By Lindsey N. Clark, MD, and Nancy J. Selfridge, MD
Dr. Clark is a Clinical Skills Facilitator, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies.
Dr. Selfridge is Professor, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies.
Dr. Clark and Dr. Selfridge report no financial relationships relevant to this field of study.
SUMMARY POINTS
• In this randomized controlled trial to study the effectiveness of scrambler therapy for pain treatment in patients with neuromyelitis optica, 22 patients completed the study — 11 each in a scrambler therapy arm and an active control arm.
• Pain scores decreased from 5.0 to 1.5 on a numeric rating scale after 10 days of scrambler therapy. There was no significant decrease in the sham arm. Therapeutic effects were sustained at a 30-day follow-up, but not at 60-day follow-up.
• Patients receiving scrambler therapy also reported decreases in anxiety and depression, with a significant decrease in depressive symptoms.
SYNOPSIS: Scrambler therapy appears to significantly reduce central neuropathic pain for patients with neuromyelitis optica spectrum disorder, although pain reduction is not shown to be sustained for more than 30 days after treatment.
SOURCE: Mealy MA, Kozachik SL, Cook LJ, et al. Scrambler therapy improves pain in neuromyelitis optica: A randomized controlled trial. Neurology 2020;94:e1900-e1907.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, inflammatory disorder of the central nervous system. Diagnosis is based on the presence of an NMO-IgG autoantibody that attacks the aquaporin-4 water channel on the feet of astrocytes in the central nervous system, resulting in demyelination, axonal damage, and axonal loss in the optic nerves and spinal cord.
Patients subsequently experience repeated episodes of optic neuritis and transverse myelitis throughout the course of the disease, manifesting as uncontrolled pain. Previous studies report that more than 80% of patients with NMOSD experience pain that severely affects their quality of life.1 Both spastic and neuropathic pain are present in NMOSD patients, with the latter reported as more common and difficult to control.2 Common current agents for treatment include antiepileptics, antispasmodics, antidepressants, and analgesics, yet often lack immediate relief and long-term efficacy for NMOSD-associated central neuropathic pain.1
Scrambler therapy has been studied and used as a treatment for persistent peripheral neuropathic pain, as seen postsurgically, in chemotherapy-induced neuropathy and in postherpetic neuralgia. Prior to this study, only two case reports described benefits of scrambler therapy in NMOSD patients, and there were no randomized controlled trials of this intervention for patients suffering central neuropathic pain.3
The scrambler therapy device consists of five artificial neurons controlled by an optimized algorithm that creates “non-pain” signals, which can be transmitted along C-fibers, ultimately leading to diminished pain sensations in the brain.4 A typical scrambler therapy regimen is 10 to 12 consecutive treatments performed over a two-week period.
In this study, the authors used a randomized, experimental design with an active placebo control. Twenty-three patients were assessed for eligibility, resulting in 22 patients (11 per arm) enrolled at Johns Hopkins Neuromyelitis Optica Clinic. One patient declined to participate.
Inclusion criteria consisted of neuropathic pain attributed to inflammatory lesions of the spinal cord, indicated on magnetic resonance imaging and persistent pain (present for more than three months) rated > 4 on an 11-point numeric rating scale (NRS).
Exclusion criteria consisted of concomitant diagnosis of peripheral neuropathy or ongoing central neurologic disorder and use of investigational pain agents within 30 days of enrollment. Patients were randomly assigned to receive either scrambler therapy or sham treatment.
The scrambler therapy device used in the study was the GEOMC Pain Scrambler model MC-5A (Seoul, South Korea). A single, trained technician administered all scrambler therapy sessions as well as sham regimens, creating a single-blinded study design. Participants receiving scrambler therapy had electrodes placed in dermatome areas above and below the level of their spinal lesion, close to their pain. The signal intensity was increased to a maximum threshold for each participant. Then, the electric signal was adjusted to create an analgesic effect in the area of pain and applied for 35 minutes for each session. Participants in the sham group were connected to electrodes that produced vibratory sensations similar to scrambler stimulation. However, no electrical signals were transmitted for participants in the control group.
The scrambler therapy device and sham equipment were kept behind a curtain, thus masked from participants. An unrelated, blinded study coordinator collected all measurements and survey data to mitigate bias.
