High-Density Spinal Cord Stimulation for the Treatment of Chronic Intractable Pain Patients

High-Density Spinal Cord Stimulation for the Treatment of Chronic Intractable Pain Patients: A Prospective Multicenter Randomized Controlled, Double-blind, Crossover Exploratory Study With 6-m Open Follow-up

The purpose of this study is to explore which mode is effective in the management of intractable chronic pain, the high-density stimulation or the conventional stimulation, in patients who undergo SCS implantation after successful pre-implantation SCS trial.

Since its introduction in 1967 (1), spinal cord stimulation (SCS) has become a well-established modality for the treatment of chronic neuropathic back and leg pain, including postlaminectomy syndrome, complex regional pain syndrome, ext. (2-5) The mechanism of action remains poorly understood but is thought to involve a combination of local neural inhibition, excitation of nearby axons, changes in neurotransmitter physiology, and jamming of pathological network activity by masking intrinsic patterns of neural activity (6). It is generally agreed that a sensory percept (paresthesia) covering the region of pain is required in order to achieve maximal effectiveness (3,7), and as a result, conventional SCS settings typically consist of intermediate frequencies (40-60 Hz), relatively long pulse width (300-500 μsec), and amplitude high enough to induce a sensory percept in the distribution of the patient's pain (2,3,5). However, paresthesia can produce some degree of discomfort, particularly with changes in position and variability of activities (8). Consequently, sometimes there is a trade-off between pain relief and paresthesia discomfort, and the clinical benefits can be offset by the side-effects of the stimulation. Recent studies have attempted to deliver energy to the spinal cord below the threshold for paresthesia ("paresthesia-free" stimulation), with variable degrees of success in the control of neuropathic pain. For example, De Ridder et al. described "burst" stimulation (trains of five pulses) in 12 patients, resulting in paresthesia-free pain relief that was superior to conventional settings (9). In a multicenter prospective study, Al-Kaisy et al. evaluated 10 kHz SCS (HFSCS) delivered below the sensory threshold and documented a long-term reduction in the mean intensity of chronic back pain (10). However, a randomized, double-blind, placebo-controlled crossover study comparing 5 kHz high-frequency subthreshold stimulation to placebo found no significant difference between the two modalities, with a tendency for better results during the first treatment administered, which suggests a strong placebo effect (11). Another randomized controlled, double-blinded, crossover study showed that subthreshold stimulation had significantly lower pain relief than the conventional, supra-threshold SCS (12). Notably, both studies included participants treated with conventional stimulation parameters and did not perform a "trial" to confirm that the study population would, in fact, demonstrate a response to subthreshold stimulation. Most systematic studies of paresthesia-free stimulation employed a high rate of energy delivery (high-density [HD] stimulation) that either required the development of specialized hardware (9,10) or modification of existing systems to allow parameters outside of normal clinical use (11). However, it is possible that rechargeable stimulators currently in widespread use may be able to deliver sufficient energy to accomplish pain relief without paresthesia in appropriately selected patients. Additionally, response to subthreshold stimulation might be heterogeneous in unpredictable ways, which implies that there might be a subset of patients who respond to the therapy better than others.

V1 SCS trial for 6 days (3d conventional + 3d HD stimulation). V2 Enrolled if positive response (≥50% pain reduction) in one of the two modes during V1 + informed consent and randomization + blinding Group C Conventional mode (2 weeks) + HD mode (2 weeks) Groups H HD mode (2 weeks) + conventional mode (2 weeks) V3 After 2 weeks (+3d allowed) from V2. Cross-over performed by the MedTronics person in charge of adjusting the SCS mode. Mode-related information will not be shared with other researchers V4 (unblinding) 2 weeks from V3 (+3d allowed). Patients will be questioned about the more effective mode (primary endpoint). The SCS will be programmed accordingly V5 (follow-up 1) 4 weeks after V4 (±5d). Short-term assessment of effectiveness and safety V6 (follow-up 2) 12 weeks after V4 (±5d). Middle-term assessment of effectiveness and safety V7 (follow-up 3) 24 weeks after V4 (±5d). Long-term assessment of effectiveness and safety

The day of the SCS implantation (RestoreSensor Surescan MRI Neurostimulator, Medtronic ©) the patients are randomized based on a random number assigned from www.randomization.com. The random number table is sent to the MedTronic representative in charge of the SCS mode control by the operating nurse who has no information about the study protocol. At this time, implantation practitioners and other research participants don't know which group is assigned first. Subjects with SCS implantation will be assigned 1:1 to either group C (conventional stimulation) or H (High-Density stimulation) to find an effective mode of pain relief.

Spinal cord stimulator (SCS) implantation with conventional stimulation mode therapy during 2 weeks followed by 2 weeks with high-density stimulation mode therapy.

Spinal cord stimulator (SCS) implantation with high-density stimulation mode therapy during 2 weeks followed by 2 weeks with conventional stimulation mode therapy.

Implantation of spinal cord stimulator in patients included in the study and divided in conventional and high density stimulation groups

Patients will be questioned about the more effective mode of pain relief between conventional and high density stimulation.

Measured by the Korean version of the Instrumental Activities of Daily Living (K-IADL) scale. The IADL require complex thinking skills, including organizational skills and they measure the ability of the person to live independently without the assistance of another person. The IADL scale includes 8 categories labeled from A to H (A. Ability to Use Telephone, B. Shopping, C. Food preparation, D. Housekeeping, E. Laundry, F. Mode of transportation, G. Responsibility for Own Medication and H. Ability to Handle Finances). For each category, the patient should mark the description that resembles the highest functional level (either 0 or 1). A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women and 0 through 5 for men to avoid potential gender bias.

