2020), which was presented at a Medtronic webinar; it has not gone through the peer-reviewed process.
The data reported were from an RCT in which SCS patients were randomized to either the treatment or control arm, with 79 subjects implanted and followed over the course of 12 months. The study previously met its primary endpoint of non-inferiority compared with conventional SCS at 3 months, and a pre-specified secondary statistical test for superiority showing the difference between DTM SCS and conventional SCS as highly significant. Medtronic previously reported 3-month data from the trial in January 2020. At 12 months, 84 % of patients with chronic back pain treated with DTM SCS reported at least 50 % pain relief, compared to 51 % of patients treated with conventional SCS (p = 0.0005). There was also a difference in the proportion of patients who reported profound back pain relief (greater than 80 % reduction in VAS score) favoring DTM SCS (69 %) compared with conventional SCS (35.1 %). The study met its primary endpoint at 3 months, and in pre-specified secondary analysis showed the superiority of DTM SCS compared to conventional SCS and has sustained these results at 12 months. Pain relief was measured by the VAS; 50 % pain relief, as measured by VAS, is a recognized industry standard to define therapy success. The majority of DTM SCS patients in this study exceeded this threshold, with 7 of 10 experiencing profound back pain relief at 12 months. Patients treated with DTM SCS also reported an average VAS score reduction of 75 % in back pain, compared with 50 % treated with conventional SCS. Average VAS scores for patients treated with DTM SCS at 12 months were 1.74 for back pain and 1.45 for leg pain. The term remitter has previously been used to classify patients with a pain score of 2.5 or less. As a group, patients in the DTM SCS group fell below this level with a mean VAS score of 1.74 for back pain and 1.4 for leg pain. The authors concluded that DTM SCS has the potential to improve outcomes for patients with chronic back pain.
Smith et al (2021) noted that while numerous studies and patient experiences have demonstrated the efficacy of SCS as a treatment for chronic neuropathic pain, the exact mechanism underlying this therapy is still uncertain. Recent studies highlighting the importance of microglial cells in chronic pain and characterizing microglial activation transcriptomes have created a focus on microglia in pain research. This research group has examined the modulation of gene expression in neurons and glial cells after SCS, specifically focusing on transcriptomic changes induced by varying SCS stimulation parameters. Previous research showed that, in rodents subjected to the spared nerve injury (SNI) model of neuropathic pain, a differential target multiplexed programming (DTMP) approach provided significantly better relief of pain-like behavior compared to high-rate programming (HRP) and low-rate programming (LRP). While these studies demonstrated the importance of transcriptomic changes in SCS mechanism of action, they did not specifically address the role of SCS in microglial activation. These investigators used microglia-specific activation transcriptomes to further understand how an SNI model of chronic pain and subsequent continuous SCS treatment with either DTMP, HRP, or LRP affects microglial activation. Genes for each activation transcriptome were identified within the authors’ dataset and gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations indicated that DTMP yielded the highest significant correlations to expression levels found in the healthy animals across all microglial activation transcriptomes. In contrast, HRP or LRP yielded weak or very weak correlations for these transcriptomes. The authors concluded that this study demonstrated that chronic pain and subsequent SCS treatments can modulate microglial activation transcriptomes, supporting previous research on microglia in chronic pain. Furthermore, this study provided evidence that DTMP was more effective than HRP and LRP at modulating microglial transcriptomes, offering potential insight into the therapeutic efficacy of DTMP.
The authors stated that this study had several drawbacks. First, the functional similarity of microglia in both mice and rats implied a similarity in the microglia-specific transcriptomes for various microglial activation states. Second, the limited data on microglia-specific transcriptomes for different activation states served to highlight the importance of this study in terms of the effects of a pain model and SCS therapy and should encourage further research into this space. Third, this study was gender-biased by design since female rats were not included. It is plausible that different results could have been obtained when using female rats based on evidence that suggested a gender-dependent mechanism on mechanical hypersensitivity in mice pain models, and gene expression in a rat pain model. These researchers stated that future studies should include animals of both genders to determine sex-based differences in microglia activation patterns.
Transcutaneous Spinal Cord Stimulation for Motor Rehabilitation in Individuals with Spinal Cord Injury
Taylor and colleagues (2021) stated that transcutaneous SCS (tSCS) is a non-invasive modality in which electrodes can stimulate spinal circuitries and facilitate a motor response. In a systematic review, these researchers examined the methodology of studies using tSCS to generate motor activity in persons with SCI and assessed the quality of included trials. They carried out a systematic search for studies published until May 2021 of the following databases: Embase, Medline (Ovid) and Web of Science. Two reviewers independently screened the studies, extracted the data, and examined the quality of included trials. The electrical characteristics of stimulation were summarized to allow for comparison across studies. Furthermore, the surface EMG (sEMG) recording methods were evaluated. A total of 3,753 articles were initially screened, of which 25 met the criteria for inclusion. Studies were divided into those using tSCS for neurophysiological investigations of reflex responses (n = 9) and therapeutic investigations of motor recovery (n = 16). The overall quality of evidence was deemed to be poor-to-fair (10.5 ± 4.9) based on the Downs and Black Quality Checklist criteria. The electrical characteristics were collated to establish the dosage range across stimulation trials. The methods employed by included studies relating to stimulation parameters and outcome measurement varied extensively, although some trends are beginning to appear in relation to electrode configuration and EMG outcomes. The authors concluded that the results of this systematic review indicated that studies examining the effects of tSCS interventions for individuals with SCI face both methodological and measurement deficiencies. While initial investigations have improved the understanding of the neurophysiological impact of this technology and demonstrated its feasibility in motor rehabilitation, greater homogeneity in the reporting of stimulation parameters and outcome measurement are needed to pool cumulative outcomes from small sample sizes. A higher quality of studies will be needed to demonstrate conclusive evidence on the standardized application and uses of tSCS.
The authors stated that this review had several drawbacks. As a consequence of the variance in terminology in this field and the lack of standardized nomenclature, it was possible that relevant studies may have been missed by their search strategy. furthermore, the eligibility criteria included studies using EMG outcomes; thus, other studies detailing the tSCS parameters may have been excluded. Finally, study outcomes were not possible to pool due to the heterogeneity of included experiments; therefore, conclusions regarding the optimal stimulation parameters and study protocols cannot be drawn. These researchers stated that future research must directly examine the effects of different tSCS parameters to determine the optimal conditions for desired motor outcomes. Greater justification for the selection of therapeutic stimulation parameters needs to be provided by experiments that bridge the gap in the understanding of parameter optimization, clinical application, and the mechanisms that promote motor recovery. The quality of future trials would be improved with better reporting of recruitment methods and intervention protocols and with the application of techniques such as randomization and sham-stimulation. The presence or absence of AEs must be detailed to provide a larger evidence base supporting the safety and feasibility. Finally, studies must also include improvement of the methodological rigor for data collection, processing and reporting in particular of EMG data.
McHugh and associates (2021) noted that epidural SCS (ESCS) emerged as a technology for eliciting motor function in the 1990's and was subsequently employed therapeutically in patients with SCI. Despite a considerable number of ESCS studies, a comprehensive systematic review of ESCS remains unpublished. These investigators carried out a review of the current literature that studied the effectiveness of ESCS for improving motor function in individuals with SCI. The conducted a search for ESCS studies using the following databases: Medline (Ovid), Web of Science and Embase. Furthermore, to maximize results, an inverse manual search of references cited by identified articles was also performed. Studies published between January 1995 and June 2020 were included. The search was constructed around the following key terms: Spinal cord stimulation, SCI and motor response generation. A total of 3,435 articles were initially screened, of which 18 met the inclusion criteria. The total sample comprised of 24 participants with SCI. All studies reported some measure of improvement in motor activity with ESCS, with 17 reporting altered EMG responses. Functional improvements were reported in stepping (n = 11) or muscle force (n = 4). Only 5 studies assessed ASIA scale pre- and post-intervention, documenting improved classification in 4 of 11 participants. Appraisal using the modified Downs and Black quality checklist determined that reviewed studies were of poor quality. Due to heterogeneity of outcome measures used in studies reviewed, a meta-analysis of data was not possible. The authors concluded that while the basic science is encouraging, the therapeutic effectiveness of ESCS remains inconclusive.