Brief Pain Inventory (BPI) and Quality of Life in Neurological Disorder (Neuro-QoL) Short Form versions 1.0 were used to assess patient baseline pain and co-occurring conditions, including anxiety, depression, and sleep disturbance. Effectiveness was defined as degree of improvement from baseline pain and compared between the study group and the control groups using Friedman one-way repeated measure analysis of variance. Subjects were tested immediately after treatment and at 30-day and 60-day follow-up. Wilcoxon signed-rank testing was used to determine the sustainability of pain improvement by comparing pain scores at 30-day and 60-day follow-ups.
With the study participant size of 11 participants per arm, Mealy et al report a study power of 80%, with a 60% difference in proportion between the two arms. The co-occurring symptoms (anxiety, depression, and sleep disturbance) were analyzed similarly to pain via Friedman one-way repeated measure. Demographic and clinical characteristics were compared between scrambler and sham groups by use of Mann-Whitney U and X2 testing.
Twenty-two participants completed the treatment and sham regimens. Results from the study provided Class II evidence of scrambler therapy use in patients with NMOSD. No serious adverse events were reported during the study. Results showed a majority of participants were female (91%) and Black (59%), consistent with the general NMOSD population. All participants were seropositive for the NMO-antibody (Anti-aquaporin-4 antibody). X2 analysis showed the masking technique was successful, with no difference between the two groups in patients who believed they had received scrambler therapy.
The baseline pain level for all participants in the study was 5.0 on NRS scale. Immediate pain measurement after scrambler therapy showed a significant reduction in NRS pain score from 5.0 to 1.5
(P = 0.001), whereas the sham group showed a reduction in NRS pain score from 5.0 to 4.0 (P = 0.4239). (See Table 1.) Additionally, the scrambler therapy group showed significantly decreased pain at the 30-day post-intervention measurement (P = 0.0195) that was not sustained at the 60-day measurement.
Table 1. Scrambler Therapy vs. Control |
|||||
|
Scrambler Therapy |
Control Group |
||||
|
Baseline median NRS pain rating |
Immediate NRS pain rating (10-day post) |
P value |
Baseline median NRS pain rating |
Immediate NRS pain rating (10-day post) |
P value |
|
5.0 (2.8) |
1.5 |
P < 0.0001 |
5.0 (3.2) |
4.0 |
P = 0.4239 |
|
NRS: numeric rating scale |
|||||
Depression was the only co-occurring symptom to be significantly reduced after treatment with scrambler therapy (P = 0.03). No significant decrease was detected in anxiety (P = 0.10) or sleep disturbance (P = 0.26). In the sham arm, there was no significant change in depression, anxiety, or sleep disturbance immediately after the study, nor at the 30-day and 60-day mark.
COMMENTARY
This well-designed study presents evidence supporting the effectiveness of scrambler therapy for the treatment of central neuropathic pain in NMOSD patients and contributes to developing theories that the “non-pain” signals generated by the scrambler therapy device serve to displace and modify pain signals generated both in the peripheral and central nervous systems.4 Ultimately, it appears the brain is being rewired to receive “non-pain” messages, creating an analgesic effect. Mealy et al have shown that scrambler therapy can successfully be studied in a randomized experimental setting using a masking technique and a clever sham simulation therapy that allows comparison and control for the placebo effect.
Scrambler therapy appears to be an effective pain treatment option for a patient population that appears to experience more frequent and intense pain when compared to other autoimmune demyelinating diseases, such as multiple sclerosis (MS). Multiple studies of pain in NMOSD cases indicate pain is a major complaint for more than 80% of patients, whereas 47% of patients with MS report pain as a major concern.5 Additionally, patients with NMOSD report significantly higher pain severity levels and experience greater life disruption because of pain than patients with MS, and pain is reported as an overlooked symptom as physicians work to address the many other debilitating symptoms of NMOSD.5,6,7
Considering that the current pain treatment regimens for NMOSD patients involve antiepileptics, antispasmodics, antidepressants, and opioid analgesics, NMOSD patients often are put at risk for unwanted side effects, including tolerance, drowsiness, sedation, and weakness.1 Additionally, NMOSD patients are more likely than MS patients to experience high prevalence of use of pain medications with a lower percentage of pain relief.
In a recent (2020) study by Hyun et al studying pain experiences in NMOSD and MS patients, NMOSD patients reported significantly greater unsatisfactory pain relief than MS patients (38% vs. 13%,
P = 0.031) combined with a higher frequency of pain medication use (82% vs. 60%, P = 0.46) and overall lower pain relief (50% vs. 60%, P = 0.037).8 Scrambler therapy, in contrast, appears to have no significant adverse effects and, thus, presents a safer alternative to these prescription drugs and may yield greater pain relief effectiveness.