The Brief Pain Inventory Short-Form (BPI-SF) scale measures the pain intensity (severity) and the impact of pain on functioning (interference). Includes a screening question about the pain on the day, pain drawing diagrams, four items about pain intensity (worst pain, least pain, average pain, pain right now), two items on pain relief treatment or medication, and one item on pain interference, with seven sub-items (general activity, mood, walking ability, normal walk, relations with other people, sleep, and enjoyment of life). Each item for pain severity is rated from 0, no pain, to 10, pain as bad as you can imagine, and contributes with the same weight to the final score (0 to 40). The seven subitems of pain interference are rated from 0, does not interfere, to 10, completely interferes, and contributes with the same weight to the final score (0 to 70). The first item, pain drawing diagrams and the items on pain relief treatment or medication do not contribute to the scoring.

The difference of Insomnia Severity Index (ISI) between the baseline screening and the evaluation at 1 month, 3 months and 6 months follow up visits

The difference of Oswestry Disability Index between the baseline screening and the evaluation at 1 month, 3 months and 6 months follow up visits

The difference of Beck Depression Inventory between the baseline screening and the evaluation at 1 month, 3 months and 6 months follow up visits

Pain catastrophizing is characterized by the tendency to magnify the threat value of a pain stimulus and to feel helpless in the presence of pain, as well as by a relative inability to prevent or inhibit pain-related thoughts in anticipation of, during, or following a painful event. The Pain Catastrophizing Scale (PCS) is a 13-item instrument derived from definitions of catastrophizing described in the literature. The PCS ask participants to reflect on past painful experiences, and to indicate the degree to which they experienced each of 13 thoughts or feelings when experiencing pain, on 5-point scales from (0) not at all and (4) all the time. The PCS total score is computed by summing responses to all 13 items, total scores range from 0 - 52. The PCS subscales are computed as follows: Rumination: Sum of items 8, 9, 10, 11 Magnification: Sum of items 6, 7, 13 Helplessness: Sum of items 1, 2, 3, 4, 5, 12 Total score <30= Negative and ≥30= Positive for catastrophizing

Resilience embodies the personal qualities that enable one to thrive in the face of adversity. The Connor-Davidson Resilience Scale (CD-RISC) contains 25 items, all of which carry a 5-point range of responses, as follows: not true at all (0), rarely true (1), sometimes true (2), often true (3), and true nearly all the time (4). The scale is rated based on how the subject has felt over the past month. The total score ranges from 0-100, with higher scores reflecting greater resilience.

The overall change in patient's pain for 6 months after the study unblinding, during the follow up visits

The overall change in patient's improvement for 6 months after the study unblinding, during the follow up visits

The difference in the patient's satisfaction evaluated during the follow-up visits using a 5-point Likert scale (5: very satisfied, 4: somewhat satisfied, 3: Dissatisfied, 1: very unsatisfied)

The difference between crossover and follow-up visits (total of 5 times evaluation) by the patient drawing the area of pain coverage. The ideal treatment with SCS will be a total coverage of the pain area, however, sometimes the covered area does not perfectly match with the stimulated area (less or more area). Therefore, a simple drawing of a human body will be presented to the patients who will draw the area of pain and then the coverage of the SCS to compare and analyze the changes throughout the study.

The difference between the randomization, crossover and follow-up visits (total of 6 evaluation) by asking patient to indicate the threshold at which he or she experiences paresthesia. The SCS transmitter allows several intensity levels which are tested before setting the SCS mode. Usually, the intensity level is tested from lowest and slowly increased until the patient experience paresthesia. Paresthesia threshold is different from patient to patient and it might change along time. Therefore, the intensity level marked by the SCS transmitter where the patient experienced the paresthesia will be recorded to evaluate the changes during the study period.

SCS stimulation parameters (active electrodes, frequency, pulse duration, amplitude and battery consumption) each visit after implantation. All parameters of SCS will be recorded in the same item as they are measured based on the SCS transmitter records and reflect the overall SCS status.

The battery usage will be measured by frequencies to recharge the battery during the follow-up visits.

Acquire information on activity from the internal diary; amount of times that patients need to fit the ideal parameters themselves) during the follow-up visits

Any related adverse events throughout the whole study period (e.g. infection, hematoma, seroma, lead breakage, lead migration, SCS removal, etc).

Inclusion Criteria: Patients with chronic intractable pain who meets the Korean SCS Reimbursement Guideline as follows: (Korea SCS Reimbursement Guideline) An ineffective patient with sustainable severe intractable pain (VAS or NRS pain score over 7 grade) who has been treated by a conservative therapy (medication and nerve block, etc.) for 6 months. cf.) CRPS is available after the conservative therapy for 3 months An ineffective cancer pain patient with over 1-year life expectancy and VAS (or NRS pain score) over 7 grade who takes active pain treatment for 6 months such as medication, nerve block, epidural morphine injection, etc. Age > 18 Patients who have been informed of the study procedures and has given written informed consent. Patients who are willing to comply with study protocol including attending the study visits Exclusion Criteria: Expected inability of patients to receive or properly operate the SCS system Active malignancy Addiction to any of the following drugs, alcohol, and/or medication Evidence of an active disruptive psychiatric disorder or other known condition significant enough to impact perception of pain, compliance to intervention and/or ability to evaluate treatment outcome as determined by investigator Local infection or other skin disorder at site of incision Pregnancy Other implanted active medical device Life expectancy < 1 year Coagulation deficiency (Platelet count < 100,000, PT INR > 1.4) Immune deficiency (HIV positive, immunosuppressive, etc.)

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