Peripheral Diabetic Neuropathy
Slangen et al (2014) stated that painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus (DM). Unfortunately, pharmacotherapy is often partially effective or accompanied by unacceptable side effects; thus, new treatments are urgently needed. Small observational studies suggested that SCS may have positive effects. These researchers carried out a multi-center randomized clinical trial in 36 PDPN patients with severe lower limb pain not responding to conventional therapy; 22 patients were randomly assigned to SCS in combination with the best medical treatment (BMT) (SCS group) and 14 to BMT only (BMT group). The SCS system was implanted only if trial stimulation was successful. Treatment success was defined as greater than or equal to 50 % pain relief during daytime or nighttime or "(very) much improved" for pain and sleep on the patient global impression of change (PGIC) scale at 6 months. Trial stimulation was successful in 77 % of the SCS patients. Treatment success was observed in 59 % of the SCS and in 7 % of the BMT patients (p < 0.01). Pain relief during daytime and during nighttime was reported by 41 % and 36 % in the SCS group and 0 % and 7 % in the BMT group, respectively (p < 0.05). Pain and sleep were "(very) much improved" in 55 % and 36 % in the SCS group, whereas no changes were observed in the BMT group, respectively (p < 0.001 and p < 0.05); 1 SCS patient died because of a subdural hematoma. The authors concluded that treatment success was shown in 59 % of patients with PDPN who were treated with SCS over a 6-month period, although this treatment was not without risks.
De Vos et al (2014) noted that PDN is a peripheral neuropathic pain condition that is often difficult to relieve; SCS is a proven effective therapy for various types of mixed neuropathic conditions, yet effectiveness of SCS treatment for PDN is not well established. To the authors’ knowledge, theirs was the 1st multi-center RCT examining the effectiveness of SCS in patients with PDN. A total of 60 patients with PDN in the lower extremities refractory to conventional medical therapy were enrolled and followed for 6 months. They were randomized 2:1 to best conventional medical practice with (SCS group) or without (control group) additional SCS therapy, and both groups were assessed at regular intervals. At each follow-up visit, the EuroQoL 5D, the short form McGill Pain Questionnaire (SF-MPQ) and a VAS (range of 0 to 100 mm) to measure pain intensity were recorded. The average VAS score for pain intensity was 73 mm in the SCS group and 67 in the control group at baseline. After 6 months of treatment, the average VAS score was significantly reduced to 31 mm in the SCS group (p < 0.001) and remained 67 mm (p = 0.97) in the control group. The SF-MPQ and EuroQoL 5D questionnaires also showed that patients in the SCS group, unlike those in the control group, experienced reduced pain and improved health and QOL after 6 months of treatment. The authors concluded that in patients with refractory PDN, SCS therapy significantly reduced pain and improved QOL.
Petersen et al (2021) stated that many patients with PDN experience chronic pain and inadequate relief despite best available medical treatments. In a prospective, open-label, multi-center, SENZA-PDN randomized clinical trial (NCT03228420), these researchers examined if 10-kHz SCS would improve outcomes for patients with refractory DPN. They compared 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 VAS, body mass index (BMI) of 45 or less, hemoglobin A1c (HbA1c) 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 U.S., including academic centers as well as community pain clinics, between August 2017 and August 2019 with 6-month follow-up and optional cross-over at 6 months. Screening of 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. The pre-specified primary endpoint was percentage of participants with 50 % pain relief or more on VAS without worsening of baseline neurological deficits at 3 months. Secondary endpoints were tested hierarchically, as pre-specified in the analysis plan. Measures included pain VAS, neurological examination, health-related quality of life (EuroQol Five-Dimension questionnaire), and HbA1c over 6 months. Of 216 randomized patients, 136 (63.0 %) were men, and the mean (SD) age was 60.8 (10.7) years. furthermore, the median (inter-quartile range [IQR]) duration of diabetes and peripheral neuropathy were 10.9 (6.3 to 16.4) years and 5.6 (3.0 to 10.1) years, respectively. The primary endpoint evaluated in the intention-to-treat (ITT) 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 to 83.0; p < 0.001). 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 to 7.3) at baseline and 6.9 cm (95 % CI: 6.5 to 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 to 7.9) at baseline and 1.7 cm (95 % CI: 1.3 to 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 to 69.6 %; p < 0.001). The authors concluded that substantial pain relief and improved health-related quality of life sustained over 6 months demonstrated 10-kHz SCS could safely and effectively treat patients with refractory PDN. Moreover, these researchers stated that follow-up of this study population will continue for 24 months and establish potential durability of this treatment beyond 6 months.
In the RCT described above (NCT03228420), Peterson, et al. (2022) examined the long-term impact of 10-kHz SCS for PDN patients with refractory symptoms. Subjects had symptoms for at least 12 months that were refractory to medications, lower limb pain of greater than or equal to 5 on the 10-cm VAS, HbA1c of less than or equal to 10 %, and BMI of less than or equal to 45 kg/m2. Subjects were eligible for cross-over at 6 months if they had less than 50 % pain relief, they were dissatisfied with treatment, and the investigator deemed it medically appropriate. Temporary trial SCS evaluated eligibility for permanent device implant with success defined as greater than or equal to 50 % pain relief. Neurologists trained investigators to perform comprehensive neurological examinations assessing lower limb motor strength, reflexes, and sensation, including pinprick and 10-g monofilament tests. Paired t-tests assessed mean percent change from baseline within treatment groups. Categorical variables were compared between treatment groups using Fisher exact test. A total of 216 patients were randomized 1:1 to continued conventional medical management (CMM) (n = 103) or the addition of 10-kHz SCS to CMM (n = 113). Treatment groups were well matched for baseline characteristics. Among subjects assigned 10-kHz SCS + CMM, 104 proceeded to temporary trial SCS and 90 received permanent device implants. In the CMM group, 95 completed 6-month follow-up and 81 % (77 of 95) crossed-over to 10-kHz SCS compared with 0 from the 10-kHz SCS + CMM arm (p < 0.001); 64 subjects received permanent device implants following cross-over. Mean lower limb pain VAS was 7.6 cm (95 % CI: 7.2 to 7.9) for 10-kHz SCS + CMM patients at baseline, 1.7 cm (95 % CI: 1.3 to 2.1) at 6 months; and maintained at 1.7 cm (9 5% CI: 1.3 to 2.1) to 12 months, representing 77.1 % mean pain relief (95 % CI: 71.8 to 82.3; p < 0.001). At both 6 and 12 months, 86 % (72 of 84) were treatment responders, defined as those with at least 50 % pain relief from baseline. For the cross-over group, mean baseline lower limb pain VAS was 7.2 cm (95 % CI: 6.8 to 7.6) with no change at 6 months but improvement after cross-over, similar to the originally assigned 10-kHz SCS group: mean 70.3 % pain relief (95 % CI: 63.4 to 77.1, p < 0.001), lower limb pain VAS score of 2.0 cm (95 % CI: 1.6 to 2.4), and 84 % responders (49 of 58). Investigators reported neurological improvements, especially improved sensory function, maintained over 12 months for the majority of patients with 10-kHz SCS: 68 % (52 of 76) of subjects originally assigned to SCS and 62 % (32 of 52) of subjects after cross-over. Insensate feet limited activities of daily living (ADL) and may result in debilitating sequelae, including injury from falling, foot ulceration, and lower limb amputation. There were 8 procedure-related infections (5.2 %): 3 resolved with conservative treatments and patients continued in the study, while 5 (3.2 %) required surgical explant of the device. There were no explants for loss of effectiveness; 2 subjects (1.3 %) had the location of the implantable pulse generator revised, and 1 subject (0.6 %) experienced lead migration that needed a revision procedure; all 3 subjects continued in the trial. The authors concluded that findings for the cross-over group replicated the findings from the original implant group, providing a cumulative sample of 154 implanted patients with long-term data. In addition to a higher proportion of pain responders compared with pharmacotherapy or low-frequency SCS, 10-kHz SCS did not induce paresthesia, an advantage for PDN patients with uncomfortable paresthesia at baseline. Furthermore, sleep disturbance due to pain, a common ailment for PDN patients, markedly improved by mean 61.7 % (95 % CI: 55.9 to 67.5) with 10-kHz SCS. This study, the largest RCT performed for SCS treatment of PDN, showed significant, durable pain relief and potentially disease-modifying neurological improvements over 12 months, providing high-quality evidence in support of 10-kHz SCS for PDN patients with refractory symptoms.
