MSCS in BURSTDR Patients

Basics of SCS Spinal cord stimulation (SCS) was developed at the end of 1960 for the treatment of chronic, untreatable pain and has since been used to treat various pain syndromes (PSPS, CRPS, ischemic pain, phantom pain, etc.). The pathophysiological basis for the development of SCS was the gate control theory, which states that stimulation of the mechanosensitive Aβ fibers suppresses the transmission of pain stimuli via the pain-sensitive C fibers to the brain in the spinal cord. Conventional SCS consists of regularly emitted tonic pulses with a frequency between 30 and 120 Hz. During implantation, the electrodes are placed in the epidural space in such a way that the paresthesia caused by the nerve stimulation covers the painful area (dermatome) and thus relieves the pain. The frequency, amplitude and pulse width can be varied to maximize pain relief. Kuechmann et al were able to show that many patients experience unpleasant stimulation when changing position and therefore have to adapt the stimulation program accordingly.

BurstDRTM-Stimulation In 2010, De Ridder et al. published the first study on a new stimulation method for SCS - BurstDR stimulation. Here, bursts of high-frequency pulses are delivered at certain intervals (bursts at a frequency of 40 Hz with 5 pulse peaks of 500 Hz per burst). According to current knowledge, this mode of signal transmission also exists in human neurons in the thalamus. Based on animal studies, it is assumed that these burst volleys have a greater effect on the cortex in the sense of a wake-up call. BurstDR has been the subject of numerous studies comparing its effectiveness with conventional SCS. A significant difference is the absence of paraesthesia in most cases and the more effective pain relief in some cases. In addition, BurstDR stimulation is thought to modulate the medial pain pathway, which can result in a change in the emotional and attention-related assessment of pain.

The problem of chronic back pain Chronic back pain is difficult to treat adequately. Physiotherapy and therapeutic exercises are usually the first treatment methods used. Medication is also administered. If there is no improvement, many patients are advised to undergo surgery on the lumbar spine. The results here are generally good. However, there is a not inconsiderable percentage (5-25%) who do not benefit from surgery or even repeated operations. These patients usually receive pain therapy. If there is no improvement here either, there is the option of a neuromodulatory procedure to relieve the pain. The most common procedure currently used for back pain is spinal cord stimulation (SCS).

However, there are problems with the use of SCS that repeatedly impair the results of this treatment for chronic back pain.

Problems of treating chronic back pain with SCS stimulation The first problem is the large number of different types of tissue in the back, all of which can cause pain: Bones (e.g. collapsed vertebral bodies), joints (facet joints), ligaments (posterior longitudinal ligament), neural structures (nerve roots) and muscles. As all these tissues have different types of pain receptors, some of which respond very differently to neurostimulation. It has so far been very difficult to treat back pain with tonic stimulation. The reason for this is that the penetration depth with tonic stimulation in the area of the posterior columns of the spinal cord is not sufficient to stimulate the neurons in the posterior horn.

Another problem is the habituation of the neurons to tonic stimulation, which leads to an additional decrease in the effectiveness of the treatment.

The use of new wave technologies The introduction of new wave technologies such as BurstDR has now made it possible to reach and stimulate the deep-seated WDR neurons in the posterior horn. This has made it possible for the first time to treat back pain neuromodulatively much more efficiently and reduce it sufficiently.

The use of eight-pole rod electrodes (octrode, percutaneous lead) and 20-pole plate electrode (Penta-lead, surgical lead) makes it possible to deliver the electrical energy to the posterior cords.

This allows the relevant neurons to be stimulated. A percutaneous lead stimulates tissue in a 360° direction. A surgical lead in 180°. The effects of muscle stimulation are based on antidromic stimulation effects, so electrode type should not exert a substantial effect on the results. However, investigators would like to perform a post-hoc analysis to confirm this.

