Clinical trial NCT03318172: High-Density Spinal Cord Stimulation for the Treatment of Chronic Intractable Pain Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Pain, Intractable
Keywords: Spinal Cord Stimulation
High Density Stimulation
Lead sponsor: Seoul National University
Sponsor class: OTHER
First posted: 2017-10-23
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.)

Primary outcomes:
measure: Percentage of high density SCS mode selected by participants
timeFrame: Four weeks after randomization
Secondary outcomes:
measure: Difference of pain intensity between the baseline screening and the evaluation at each visit
timeFrame: Six month from baseline screening
measure: Change of pain characteristics between the baseline screening and the evaluation at each visit
timeFrame: Six month from baseline screening
measure: The ability in daily living
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: The current pain intensity and interference status
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: Subjective sleep quality
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: Oswestry Disability Index
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: Beck Depression Inventory
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: Pain Catastrophizing scale
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: The Connor-Davidson Resilience Scale (CD-RISC)
timeFrame: Screening and follow up at 1 month, 3 months and 6 months
measure: Patient Global Impression of Change (PGIC)
timeFrame: Follow up visits 1 month, 3 months and 6 months
measure: Clinical Global Impressions-Improvement (CGI-I)
timeFrame: Follow up visits 1 month, 3 months and 6 months
measure: Patient's satisfaction with the stimulation mode
timeFrame: Follow up visits 1 month, 3 months and 6 months
measure: Any change of pain medication
timeFrame: Six month from baseline screening
measure: Pain area coverage by the SCS
timeFrame: Crossover and follow-up visits 1 month, 3 months and 6 months
measure: Paresthesia threshold
timeFrame: Randomization, crossover and follow-up visits 1 month, 3 months and 6 months
measure: Change in the overall SCS stimulation parameters
timeFrame: From week 1 (randomization) to 6 months follow-up visit
measure: Battery efficiency of the neuro-stimulator
timeFrame: Follow up visits 1 month, 3 months and 6 months
measure: Adaptive Stim use
timeFrame: Follow up visits 1 month, 3 months and 6 months
measure: Measurement of adverse events
timeFrame: Six month from baseline screening
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
affiliation: Clinical Associate Professor
name: Jee Y Moon, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg. 1967 Jul-Aug;46(4):489-91. No abstract available.
citation: North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery. 2005;56(1):98-106; discussion 106-7. doi: 10.1227/01.neu.0000144839.65524.e0.
citation: Kumar K, Buchser E, Linderoth B, Meglio M, Van Buyten JP. Avoiding complications from spinal cord stimulation: practical recommendations from an international panel of experts. Neuromodulation. 2007 Jan;10(1):24-33. doi: 10.1111/j.1525-1403.2007.00084.x.
citation: Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol. 2007 Sep;14(9):952-70. doi: 10.1111/j.1468-1331.2007.01916.x.
citation: Schu S, Slotty PJ, Bara G, von Knop M, Edgar D, Vesper J. A prospective, randomised, double-blind, placebo-controlled study to examine the effectiveness of burst spinal cord stimulation patterns for the treatment of failed back surgery syndrome. Neuromodulation. 2014 Jul;17(5):443-50. doi: 10.1111/ner.12197. Epub 2014 Jun 19.
citation: Meyerson BA, Linderoth B. Mechanisms of spinal cord stimulation in neuropathic pain. Neurol Res. 2000 Apr;22(3):285-92. doi: 10.1080/01616412.2000.11740672.
citation: Wolter T. Spinal cord stimulation for neuropathic pain: current perspectives. J Pain Res. 2014 Nov 18;7:651-63. doi: 10.2147/JPR.S37589. eCollection 2014.
citation: Kuechmann C, Valine T,Wolfe D. Could automatic position-adaptive stimulation be useful in spinal cord stimulation? Eur J Pain 2009;13:S243.
citation: De Ridder D, Vanneste S, Plazier M, van der Loo E, Menovsky T. Burst spinal cord stimulation: toward paresthesia-free pain suppression. Neurosurgery. 2010 May;66(5):986-90. doi: 10.1227/01.NEU.0000368153.44883.B3.
citation: Al-Kaisy A, Van Buyten JP, Smet I, Palmisani S, Pang D, Smith T. Sustained effectiveness of 10 kHz high-frequency spinal cord stimulation for patients with chronic, low back pain: 24-month results of a prospective multicenter study. Pain Med. 2014 Mar;15(3):347-54. doi: 10.1111/pme.12294. Epub 2013 Dec 5.
citation: Perruchoud C, Eldabe S, Batterham AM, Madzinga G, Brookes M, Durrer A, Rosato M, Bovet N, West S, Bovy M, Rutschmann B, Gulve A, Garner F, Buchser E. Analgesic efficacy of high-frequency spinal cord stimulation: a randomized double-blind placebo-controlled study. Neuromodulation. 2013 Jul-Aug;16(4):363-9; discussion 369. doi: 10.1111/ner.12027. Epub 2013 Feb 20.