In a 3rd publication from the same RCT (NCT03228420), Peterson et al (2022) reported on additional secondary endpoints related to health-related quality of life (HRQoL). The investigators reported that treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95 % CI: 0.104 to 0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92 %) participants were "satisfied" or "very satisfied" with the 10-kHz SCS treatment.
D'Souza et al (2022) stated that PDN manifests with pain typically in the distal lower extremities and can be challenging to treat. These investigators examined the available evidence on conservative, pharmacological, and neuromodulation therapeutic options for PDN. Intensive glycemic control with insulin in patients with type 1 DM may be associated with lower odds of distal symmetric polyneuropathy compared to patients who receive conventional insulin therapy. First-line pharmacotherapy for PDN includes gabapentinoids (pregabalin and gabapentin) and duloxetine. Additional pharmacologic modalities that are approved by the FDA but are considered 2nd-line agents include tapentadol and 8 % capsaicin patch, although studies have revealed modest treatment effects from these modalities. There is level I evidence on the use of dorsal column SCS for treatment of PDN, delivering either a 10-kHz waveform or tonic waveform.
Furthermore, an UpToDate review on “Management of diabetic neuropathy” (Feldman, 2022) states that “For patients who do not tolerate any of the first-line medications or who prefer nonpharmacologic therapies, we discuss capsaicin cream, lidocaine patch, alpha-lipoic acid, transcutaneous electrical nerve stimulation, and spinal cord stimulation”.
Evoke Spinal Cord Stimulation
Levy et al (2019) noted that spinal cord (SC) response to stimulation has yet to be studied in a pivotal clinical study. These investigators reported the study design of an ongoing multi-center, randomized, double-blind, controlled, parallel-arm study of an evoked compound action potential (ECAP) controlled closed-loop spinal cord stimulation (SCS) system, which aims to gain FDA approval. This study will enroll 134 SCS participants with chronic trunk and limb pain from up to 20 U.S. sites. Subjects will be randomized 1:1 to receive ECAP-controlled closed-loop or open-loop, conventional SCS. The primary objective is non-inferiority of closed-loop stimulation determined by the proportion of subjects with 50 % or more reduction in overall trunk and limb pain, and no increase in pain medications at the 3-month visit. If non-inferiority is met, superiority is tested. Furthermore, measures recommended by IMMPACT (e.g., pain intensity, functional disability, emotional functioning, QOL, impression of change, and sleep), neurophysiological properties (e.g., SC activation, conduction velocity, chronaxie, and rheobase), and safety are analyzed. The authors concluded that all approved SCS therapies, regardless of the presence or absence of stimulation induced paresthesia, produce fixed-output stimuli; namely, the energy delivered from the electrode array has a defined output irrespective of the neural response of SC fibers. An SCS system has been developed that directly measures the neurophysiologic activation of the SC to stimulation (i.e., ECAP amplitude) and uses this information in a feedback mechanism to produce closed-loop SCS to maintain optimal and stable activation of the SC. This study represents the 1st randomized, double-blind, pivotal study in the field of neuromodulation to measure SC activation in ECAP-controlled closed-loop versus open-loop stimulation; and is expected to yield important information regarding differences in safety, effectiveness, and neurophysiological properties. The potential clinical utility of these objective measurements of SC activation and other neurophysiological properties promises to improve outcomes of SCS for chronic pain patients.
Mekhail et al (2020) stated that spinal cord stimulation (SCS) has been an established method for the treatment of chronic back and leg pain for more than 50 years; however, outcomes are variable and unpredictable, and objective evidence of the mechanism of action is needed. A novel SCS system provided the first in-vivo, real-time, continuous objective measure of spinal cord activation in response to therapy via recorded evoked compound action potentials (ECAPs) in patients during daily use. These ECAPs were also used to optimize programming and deliver closed-loop SCS by adjusting the stimulation current to maintain activation within patients' therapeutic window. In a double-blind, parallel-arm, randomized-controlled, multi-center trial, these researchers examined pain relief and the extent of spinal cord activation with ECAP-controlled closed-loop versus fixed-output, open-loop SCS for the treatment of chronic back and leg pain. This trial was carried out at 13 specialist clinics, academic centers, and hospitals in the U.S. Patients with chronic, intractable pain of the back and legs (VAS pain score 60 mm or more; ODI score of 41 to 80) who were refractory to conservative therapy, on stable pain medications, had no previous experience with SCS, and were appropriate candidates for a SCS trial were screened. Eligible patients were randomly assigned (1:1) to receive ECAP-controlled closed-loop SCS (investigational group) or fixed-output, open-loop spinal cord stimulation (control group). The randomization sequence was computer-generated with permuted blocks of size 4 and 6 and stratified by site. Patients, investigators, and site staff were masked to the treatment assignment. The primary outcome was the proportion of patients with a reduction of 50 % or more in overall back and leg pain with no increase in pain medications. Non-inferiority (δ = 10 %) followed by superiority were tested in the intention-to-treat (ITT) population at 3 months (primary analysis) and 12 months (additional pre-specified analysis) after the permanent implant. Between February 21, 2017, and February 20, 2018, a total of 134 patients were enrolled and randomly assigned (67 to each treatment group). The ITT analysis comprised 125 patients at 3 months (62 in the closed-loop group and 63 in the open-loop group) and 118 patients at 12 months (59 in the closed-loop group and 59 in the open-loop group). The primary outcome was achieved in a greater proportion of patients in the closed-loop group than in the open-loop group at 3 months (51 [82.3 %] of 62 patients versus 38 [60.3 %] of 63 patients; difference 21.9 %, 95 % CI: 6.6 to 37.3; p = 0.0052) and at 12 months (49 [83.1 %] of 59 patients versus 36 [61.0 %] of 59 patients; difference 22.0 %, 6.3 to 37.7; p = 0.0060). These investigators found no differences in safety profiles between the 2 groups. The most frequently reported study-related AEs in both groups were lead migration (9 [7 %] patients), implantable pulse generator pocket pain (5 [4 %]), and muscle spasm or cramp (3 [2 %]). The authors concluded that ECAP-controlled closed-loop stimulation provided significantly greater and more clinically meaningful pain relief up to 12 months than open-loop spinal cord stimulation. Greater spinal cord activation observed in the closed-loop group suggested a mechanistic explanation for the superior results, which aligned with the putative mechanism of action for SCS and warrants further investigation. Moreover, these researchers stated that although preliminary, they believed this was the 1st-step in the field of neuromodulation, moving towards a mechanism-based, personalized therapy founded on an objective outcome measure. This study was funded by Saluda Medical.
The National Institute for Health and Clinical Excellence’s MedTech Innovation Briefing on “Evoke spinal cord stimulator for managing chronic neuropathic or ischemic pain” (NICE, 2020) provided the following information:
- The technology described in this briefing was the Evoke Spinal Cord Stimulator System. It is used for managing chronic neuropathic or ischemic pain.
- The innovative aspects are that Evoke uses a “closed-loop” feedback control. It does this by recording activation of neural tissue and automatically adjusting stimulation to ensure it remains in the therapeutic range.
- The intended place in therapy would be as a replacement or alternative to current open-loop (fixed-output) SCS therapy in individuals with leg and back pain.
- The main points from the evidence summarized in this briefing were from 2 studies: a RCT and an observational study, including a total of 184 adults with intractable back and leg pain. They showed that Evoke was more effective than open-loop SCS in individuals with intractable back and leg pain.
- Key uncertainties around the evidence are that there were no studies reporting the economic impact of the Evoke Spinal Cord Stimulator System.
- The cost of Evoke ranged from £17,595 to £19,395 for the device. The trial phase cost ranges from £1,920 to £4,975. The resource impact would be comparable with standard care, which ranged from £13,726 to £22,418 for a rechargeable spinal cord stimulation system.
This study had 2 main drawbacks. First, it may be under-powered to detect a difference from baseline in pain ratings. Second, it was funded by Saluda Medical; and the principal author has previously served as a consultant to the company.
