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.

Inclusion Criteria:

1. Patients with chronic intractable pain who meets the Korean SCS Reimbursement Guideline as follows:

   (Korea SCS Reimbursement Guideline)

   1. 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
   2. 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.

2. Age > 18

3. Patients who have been informed of the study procedures and has given written informed consent.

4. Patients who are willing to comply with study protocol including attending the study visits

Exclusion Criteria:

1. Expected inability of patients to receive or properly operate the SCS system
2. Active malignancy
3. Addiction to any of the following drugs, alcohol, and/or medication
4. 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
5. Local infection or other skin disorder at site of incision
6. Pregnancy
7. Other implanted active medical device
8. Life expectancy < 1 year
9. Coagulation deficiency (Platelet count < 100,000, PT INR > 1.4)
10. Immune deficiency (HIV positive, immunosuppressive, etc.)