Even though scrambler therapy may be an effective way to treat pain in NMOSD patients, initial results from this study showed a sustained reduction in pain only at the 30-day follow-up. The authors noted a lack of sustained pain improvement in study participants receiving scrambler therapy at the 60-day follow-up, which may be explained by a lack of statistical power with the low number of subjects in this study.
The authors noted that an enrollment of 29 patients per arm would be required to give a similarly devised study the power to detect a significant change at 60 days post-treatment. Further work should include larger study populations with the power to detect the ability of scrambler therapy to induce long-term pain reduction in patients with central neuropathic pain.
While awaiting further studies, scrambler therapy can be recommended to patients with neuropathic pain as a safe, alternative treatment that may provide at least a few months of relief for most patients.
Recent estimates report an average cost of a scrambler therapy session costing $200 to $500 per session in cancer pain therapy programs, where it is used more widely.9,10 Insurance coverage for sessions is variable among insurance companies, with many patients opting to pay in cash.
However, in 2014, a federal ruling stating that scrambler therapy is effective and should be covered under Medicare may lead to more cost-effective and wider treatment availability for patients.11 Many insurance providers continue to cite insufficient evidence regarding effectiveness as the primary reason for lack of coverage.12,13
Future studies using a randomized control design, such as Mealy et al, to study scrambler therapy for central neuropathic pain relief are necessary to build a substantial body of evidence to support scrambler therapy for pain relief in NMOSD patients.
REFERENCES
- Bradl M, Kanamori Y, Nakashima I, et al. Pain in neuromyelitis optica — prevalence, pathogenesis and therapy. Nat Rev Neurol 2014 Sep;10:529-536.
- Kessler RA, Mealy MA, Levy M. Treatment of neuromyelitis optica spectrum disorder: Acute, preventive, and symptomatic. Curr Treat Options Neurol 2016;18:2.
- Mealy MA, Newsome SD, Kozachik SL, et al. Case report: Scrambler therapy for treatment-resistant central neuropathic pain in a patient with transverse myelitis. Int J MS Care 2019;21:76-80.
- Marineo G. Inside the scrambler therapy, a noninvasive treatment of chronic neuropathic and cancer pain: From the gate control theory to the active principle of information. Integr Cancer Ther 2019;18:1534735419845143.
- Kanamori Y, Nakashima I, Takai Y, et al. Pain in neuromyelitis optica and its effect on quality of life: A cross-sectional study. Neurology 2011;77:652-658.
- Qian P, Lancia S, Alvarez E, et al. Association of neuromyelitis optica with severe and intractable pain. Arch Neurol 2012;69:1482-1487.
- Zhao S, Mutch K, Elsone L, et al. Pain in neuromyelitis optica is an under-recognized but disabling symptom. J Neurol Neurosurg Psychiatry 2013;84:e2.
- Hyun JW, Jang H, Yu J, et al. Comparison of neuropathic pain in neuromyelitis optica spectrum disorder and multiple sclerosis. J Clin Neurol 2020;16:124-130.
- Southall J. Mayo Clinic researchers test scrambler therapy for pain. HemOnc Today. Published Jan. 6, 2016. https://www.healio.com/news/hematology-oncology/20160106/mayo-clinic-researchers-test-scrambler-therapy-for-pain
- Hopkins Health & Wellness Center. Scrambler therapy. https://www.hopkinswellness.com/scrambler-therapy/
- Anson P. Calmare therapy gets favorable Medicare ruling. National Pain Report. Published Feb. 7, 2014. http://nationalpainreport.com/calmare-therapy-gets-favorable-medicare-ruling-8822947.html
- United Healthcare Services, Inc. Electrical stimulation for the treatment of pain and muscle rehabilitation. https://www.uhcprovider.com/content/dam/provider/docs/public/policies/medicaid-comm-plan/electrical-stimulation-treatment-pain-muscle-rehabilitation-cs.pdf
- Aetna, Inc. Electrical stimulation for pain. http://www.aetna.com/cpb/medical/data/1_99/0011.html
Scrambler therapy appears to significantly reduce central neuropathic pain for patients with neuromyelitis optica spectrum disorder, although pain reduction is not shown to be sustained for more than 30 days after treatment.
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