Mekhail et al (2022) noted that chronic pain is debilitating and profoundly affects HRQoL; and SCS is a well-established treatment for patients with chronic pain. However, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the ECAPs to produce a real-time physiological closed-loop control system. In a double-blind, randomized-controlled, parallel-arm clinical trial (the Evoke Trial) , these researchers examined if ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. This study entailed 36 months of follow-up. Subjects were enrolled from February 2017 to 2018, and the study was conducted at 13 U.S. centers. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain VAS score of 60 mm or more; ODI score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Main outcomes measures included the 24-month outcomes of the trial, which included all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50 % or more in overall back and leg pain assessed at 3 and 12 months (previously published – Mekhail et al, 2020). Of 134 randomized patients, 65 (48.5 %) were women and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (50 % or more reduction) in overall pain (53 of 67 [79.1 %] in the closed-loop group; 36 of 67 [53.7 %] in the open-loop group; difference, 25.4 % [95 % CI: 10.0 % to 40.8 %]; p = 0.001). There was no difference in safety profiles between groups (difference in rate of study-related AEs: 6.0 [95 % CI: −7.8 to 19.7]). Improvements were also observed in HRQoL, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. The authors concluded that ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes. This was an extension of the authors’ 2020 study extending follow-up observations to 24 months.
The authors stated that one study limitation may be its control arm, which had advantages over other open-loop systems owing to the ability to measure the neural response to inform programming and may improve clinical outcomes. Thus, the advantages of closed-loop SCS may be even more profound when compared with other open-loop systems. The choice to use the same device in both treatment groups was made to ensure proper double blinding and to facilitate measurement of neural response in both groups. Participants in both groups received identical care, with the same degree of device programming. Blinded investigators documented their oversight to confirm comprehensive programming and optimization for all study participants and to ensure that no bias was introduced. The successful randomization and blinding resulted in equivalent baseline characteristics, programming parameters, and underlying neurophysiology, indicating that the observed differences between groups were likely attributed to the differences in spinal cord activation achieved with each of the stimulation modes.
Costandi et al (2023) noted that SCS is considered an effective interventional non-pharmacologic therapeutic option for several chronic pain conditions. In a randomized, double-blind, controlled study (the EVOKE trial), these investigators examined the effects of the ECAP controlled closed-loop (ECAP-CL) SCS system on long-term sleep quality outcomes from the EVOKE study. This trial was carried out at 13 sites in the U.S. (n = 134 patients). The clinical trial employed SCS to manage chronic pain and compared ECAP-CL technology to open-loop SCS. In addition, sleep quality data was collected using the Pittsburgh Sleep Quality Index (PSQI) at baseline and all study visits. The mean PSQI global score for ECAP-CL patients at baseline was 14.0 (n = 62; ± 0.5, SD 3.8), indicating poor sleep quality. Clinically meaningful and statistically significant reductions (p < 0.001) in the global PSQI scores were noted at 12 months (n = 55; 5.7 ± 0.6, SD 4.2). A total of 76.4 % of ECAP-CL patients met or exceeded minimal clinically important difference (MCID) from baseline in PSQI at 12 months. Furthermore, 30.9 % of ECAP-CL patients achieved "good sleep quality" scores (PSQI of 5 or less), and 29.1 % achieved sleep quality remission. "Normative" sleep scores were observed in 29.6 % of ECAP-CL patients at 12 months, and these scores were better than the U.S. general population. In addition, ECAP-CL patients achieved statistically significant changes from baseline (p < 0.01) across all 7 subcomponent scores of PSQI at 12 months. The authors concluded that the ECAP-CL SCS elicited consistent neural activation of the target resulting in less variability in long-term therapy delivery. In the EVOKE Trial, this resulted in ECAP-CL patients reporting clinically superior and sustained pain relief. Results from this study provided new evidence of long-term improvement in sleep quality and quantity in patients with chronic pain resulting from the use of the ECAP-CL SCS technology.
Nijhuis et al (2023) a CL-SCS system has recently been approved for use that records ECAPs from the spinal cord, and uses these recordings to automatically adjust the stimulation strength in real time. It automatically compensates for fluctuations in distance between the epidural leads and the spinal cord by maintaining the neural response (ECAP) at a determined target level. This data collection was designed to examine the performance of this 1st CL-SCS system in a “real-world'” setting under normal conditions of use in a single European center. In this prospective, single-center, observational data collection, 22 patients were recruited at the out-patient pain clinic of the St. Antonius Hospital. All subjects were suffering from chronic pain in the trunk and/or limbs due to PSPS type 2 (persistent spinal pain syndrome). As standard of care (SOC), follow-up visits were completed at 3 months, 6 months, and 12 months post-device activation. Patient-reported outcome data (pain intensity, patient satisfaction) and electrophysiological and device data (ECAP amplitude, conduction velocity, current output, pulse width, frequency, usage), and patient interaction with their controller were collected at baseline and during SOC follow-up visits. Significant decreases in pain intensity for overall back or leg pain scores (verbal NRS [VNRS]) were observed between baseline [mean ± SEM (standard error of the mean); n = 22; 8.4 ± 0.2)], 3 months (n = 12; 1.9 ± 0.5), 6 months (n = 16; 2.6 ± 0.5), and 12 months (n = 20; 2.0 ± 0.5), with 85.0 % of the patients being satisfied at 12 months. Furthermore, no significant differences in average pain relief at 3 months and 12 months between the real-world data (77.2 %; 76.8 %) and the AVALON (71.2 %; 73.6 %) and EVOKE (78.1 %; 76.7 %) Trials were observed. The authors concluded that these “real-world” data on ECAP-controlled, CL-SCS in a real-world clinical setting provided novel insights of the beneficial effect of ECAP-controlled, CL-SCS. The presented results showed a note-worthy maintenance of pain relief over 12 months and corroborated the outcomes observed in the AVALON prospective, single-arm, multi-center study and the EVOKE double-blind, multi-center RCT.
Mekhail et al (2024) reported a cohort of the EVOKE double-blind RCT, who were treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements. A total of 41 patients randomized to CL-SCS remained in their treatment allocation and were followed-up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with 50 % or more and 80 % or more reduction in overall back pain and leg pain, respectively. The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4 µV of the target ECAP set on the system across all time-points. Percent time stimulating above the ECAP threshold was greater than 98%, and the ECAP dose was 19.3 µV or higher. Most patients obtained 50 % or more reduction (83 %) and 80 % or more reduction (59 %) in overall back pain and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p = 0.083; and p = 0.405, respectively). The authors concluded that these findings suggested that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS resulted in durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.
Su et al (2024) stated that neuromodulation has emerged as a promising therapy for the management of chronic pain, movement disorders, and other neurological conditions; and SCS is a widely used form of neuromodulation that entails the delivery of electrical impulses to the spinal cord to modulate the transmission of pain signals to the brain. In recent years, there has been increasing interest in the use of automation systems to improve the safety and effectiveness of SCS. These investigators examined the status of FDA-approved autonomous neuromodulation devices including CL, feed-forward, and feed-back systems. This review discussed the advantages and disadvantages of each system and focused specifically on the use of these systems for SCS. The authors concluded that the effectiveness of open-loop and closed-loop feedback SCS have been established via double-blind RCTs, while the effectiveness of a feed-forward system has been characterized in a single, prospective, open-label, randomized trial. Other means of utilizing automated control system (ACS) based on the ongoing pathophysiology within disease states, the plasticity of the nervous system, or other notable responses to therapy (or as yet unknown information within the body) may become standard in most neuromodulation therapies and will require specific thresholds of efficacy and precision for approval.
Disorders of Consciousness
Bai et al (2017) noted that SCS has been suggested as a therapeutic technique for the treatment of patients with disorder of consciousness (DoC). Although studies have reported its benefits for patients, the underlying pathophysiological mechanisms remain unclear. These researchers examined the effects of SCS on the EEG of patients in a MCS, which would allow these investigators to examine the possible workings underpinning of the approach. Resting state EEG was recorded before and immediately after SCS, using various frequencies (5-Hz, 20-Hz, 50-Hz, 70-Hz and 100-Hz), for 11 patients in MCS. Relative power, coherence, S-estimator and bicoherence were calculated to assess the EEG changes. A total of 5 frequency bands (delta, theta, alpha, beta, and gamma) and 3 regions (frontal, central, and posterior) were divided in the calculation. The 2 key findings of this study were: First -- significantly altered relative power and synchronization was found in delta and gamma bands after 1 SCS stimulation using 5-Hz, 70-Hz or 100-Hz; and second -- bicoherence showed that coupling within delta was significantly reduced following stimulation using 70-Hz, while reduction of coupling between delta and gamma was found when using 5-Hz and 100-Hz. However, SCS of 20-Hz, 50-Hz and sham stimulation did not induce changes in any frequency band at any region. The authors concluded that the findings of this study showed EEG evidence that SCS could modulate the brain function of MCS patients, speculatively by activating the formation-thalamus-cortex network.