However, there is a further optimization option:

The musculature is another pain factor that has not yet been reached with neuromodulation, as the receptor types of the musculature still respond inadequately to neurostimulation. One way to reach the muscles nevertheless is to stimulate the motor neurons in the anterior horn directly with a stimulation frequency of 2-20 Hz and thus achieve a massage effect on the muscles. Many patients find this very pleasant, like a gentle muscle massage. A pilot study has already been carried out which has shown that it is possible to achieve this effect in patients with low-frequency SCS stimulation.

In the present study, the following components will be used:

• BurstDR stimulation
• Already implanted pentalead or octrode (either existing patients or new patients after trial phase and permanent implantation)
• Additional muscle stimulation can be used in a combined system for the treatment of back pain.

These components are already in clinical use. However, the combination for the treatment of back pain has not yet been used in this constellation. Hence there is CE mark for the indication and the stimulation types. This study is out of the scope of MDR. The aim of the study is to determine whether patients experience a further improvement in pain symptoms through muscle stimulation in addition to their existing neuromodulatory therapy with an Octrode.

Summary description and brief justification of the study The treatment of chronic back pain remains difficult. Neuromodulatory procedures using novel wave technologies can now be used to treat back pain for the first time. However, the methods are still inadequate and not fully developed. A combined system of neuromodulatory treatment and additional muscle stimulation will therefore be used to treat chronic back pain in this study. The patients included in this study have already undergone the process of probe implantation and adjustment to their individually suitable stimulation pattern. Patients will be selected if the probe was implanted 0 - 5 years ago. Patients with implanted rod electrodes (octrodes) and plate electrodes will be included in the study. The aim of this study is to investigate whether additional muscle stimulation can optimize the current pain therapy. After being informed about the study and providing informed consent, the questionnaires (baseline) are completed before the start of the study. Then, in addition to the existing BurstDR stimulation, additional muscle stimulation is started twice a day for 30 minutes at a time and continued for 3 months. During this time, the pain values are also determined every 4 weeks using the visual analog scale (VAS), Oswestry Disabillity Index (ODI), EQ5D-5L, Pain Catastrophizing Scale (PCS), Pain Disability Index (PDI), Patient Global Impression of Change (PGIC). At the end of 3 months, the questionnaires are completed again. The VAS values and the values from the questionnaires are compared with the baseline values. In addition, possible side effects and adverse reactions that could be triggered by the stimulation are recorded at this time. This study makes it possible to investigate the combination of pain treatment with BurstDR and simultaneous muscle stimulation with an Octrodes and pentaleads for chronic back pain in a prospective study.

Objectives

• Compare BurstDR stimulation with BurstDR stimulation + MSCS stimulation

• Primary outcome: VAS difference
• Secondary outcomes: pain catastrophizing scale (PCS), Oswestry Disability index (ODI), EQ5D-5L, Pain Disability Index (PDI)
• Evaluate patient satisfaction (Patient Global Impression of Change (PGIC)), patient preference
• Compare the effects between a surgical lead group and percutaneous lead group
• Compare the effects between new implanted patients (direct after trial) vs implanted patients

Study design Statement of study design Prospective, non-randomized open label study study population

• patients succesfuly treated with burst DR stimulation, treated at the Jessa Hospital Belgium. In accordance with the inclusion and exclusion criteria.
• Investigators aim to include 60 patients in total (A priori T test with effect size 0.25, alfa 0.1, power 0.80)
• Investigators aim to include an equal amount of percutaneous and surgical leads
• We aim to include an equal amount of new implanted patients (directly after trial and permanent implantation) and patients already in treatment with Burst DR in the existing population.
• Hence investigators will include:

• 15 octrode patients new in treatment
• 15 paddle lead patients new in treatment
• 15 octrode patients already in treatment
• 15 paddle lead patients already in treatment
• Study control group: patients are their own controls

Study sites Patients will be recruited at the Jessa Hospital Hasselt, Universiteits Klinikum Düsseldorf (Germany), VNeuro Praxia (Germany), Leeds Teaching Hospital (UK)