Yang et al (2022) stated that DoC are one of the most frequent complications in patients after severe brain injury, mainly caused by trauma, stroke, and anoxia. With the development of neuromodulation techniques, novel therapies including DBS and SCS have been used to treat DOC. These investigators reported the case of a DoC patient receiving short-term SCS (st-SCS) treatment and showing improvement monitored by resting-state fMRI (rs-fMRI) and quantitative EEG (qEEG). Subject was a 35-year-old man with severe traumatic brain injury (TBI) who remained comatose for 3 months. The patient was examined using JFK coma recovery scale-revised (CRS-R) and showed no improvement within 1 month. He received st-SCS surgery 93 days after the injury and the stimulation was applied the day after surgery. He regained communication according to instructions on day 21 after surgery and improved from a VS/un-wakefulness syndrome to an emergence from an MCS. To the authors’ knowledge, this report was the 1st published case of st-SCS in a patient with DoC. They stated that these findings shed light that st-SCS may be effective in the treatment of certain patients with DoC, which may reduce patients' suffering during treatment and lessen financial burden. Moreover, these researchers stated that large RCTs are needed to confirm these preliminary findings.
Wu et al (2023) noted that the use of SCS and DBS for DoC has been increasingly reported; however, there is insufficient evidence to determine safety and effectiveness of SCS and DBS for the management of DoC owing to various methodological limitations. In a systematic review, these investigators examined the safety and effectiveness of SCS and DBS for DoC by reviewing related literature by searching PubMed, Embase, Medline, and Cochrane Library. A total of 20 eligible studies with 608 patients were included in this study – 10 studies with 508 patients reported the effectiveness of SCS for DoC, and the estimated overall effectiveness rate was 37 % ; 5 studies with 343 patients reported the effectiveness of SCS for VS, and the estimated effectiveness rate was 30 %; 3 studies with 53 patients reported the effectiveness of SCS for MCS, and the estimated effectiveness rate was 63 %; 5 studies with 92 patients reported the effectiveness of DBS for DoC, and the estimated overall effectiveness rate was 40 %; 4 studies with 63 patients reported the effectiveness of DBS for VS, and the estimated effectiveness rate was 26 %; 3 studies with 19 patients reported the effectiveness of DBS for MCS, and the estimated effectiveness rate was 74 %. The AE rate of DoC was 8.1 % and 18.2 % after SCS and DBS, respectively. The authors concluded that these findings suggested that SCS and DBS could be considered reasonable treatments for DoC with considerable safety and effectiveness.
Gait and Balance Disorders
Ciocca et al (2023) noted that falls in patients with extra-pyramidal disorders, especially PD, multi-system atrophy (MSA), and progressive supranuclear palsy (PSP), are principal milestones affecting patients' QOL, incurring increased morbidity/mortality and high healthcare costs. Unfortunately, gait and balance in parkinsonisms respond poorly to currently available treatments. A serendipitous observation of improved gait and balance in patients with PD receiving SCS for back pain kindled an interest in using SCS to treat gait disorders in parkinsonisms. In a systematic review, these investigators examined pre-clinical as well as clinical studies of SCS for the treatment of gait dysfunction in parkinsonisms, covering its putative mechanisms and effectiveness. Pre-clinical studies in animal models of PD and clinical studies in patients with PD, PSP, and MSA who received SCS for gait disorders were included. The main outcome measure was clinical improvement in gait, together with outcome measures used and possible mechanism of actions. These researchers identified 500 references, and 45 met the selection criteria and were included for analysis. Despite positive results in animal models, the outcomes in human studies were inconsistent. The authors concluded that the lack of blind and statistically powered studies, the heterogeneity in patient selection and study outcomes, as well as the poor understanding of the underlying mechanisms of action of SCS were some of the limitations in the field. These investigators stated that addressing these limitations will allow researchers to draw more reliable conclusions on the effects of SCS on gait and balance in patients with extra-pyramidal disorders.
Opova et al (2023) stated that evidence from case reports and small descriptive studies has emerged suggesting a role for SCS in patients with gait dysfunction, such as freezing of gait (FoG) and postural imbalance, which are severely debilitating symptoms of advanced PD. These investigators examined the available evidence for the potential application of SCS on gait and balance dysfunction in PD patients. A total of 3 online databases were screened for relevant manuscripts; 2 separate searches and 4 different search strategies were applied to yield relevant results. The main parameters of interest were postural and gait symptoms; secondary outcomes were QOL and adverse effects. A total of 19 studies met the inclusion criteria. Motor improvements using section III of the UPDRS (UPDRS-III) were available in 13 studies. Measurements to evaluate FoG reported the following improvements: FoG questionnaires (in 1/19 studies); generalized freezing parameters (2 studies); and walkway/wireless accelerometer measurements (2 studies). Parameters of postural imbalance and falling improved as follows: BBS (1 study); posture sagittal vertical axis (1 study); and generalized data on postural instability (8 studies). Two studies reported on adverse effects; and QOL was shown to improve as follows: EQ-5D (2 studies); ADL (1 study); SF-36 (1 study); Beck Depression Inventory (BDI)-II (1 study); PDQ-8 (1 study); HDRS (1 study); and VAS (5 studies). The authors concluded that SCS for postural instability and gait disorder (PIGD) in PD is a therapy that is worth investigating further. The available evidence within this patient population, weak as it is, suggests that the procedure is relatively safe, and may have beneficial effects on QOL and motor scores. These researchers stated that there is a pressing need for an adequately powered clinical trial with clearly described statistical analysis methods, patient cohort and tools for clinical evaluation. This will aid researchers to draw more solid conclusions regarding the therapeutic potential of SCS in PD patients with gait complications and open new research opportunities in the field of preventative medicine or combined treatment.
MRI Compatibility
Moeschler et al (2015) noted that SCS systems are implanted for the treatment of chronic pain conditions such as neuropathic, radicular, and ischemic pain syndromes. Before July 2013, SCS systems were not MRI compatible due to the risk of thermal injury at the site of the leads and generator. Although there are some case reports of patients undergoing MRI studies with SCS systems in place, these stimulators are often explanted when clinical care has necessitated an MRI. In a case-series study, these investigators examined the role of SCS explantation in order to acquire an MRI. This study was carried out at a tertiary academic pain medicine clinic. After exempt status was obtained via the institutional review board (IRB), patients were identified via the use of Common Procedural Terminology (CPT) codes for implantable devices. A chart review was carried out to identify all patients 18 years of age or older who had a lumbar or thoracic dorsal column SCS implanted between January 2001 and December 2011. The charts were then followed to identify any patients who underwent a surgery for explantation of the device. Data collection included the total number of patients undergoing permanent SCS implantation, the total number of explantation of these devices, patient demographic factors, indication for SCS implantation, incidence of revisions and the indication, duration between implantation and explant of the device, and indication for explantation. During the time between 2001 and 2011, a total of 199 patients were identified who underwent a thoracic or lumbar SCS implant after a successful trial. Among 199 implants, 33 devices were explanted, and of these, 4 were explanted due to the primary need for an MRI scan.
Dupre et al (2018) stated that despite requiring successful trials before implantation, SCS systems for pain are often later removed. The removal of surgically implanted hardware subjects patients to the risks and discomfort of a second surgery, threatens the cost-effectiveness of SCS, and limits the perceived durability of SCS technology for pain problems. These investigators examined patterns of reasons given among patients who underwent SCS explant surgery (SCSES). They carried out a retrospective review of SCSES cases over 17 years at Allegheny General Hospital, Pittsburgh, PA. A total of 165 patients underwent SCSES between 1997 and 2014. The top 3 reasons for explantation were inadequate pain control (IPC; 73 %), hardware discomfort (22 %), and need for MRI (10 %). Other less frequent reasons were infection (9 %), painful dysesthesias (9 %), electrical arcing (4 %), resolution of inciting symptoms (4 %), weakness (2 %), pseudo-meningocele (1 %), and muscle spasms (1 %). The authors concluded that inadequate pain control was the most common reason for SCSES. Advances in technology are needed to improve the quality and duration of pain control, as well as to design improvements to make the hardware more comfortable. A significant number of implants were removed due to need for MRI, a fact obviating the need for MRI-compatible systems.
Furthermore, an UpToDate review on “Spinal cord stimulation: Placement and management” (McKenzie-Brown and Pritzlaff, 2023) states that “Over 80 % of patients with SCS will need an MRI within 5 years of implantation. Therefore, MRI compatibility is an important feature for all spinal cord stimulator components. Concerns include the possibility of lead movement or heating, hardware damage, and reprogramming as a result of radiofrequency (RF) energy. Most spinal cord stimulator components are designated as MRI conditional and can safely be used for MRI of the head and extremities under specific conditions. Some systems are MRI conditionally safe for whole-body MRI; manufacturers' specifications vary and should be followed”.
Nalu Micro-IPG for Spinal Cord Stimulation
Hasoon et al (2022) noted that SCS is a commonly used therapy for the treatment of neuropathic pain. The primary indications for SCS therapy are post-laminectomy syndrome as well as CRPS. SCS therapy is minimally invasive and reversible. It entails the implantation of percutaneous or paddle leads along with a surgically implanted pulse generator (IPG). Severe pocket pain from the IPG is a well-known complication following SCS implantation that can be challenging to treat and can result in an explant of the SCS system. These investigators presented the case of a patient with post-laminectomy syndrome who underwent an explant of her SCS system due to severe pocket pain complaints. The patient was successfully re-implanted with a Nalu micro-IPG for SCS therapy with 75 % improvement in her post-laminectomy pain complaints with no complaints of pocket pain.
Malinowski et al (2022) stated that SCS is effective for the treatment of chronic intractable pain of the trunk and limbs. The mechanism of action (MOA) may be based, at least in part, upon the gate control theory; however, new waveforms may suggest other mechanisms. Although benefits of the SCS technology generally out-weigh the complications associated with SCS, some complications such as infection and skin erosion over the implant can result in device removal. Additional reasons for device removal, such as pocket pain and battery depletion, have driven technological innovations including battery-free implants and device miniaturization. The neurostimulation system described here was specifically designed to address complications commonly associated with implantable batteries and/or larger implantable devices. The benefits of the small size are further augmented by a minimally invasive implant procedure. Usability data showed that patients found this novel neurostimulation system to be easy to use and comfortable to wear. What is more, clinical data showed that the use of this system provided statistically significant reduction in pain scores with responder rates (defined as 50 % or greater reduction in pain) of 78 % in the low back and 83 % in the leg(s). Advances in miniaturization technology arose from the considerable shrinkage of the integrated circuit, with an increase in performance; however, commensurate improvements in battery technology have not maintained a similar pace. This has prompted some manufacturers to place the battery outside, against the skin; thus, allowing a massive reduction in the implant volume, with the hopes of fewer device-related complications.
In a prospective, open-label, multi-center study, Salmon et al (2023) examined the feasibility of a novel SCS system with a battery-free miniaturized implantable pulse generator (IPG). The system employs an external power source that communicates bi-directionally with the IPG (less than 1.5 cm3). Human factors, subject comfort, and effects on low back and leg pain were evaluated in this first-in-human study. This trial was designed to examine the safety and performance of a novel miniaturized stimulator in the treatment of chronic, intractable leg pain and LBP. Participants who passed the screening/trial phase (defined as 50 % or greater reduction in pain) continued to the long-term implant phase and were followed-up at pre-defined time-points after device activation. Interim clinical and usability outcomes were captured and reported at 90 days. Results of 22 participants who chose a novel pulsed stimulation pattern therapy using the battery-free IPG (less than 1.5 cm3) were described here. At 90-days follow-up, the average pain reduction was 79 % in the leg (n = 22; p < 0.0001) and 76 % in the low back (n = 21; p < 0.0001) compared with baseline. Responder rates (50 % or greater pain relief) at 90 days were 86 % in leg pain (19/22) and 81 % in LBP (17/21). Participants rated the level of comfort of the external wearable power source to be 0.41 ± 0.73 at 90 days on an 11-point rating scale (0 = very comfortable, 10 = very uncomfortable). The authors concluded that these interim results from the ongoing study showed the favorable effectiveness and usability of a novel, externally powered, battery-free SCS IPG (less than 1.5 cm3) for leg pain and LBP. Participants wore the external power source continuously and found it comfortable, and the system provided significant pain relief. Moreover, these researchers stated that these preliminary findings warrant further investigations.
Desai et al (2023b) discussed the possible MOAs and results of a pilot study of a novel, anatomically placed, and paresthesia-independent, neuro-stimulation waveform for the management of chronic intractable pain. A novel, multi-layered pulsed stimulation pattern (PSP) that comprises 3 temporal layers, a Pulse Pattern layer, Train layer, and Dosage layer, was developed for the treatment of chronic intractable pain. During preliminary development, the use was evaluated of anatomical PSP (aPSP) in human subjects with chronic intractable pain of the leg(s) and/or low back, compared with that of traditional SCS (T-SCS) and physiological PSP. The scientific theory and testing presented in this article provided the preliminary justification for the potential MOAs by which PSP may operate. During the pilot study, aPSP (n = 31) yielded a greater decrease in both back and leg pain than did T-SCS (back: -60 % versus -46 %; legs: -63 % versus -43 %). Furthermore, aPSP yielded higher responder rates for both back and leg pain than did T-SCS (61 % versus 48 % ;and 78 % versus 50 %, respectively). The authors concluded that the novel, multi-layered approach of PSP may provide multi-mechanistic therapeutic relief via preferential fiber activation in the dorsal column, optimization of the neural onset response, and use of both the medial and lateral pathway through the thalamic nuclei. The findings of this pilot trial suggested a robust responder rate, with several subjects (5 subjects with back pain and 3 subjects with leg pain) achieving complete relief from PSP during the acute follow-up period. These results suggested that PSP may provide a multi-mechanistic, anatomical, and clinically effective management for intractable chronic pain. Moreover, these researchers stated that because of the limited sample size of clinical data, further investigations and long-term clinical assessments are needed to confirm these preliminary findings.
In a prospective, observational, open-label, single-arm, multi-center, post-market study, Desai et al (2023a) reported the findings of an SCS clinical trial for the treatment of chronic leg pain and LBP with a micro-IPG. Subjects were recruited from 15 U.S. based comprehensive pain centers. This trial was designed to examine the performance of the Nalu Neurostimulation System (Nalu Medical, Inc., Carlsbad, CA) in the treatment of leg pain and LBP. Patients, who provided informed consent and were successfully screened for study entry, were implanted with temporary trial leads. Participants went on to receive a permanent implant of the leads and micro-IPG if they reported a 50 % or greater reduction in pain during the temporary trial period. Patient-reported outcomes (PROs), such as pain scores, functional disability, mood, patient impression of change, comfort, therapy use profile, and device ease of use, were captured. At baseline, the average pain VAS score was 72.1 ± 17.9 in the leg, and 78.0 ± 15.4 in the low back. At 90 days following permanent implant (end of study), pain scores improved by 76 % (VAS 18.5 ± 18.8) in the leg, and 75 % (VAS 19.7 ± 20.8) in the low back. A total of 86 % of both leg pain and LBP patients showed a 50 % or greater reduction in pain at 90 days following implant. The comfort of the external wearable (Therapy Disc and Adhesive Clip) was rated 1.16 ± 1.53, on average, at 90 days on an 11-point rating scale (0 = very comfortable, 10 = very uncomfortable). All PROs showed statistically significant symptomatic improvement at 90 days following implant of the micro-IPG. The authors concluded that this clinical study showed profound leg pain and LBP relief in terms of overall pain reduction, as well as the proportion of therapy responders. The study patients reported the wearable aspects of the system to be very comfortable.
These researchers stated that drawbacks of this trial included the lack of long-term results (beyond 90 days) and a relatively small sample size of 35 patients who were part of the analysis. Furthermore, there was no control arm or randomization as this was a single-arm study, without a comparator, designed to document the safety and effectiveness of the device; thus, no direct comparisons to other SCS systems were possible.