Number of subjects 60 subjects

Sample size calculation and planned statistical analyses Sample size calculation has been perfomed and suggests to include 60 patients in total (A priori T test with effect size 0.25, alfa 0.1, power 0.80)

Inclusion - exclusion criteria

Main criteria for inclusion:

• Patients with PSPS type 2
• Patients with predominant back pain
• Patients with SCS(BurstDR) stimulation in situ with >50% pain relief. Patients have to be satisfied with their existing SCS therapy and predominantly use a BurstDR stimulation program. ) (Only responders to that therapy should be included, not patients who have not responded to their therapy so far.)
• Patient must be willing and able to provide written informed consent before any clinical investigation-related procedure
• Age ≥18 y
• Low back pain baseline score of ≥6 on NRS before spinal cord stimulation therapy and a MCID (Minimal clinically important difference) of >30% with SCS(BurstDR) stimulation.
• Willing and able to comply with the instructions for use, operate the study device, and comply with this clinical investigation plan

Main criteria for exclusion:

• Pathology seen on imaging tests that is clearly identified and is likely the cause of the CLBP, that can be addressed with surgery, or related to these origins:

• vascular causes (eg, aortic aneurysm)
• spinal infection (eg, osteomyelitis)
• inflammation or damage to the spinal cord (eg, arachnoiditis or syringomyelia)
• tumor or spinal metastases
• Severe scoliotic deformity (>11◦ in thoracic or lumbar spine)
• Primary symptom of leg pain, or leg pain is greater than back pain
• Has widespread pain (eg, fibromyalgia) or pain in other area(s), not intended to be treated in this study (eg, neck pain, shoulder pain)
• Patient has used a morphine equivalent daily dose of >50 MME in the last 30 d
• Patients with regular intake of systemic steroids (except inhaled steroids used to treat asthma)
• Known allergic reaction to implanted materials
• Patient has a history of or existing intrathecal drug pump
• Patient has previous experience with neuromodulation devices, including a failed trial
• BMI >40
• Patient is enrolled, or intends to participate, in another clinical drug and/or device study or registry that may interfere with the results of this study.
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychologic conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results
• Failed psychologic evaluation
• Suspicion or evidence of untreated mental illness, substance abuse, or drug-seeking behavior
• Patient is in current litigation for back pain/injury, or is currently receiving worker's compensation
• Pregnant or nursing subjects and those who plan pregnancy during the clinical investigation follow-up period.

• Subject procedures Data collection will be elementary and based on retrospective extraction from clinical record and of data which are part of a routinely clinically collection. Reprogramming will occur in which the subject will get an additional stimulation program on top of the running BURST DR program. Patients will be asked to fill-out specific patient-administered questionnaires in order to evaluate treatment results.

Neurostimulation After the patients have been recruited, they are called to the clinic as outpatients and informed about the study. This is followed by written consent. The baseline questionnaires are then completed to assess the current pain situation. This is followed by a physical examination. The most suitable form of muscle stimulation for the patient is then tested.

During the examination, the patient lies comfortably in a prone position on a bed.

The muscle stimulation is correlated with the position of the probe in the X-ray image (e.g.

probe position thoracic 8-9, probe position thoracic 9-10, probe position thoracic 11-12).

The frequencies 4Hz, 8Hz, 12Hz, 16Hz and 20Hz are tested. These frequencies are each tested with different contact combinations of the electrode. It is then determined which frequency produces the best effect for the patient with which contacts. As soon as the optimum stimulation pattern has been found, the patient is asked to lie on their back. The previously tested optimal stimulation pattern is now tested again to check whether it remains the optimal stimulation pattern despite minimal changes in the position of the electrode in the supine position and muscles under a different load. If this is not the case, further adjustments are made until the ideal stimulation pattern for the patient is achieved. Once this has been determined, the muscle stimulation is continued in this way.

Muscle stimulation is now carried out with the optimum contact combination of electrode and frequency determined for the patient. Muscle stimulation is carried out as follows: it is performed twice a day for half an hour at 9 am and 8 pm. A special program is created for this purpose. The patient can switch this on and off independently. The BurstDR program stops running during muscle stimulation and is switched off by the patient during muscle stimulation alone. The technicians are always present during operations and carry out the programming. They also carry out the settings on the patient after the operation and continue to work closely with the patient. If patients have any questions about the system, they can also contact the technicians directly (by phone) for advice, e.g. if they have problems with the stimulation settings. The technicians are very familiar with the system as some of them have worked with the patients for years.

Questionnaires:

The following data will be acquired during Baseline, 4 weeks, 8 weeks and 12 weeks after MSCS by the patient:

• Visual analogue Scale (in accordance with the complaints) for leg and back pain
• Pain disability Index (PDI)
• Pain Catastrophizing Scale (PCS)
• Oswestry Disability index (neck or back, ODI)
• EuroQol - 5D (EQ5D)
• Patient Global Impression of Change (PGIC)

The following data will be acquired during Baseline, 4 weeks, 8 weeks and 12 weeks after MSCS by the physician:

• Pain medication (WHO classification)
• Pain information: duration, location and type of pain (categorical)
• Electrode implantation location
• Electrode Type, IPG type
• Programming parameters for BURST DR (anodes, cathodes, frequency, burst-frequency, pulsewidth, amplitude)
• Programming parameters for MSCS (anodes, cathodes, frequency, pulsewidth, amplitude) Questionnaires will be provided digital, on an Ipad (provided by the neurochirurgy department during the study visit) with the back-app in a specific design for this study. If patients are not capable of using the Ipad, the study team will help them. If necessary, paper questionnaires can be provided and filled out in the eCRF afterwards by the study team.

Inclusion criteria

• Patients with PSPS type 2
• Patients with predominant back pain
• Patients with SCS(BurstDR) stimulation in situ with >50% pain relief. Patients have to be satisfied with their existing SCS therapy and predominantly use a BurstDR stimulation program. ) (Only responders to that therapy should be included, not patients who have not responded to their therapy so far.)
• Patient must be willing and able to provide written informed consent before any clinical investigation-related procedure
• Age ≥18 y
• Low back pain baseline score of ≥6 on NRS before spinal cord stimulation therapy and a MCID (Minimal clinically important difference) of >30% with SCS(BurstDR) stimulation.
• Willing and able to comply with the instructions for use, operate the study device, and comply with this clinical investigation plan

Exclusion criteria

• Pathology seen on imaging tests that is clearly identified and is likely the cause of the CLBP, that can be addressed with surgery, or related to these origins:

• vascular causes (eg, aortic aneurysm)
• spinal infection (eg, osteomyelitis)
• inflammation or damage to the spinal cord (eg, arachnoiditis or syringomyelia)
• tumor or spinal metastases
• Severe scoliotic deformity (>11◦ in thoracic or lumbar spine)
• Primary symptom of leg pain, or leg pain is greater than back pain
• Has widespread pain (eg, fibromyalgia) or pain in other area(s), not intended to be treated in this study (eg, neck pain, shoulder pain)
• Patient has used a morphine equivalent daily dose of >50 MME in the last 30 d
• Patients with regular intake of systemic steroids (except inhaled steroids used to treat asthma)
• Known allergic reaction to implanted materials
• Patient has a history of or existing intrathecal drug pump
• Patient has previous experience with neuromodulation devices, including a failed trial
• BMI >40
• Patient is enrolled, or intends to participate, in another clinical drug and/or device study or registry that may interfere with the results of this study.
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychologic conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results
• Failed psychologic evaluation
• Suspicion or evidence of untreated mental illness, substance abuse, or drug-seeking behavior
• Patient is in current litigation for back pain/injury, or is currently receiving worker's compensation
• Pregnant or nursing subjects and those who plan pregnancy during the clinical investigation follow-up period.