Salmon et al (2024) noted that SCS is a highly effective treatment for chronic neuropathic pain. Despite recent advances in technology, treatment gaps remain. A small SCS system with a miniaturized IPG (micro-IPG; less than 1.5 cm3 in volume) and an externally worn power source may be preferred by patients who do not want a large, implanted battery. In a prospective, open-label, single-arm, multi-center study, these investigators reported the long-term outcomes from the 1st-in-human study examining the safety and performance of a new neurostimulation system. These researchers examined this SCS system in the treatment of chronic, intractable leg pain and LBP. Consented subjects who passed screening continued on to the long-term phase of the study. One-year PROs such as pain (NRS), functional disability, QOL, and mood were captured. A total of 26 evaluable subjects with permanent implants were included in this analysis. The average leg pain NRS score decreased from 6.8 ± 1.2 at baseline to 1.1 ± 1.2 at the end of the study (p < 0.001), while the average LBP NRS score decreased from 6.8 ± 1.2 to 1.5 ± 1.2 (p < 0.001). The responder rate (proportion with 50 % or greater pain relief) was 91 % in the leg(s) and 82 % in the low back. There were significant improvements in functional disability (ODI) and in mood (BDI), showing a 46 % and 62 % improvement, respectively (p < 0.001). A 11-point Likert scale revealed the wearable to be very comfortable and very easy to use. The authors concluded that there were considerable challenges performing a clinical study during the COVID-19 pandemic, such as missed study programming visits; however, subjects had significant PRO improvements through 1-year. The small size of the implanted device, along with a proprietary waveform, may allow for improved SCS outcomes and a drop in incidence of IPG-pocket pain. These investigators stated that these findings showed that SCS therapy with a micro-IPG, an external TD, and the PSP waveform may represent an new therapeutic option for patients with intractable pain.
The authors stated that drawback of this trial included its relatively small sample size (n = 26 evaluable subjects) and instances of missing data, which was unavoidable due to the COVID-19 pandemic. Last observation carried forward (LOCF; employed here) is a common statistical approach used in the analysis of longitudinal repeated measures data where some follow-up observations may be missing. In this analysis, a missing follow-up visit value was replaced by a subject’s previously (most recently) observed value. The combination of the observed and imputed data was then analyzed as though there were no missing data. Unfortunately, an inherent assumption of the LOCF approach is that all the samples (actual and imputed) were drawn from the same distribution, which may not be the case; thus, caution should be exercised when interpreting the results of the LOCF analysis.
Appendix
DCS for intractable angina pectoris is contraindicated in any of the following conditions:
- Myocardial infarction or unstable angina in the previous 3 months, or
- Significant valve abnormalities as demonstrated by echocardiography, or
- Somatic disorders of the spine leading to insurmountable technical problems in treatment with DCS.
Budapest Criteria for CRPS:
The diagnosis of complex regional pain syndrome (CRPS) is based upon the clinical features as determined by the history and physical examination. The Budapest Criteria is used to make the clinical diagnosis of CRPS. The criteria include the following (Harden et al, 2007, 2010, 2013; Abdi, 2022):
- Continuing pain, which is disproportionate to any inciting event;
- Must report at least one symptom in all four of the following categories:
- Sensory – reports of hyperaesthesia and/or allodynia
- Vasomotor – reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
- Sudomotor/edema – reports of edema and/or sweating changes and/or sweating asymmetry
- Motor/trophic – reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin);
-
Must display at least one sign at time of evaluation in two or more of the following categories:
- Sensory – evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
- Vasomotor – evidence of temperature asymmetry (greater than 1 °C) and/or skin color changes and/or asymmetry
- Sudomotor/edema – reports of edema and/or sweating changes and/or sweating asymmetry
- Motor/trophic – evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin);
-
There is no other diagnosis that better explains the signs and symptoms.
References
The above policy is based on the following references:
Dorsal Column Stimulator for Chronic Pain
- Agency for Healthcare Policy and Research (AHCPR). Management of cancer pain. Clinical Guideline No. 9. AHCPR Publication No. 94-0592. Rockville, MD: AHRQ; March 1994.
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Dorsal Column Stimulator for Angina Pectoris
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Cervical Spinal Cord Stimulation
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Dorsal Column Stimulator for Conditions Other Than Pain
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High-Frequency Spinal Cord Stimulation
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- Chen JL, Hesseltine AW, Nashi SE, et al. A real-world analysis of high-frequency 10 kHz spinal cord stimulation for the treatment of painful diabetic peripheral neuropathy. J Diabetes Sci Technol. 2022;16(2):282-288.
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- Kapural L, Yu C, Doust MW, 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. Anesthesiology.
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- Petersen EA, Stauss TG, Scowcroft JA, et al. Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful diabetic neuropathy: A randomized clinical trial. JAMA Neurol. 2021;78(6):687-698.
- Rapcan R, Mlaka J, Venglarcik M, et al. High-frequency - spinal cord stimulation. Bratisl Lek Listy. 2015;116(6):354-356.
- Russo M, Van Buyten JP. 10-kHz high-frequency SCS therapy: A clinical summary. Pain Med. 2015;16(5):934-942.
- Strand NH, Burkey AR. Neuromodulation in the treatment of painful diabetic neuropathy: A review of evidence for spinal cord stimulation. J Diabetes Sci Technol. 2022;16(2):332-340.
- Tiede J, Brown L, Gekht G, et al. Novel spinal cord stimulation parameters in patients with predominant back pain. Neuromodulation. 2013;16(4):370-375.
Burst Spinal Cord Stimulation
- Deer T, Slavin KV, Amirdelfan K, et al. Success Using Neuromodulation with BURST (SUNBURST) Study: Results from a prospective, randomized controlled trial using a novel burst waveform. Neuromodulation. 2018;21(1):56-66.
Limb Ischemia
- Abu Dabrh AM, Steffen MW, Asi N, et al. Nonrevascularization-based treatments in patients with severe or critical limb ischemia. J Vasc Surg. 2015;62(5):1330-1339.
- Asimakidou E, Matis GK. Spinal cord stimulation in the treatment of peripheral vascular disease: A systematic review - revival of a promising therapeutic option?. Br J Neurosurg. 2022;36(5):555-563.
- Horsch S, Claeys L. Epidural spinal cord stimulation in the treatment of severe peripheral arterial occlusive disease. Ann Vasc Surg. 1994;8(5):468-474.
- Mingoli A, Sciacca V, Tamorri M, et al. Clinical results of epidural spinal cord electrical stimulation in patients affected with limb-threatening chronic arterial obstructive disease. Angiology. 1993;44(1):21-25.
- Naoum JJ, Arbid EJ. Spinal cord stimulation for chronic limb ischemia. Methodist Debakey Cardiovasc J. 2013;9(2):99-102.
- Neschis DG, Golden MA. Treatment of chronic limb-threatening ischemia. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2018.
- Piedade GS, Vesper J, Reichstein D, et al. Spinal cord stimulation in non-reconstructable critical limb ischemia: A retrospective study of 71 cases. Acta Neurochir (Wien). 2023;165(4):967-973.
- Ubbink DT, Vermeulen H. Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev. 2003;(3):CD004001.
Spinal Cord Stimulators Using More Than 16 Contacts or More Than 2 Percutaneous Leads
- Hayek S, Veizi E, North J, et al. Long-term back pain relief with anatomically guided neural targeted SCS. Abstract presented at the International Neuromodulation Society, 12th World Congress, Montreal, Canada, 2015.
- Veizi E, Hayek SM, North J, et al. Spinal cord stimulation (SCS) with anatomically guided (3D) neural targeting shows superior chronic axial low back pain relief compared to traditional SCS - LUMINA Study. Pain Med. 2017;18(8):1534-1548.
Dorsal Root Ganglion Stimulation
- Abdi S. Complex regional pain syndrome in adults: Prevention and management. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2016.
- Anderson BC. Meralgia paresthetica (lateral femoral cutaneous nerve entrapment). UpToDate [online serial]. Waltham, MA: UpToDate; reviewed November 2019.
- Chang Chien GC, Mekhail N. Alternate intraspinal targets for spinal cord stimulation: A systematic review. Neuromodulation. 2017;20(7):629-641.
- Deer TR, Grigsby E, Weiner RL, et al. A prospective study of dorsal root ganglion stimulation for the relief of chronic pain. Neuromodulation. 2013;16(1):67-71; discussion 71-72.
- Deer TR, Levy RM, Kramer J, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for CRPS and causalgia at 3 and 12 months: Randomized comparative trial. Pain. 2017;158(4):669-681.
- Eldabe S, Burger K, Moser H, et al. Dorsal root ganglion (DRG) stimulation in the treatment of phantom limb pain (PLP). Neuromodulation. 2015;18(7):610-616; discussion 616-617.
- 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. Pain Pract. 2018;18(1):104-108.
- Hunter CW, Yang A. Dorsal root ganglion stimulation for chronic pelvic pain: A case series and technical report on a novel lead configuration. Neuromodulation. 2019;22(1):87-95.
- Huygen F, Liem L, Cusack W, Kramer J. Stimulation of the L2-L3 dorsal root ganglia induces effective pain relief in the low back. Pain Pract. 2018;18(2):205-213.
- Liem L, Russo M, Huygen FJ, et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation. 2015;18(1):41-48; discussion 48-49.
- Maino P, Koetsier E, Kaelin-Lang A, et al. Efficacious dorsal root ganglion stimulation for painful small fiber neuropathy: A case report. Pain Physician. 2017;20(3):E459-E463.
- Rowland DC, Wright D, Moir L, et al. Successful treatment of pelvic girdle pain with dorsal root ganglion stimulation. Br J Neurosurg. 2016;30(6):685-686.
- Schu S, Gulve A, ElDabe S, et al. Spinal cord stimulation of the dorsal root ganglion for groin pain-a retrospective review. Pain Pract. 2015;15(4):293-299.
- Thomson S. Spinal cord stimulation for neuropathic pain. San Francisco, CA: International Neuromodulation Society (INS); April 24, 2016. Available at: http://www.neuromodulation.com/spinal-cord-stimulation-for-neuropathic-pain. Accessed October 26, 2016.
- van Bussel CM, Stronks DL, Huygen FJ. Successful treatment of intractable complex regional pain syndrome type I of the knee with dorsal root ganglion stimulation: A case report. Neuromodulation. 2015;18(1):58-60; discussion 60-61.
- Van Buyten JP, Smet I, Liem L, et al. Stimulation of dorsal root ganglia for the management of complex regional pain syndrome: A prospective case series. Pain Pract. 2015;15(3):208-216.
- Vuka I, Vucic K, Repic T, et al. Electrical stimulation of dorsal root ganglion in the context of pain: A systematic review of in vitro and in vivo animal model studies. Neuromodulation. 2018;21(3):213-224.
- Weiner RL, Yeung A, Montes Garcia C, et al. Treatment of FBSS low back pain with a novel percutaneous DRG wireless stimulator: Pilot and feasibility study. Pain Med. 2016;17(10):1911-1916.
- Yang A, Hunter CW. Dorsal root ganglion stimulation as a salvage treatment for complex regional pain syndrome refractory to dorsal column spinal cord stimulation: A case series. Neuromodulation. 2017;20(7):703-707.
- Yang F, Zhang T, Tiwari V, et al. Effects of combined electrical stimulation of the dorsal column and dorsal roots on wide-dynamic range neuronal activity in nerve-injured rats. Neuromodulation. 2015;18(7):592-598.
Medtronic’s DTM™ SCS
- Fishman M, Cordner H, et al. DTM™ SCS RCT 12-month data results. Presented at a Medtronic webinar, jointly supported by the North American Neuromodulation Society (NANS), World Institute of Pain (WIP), and the American Society for Pain and Neuroscience (ASPN). October 19, 2020.
- Fishman M, Cordner H, Justiz R, et al. Twelve-Month results from multicenter, open-label, randomized controlled clinical trial comparing differential target multiplexed spinal cord stimulation and traditional spinal cord stimulation in subjects with chronic intractable back pain and leg pain. Pain Pract. 2021;21(8):912-923.
- Smith WJ, Cedeño DL, Thomas SM, et al. Modulation of microglial activation states by spinal cord stimulation in an animal model of neuropathic pain: Comparing high rate, low rate, and differential target multiplexed programming. Mol Pain. 2021;17:1744806921999013.
Evoke Spinal Cord Stimulation
- Costandi S, Kapural L, Mekhail NA, et al. Impact of long-term evoked compound action potential controlled closed-loop spinal cord stimulation on sleep quality in patients with chronic pain: An EVOKE randomized controlled trial study subanalysis. Neuromodulation. 2023;26(5):1030-1038.
- Levy R, Deer TR, Poree L, et al. Multicenter, randomized, double-bind study protocol using human spinal cord recording comparing safety, efficacy, and neurophysiological responses between patients being treated with evoked compound action potential-controlled closed-loop spinal cord stimulation or open-loop spinal cord stimulation (the Evoke Study). Neuromodulation. 2019;22(3):317-326.
- Mekhail N, Levy RM, Deer TR, et al; Evoke Study Group. Safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): A double-blind, randomised, controlled trial. Lancet Neurol. 2020;19(2):123-134.
- Mekhail N, Levy RM, Deer TR, et al; and the Evoke Study Group. Durability of clinical and quality-of-life outcomes of closed-loop spinal cord stimulation for chronic back and leg pain. JAMA Neurol. 2022;79(3):251-260.
- Mekhail NA, Levy RM, Deer TR, et al. Neurophysiological outcomes that sustained clinically significant improvements over 3 years of physiologic ECAP-controlled closed-loop spinal cord stimulation for the treatment of chronic pain. Reg Anesth Pain Med. 2024 Mar 15 [Online ahead of print].
- Nijhuis HJA, Hofste W-J, Krabbenbos IP, et al. First report on real-world outcomes with evoked compound action potential (ECAP)-controlled closed-loop spinal cord stimulation for treatment of chronic pain. Pain Ther. 2023;12(5):1221-1233.
- National Institute for Health and Care Excellence (NICE). Evoke spinal cord stimulator for managing chronic neuropathic or ischaemic pain. Medtech Innovation briefing 238. London, UK: NICE; December 8, 2020.
- Su PYP, Arle J, Poree L, et al. Closing the loop and raising the bar: Automated control systems in neuromodulation. Pain Pract. 2024;24(1):177-185.
Budapest Criteria for Complex Regional Pain Syndrome (CRPS)
- Abdi S. Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2022.
- Harden NR, Bruehl S, Perez RSGM, et al. Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome. Pain. 2010;150(2):268-274.
- Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326-331.
- Harden RN, Oaklander AL, Burton AW, et al. Complex regional pain syndrome: Practical diagnostic and treatment guidelines, 4th edition. Pain Med. 2013;14(2):180-229.
Nalu Micro-IPG for Spinal Cord Stimulation
- Desai MJ, Raju T, Ung C, et al. Results from a prospective, clinical study (US-nPower) evaluating a miniature spinal cord stimulator for the management of chronic, intractable pain. Pain Physician. 2023a;26(7):575-584.
- Desai MJ, Salmon J, Verrills P, et al. A novel pulsed stimulation pattern in spinal cord stimulation: Clinical results and postulated mechanisms of action in the treatment of chronic low back and leg pain. Neuromodulation. 2023b;26(1):182-191.
- Hasoon J, Urits I, Mahmood S, Kaye AD. Restoring successful spinal cord stimulation therapy for a patient with severe pocket pain utilizing Nalu micro-implantable pulse generator. Orthop Rev (Pavia). 2022;14(4):35326.
- Malinowski MN, Heit G, Poree LR, et al. Novel spinal cord stimulation system with a battery-free micro-implantable pulse generator. Pain Pract. 2022;22(6):592-599.
- Salmon J, Bates D, Du Toit N, et al. Early experience with a novel miniaturized spinal cord stimulation system for the management of chronic intractable pain of the back and legs. Neuromodulation. 2023;26(1):172-181.
- Salmon J, Bates D, Du Toit N, et al. Treating chronic, intractable pain with a miniaturized spinal cord stimulation system: 1-year outcomes from the AUS-nPower Study during the COVID-19 pandemic. J Pain Res. 2024;17:293-304.
