Electrical Stimulation Via the Scrambler Device as a Treatment for Restless Legs Syndrome/Willis Ekbom Disease
Phase: NA
Conditions: Restless Legs Syndrome, Willis-Ekbom Disease
Sponsor: Mayo Clinic

 
 
 
 
 
 
 
Pilot Study: Electrical Stimulation via the 
Scrambler Device as a Treatment for Restless 
Legs Syndrome/Willis Ekbom Disease  
 
NCT03249779 
November 10, 2016 

Pilot Study: Electrical Stimulation via the Scrambler Device as a 
Treatment for Restless Legs Syndrome/Willis Ekbom Disease  
 
 
Research Team: 
(PI) Melissa C. Lipford, M.D1 
Timothy I. Morgenthaler, M.D.1 
Daniel L. Herold, RPSGT1 
Carrie O’Neill, R.N.2 
Charles L. Loprinzi, M.D.2 
 
1Center for Sleep Medicine, Mayo Clinic, Rochester, MN 
2Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 
 
Mayo Clinic IRB: 16-005286  
 
Objectives: To evaluate, in a pilot fashion, efficacy and tolerability of electrical counter-
stimulation using the Scrambler device in alleviating uncomfortable sensations and urge 
to move in patients with restless legs syndrome/Willis Ekbom Disease (RLS/WED).  
 
Hypotheses: Electrical stimulation applied to the lower extremities using the Scrambler 
device will improve discomfort and alleviate urge to move in patients with RLS/WED. 
This form of therapy will be well-tolerated and without significant side effects. 
 
 
Background Information: 
 
Clinical Description of RLS/WED 
Restless legs syndrome/ Willis Ekbom Disease (RLS/WED) is characterized by an 
unpleasant or uncomfortable urge to move the legs which comes on at rest and is at 
least partially alleviated by movement. Symptoms occur in the evening and nighttime 
hours1. It is estimated that 7.2% of the Western population has RLS/WED, with 2.7% of 
the population experiencing moderate to severe symptoms.  
 
RLS/WED has a significant negative impact on quality of life and is associated with 
anxiety and depression.  Patients often experience significant sleep fragmentation due 
to symptoms which leads to daytime sleepiness and fatigue, cognitive symptoms, and 
loss of productivity at work2.  
 
One-third of RLS/WED patients require daily pharmacologic therapy to manage 
symptoms3. Patients with refractory symptoms often require multiple drugs of different 
classes4. Adverse effects from the most common agents used in treating RLS/WED 
include: drowsiness, dizziness, unsteadiness, weight gain, depression, augmentation, 
and development of impulse control disorders5-7. 
 

Nonpharmacologic modalities are an important means of treating symptoms. Many 
nonpharmacologic strategies are based on counter-stimulation techniques to mask 
RLS/WED symptoms such as warm baths and massage.  Sequential compression 
devices have been shown to be helpful in alleviating symptoms8.  Nonpharmacologic 
counterstimulation modalities may be an important means of reducing medication 
burden in patients with RLS/WED and complementing pharmacotherapies in medically 
refractory patients.  
 
Electrical Stimulation in the management of centrally driven neurogenic pain 
Electrical stimulation has been utilized as an intervention in treatment of various forms 
of neurogenic pain (including peripheral neuropathy, trigeminal neuralgia, and multiple 
sclerosis).  Much of the published data involves use of transcutaneous electrical nerve 
stimulation (TENS). TENS appears to work to reduce pain through both central and 
peripheral mechanisms.  Animal and clinical studies demonstrate that the electrical 
impulses have a local effect on peripheral nerves to reduce pain at area of application. 
There also appear to be effects on central nervous system pathways (periaqueductal 
gray, medulla, and spinal cord) thus reducing pain at sites outside of the area of 
stimulation9,10.  The opiate and GABA receptors are implicated in the effects of TENS.  
These receptors are also targeted by pharmacologic therapies commonly used in RLS 
management. There are no good data regarding the efficacy of TENS for RLS. 
 
 
Scrambler Therapy is a specific form of electrical stimulation which has also been 
utilized in chronic neurogenic pain11. This modality of therapy differs from TENS in that 
the goal is to mediate the patient’s perception of pain, rather than masking the 
peripheral pain signal. The results of this modality of treatment may be longer-lasting 
than TENS, presumably via reduction in central signal generation. Scrambler therapy 
works through C fibers to retrain the peripheral sensation in the area being treated. 
Further description of this technology is available at: International Patent 
PCT/IT2007/000647 and U.S. Patent No. 8,380,317.  Literature search does not yield 
prior studies regarding efficacy of Scrambler therapy in treating RLS. 
 
Multiple clinical trials have shown that electrical stimulation using Scrambler Therapy is 
an effective method of treating chronic neurogenic pain. Table 1 reviews the literature 
regarding the use of Scrambler Therapy in over 800 patients. Treatment is well tolerated 
and without significant side effects.  
 
Electrical stimulation as a potential treatment of RLS/WED 
Most patients with RLS/WED experience discomfort in the lower limbs which is 
described using terminology including: crawling, tingling, restless, electric, tension, and 
itching12. The peripheral discomfort localized to the lower extremities in RLS/WED 
appears to be driven by a central mechanism.  Functional neuroimaging studies have 
elucidated that RLS/WED stems from striatal dopaminergic dysfunction13,14. This is 
corroborated by the positive response obtained when treating patients with 
dopaminergic medications15.  The above data demonstrating efficacy of electrical 

stimulation in other forms of centrally-mediated neurogenic pain, would suggest that this 
modality may also be an effective treatment in RLS/WED. 
 
Significance: If electrical stimulation via Scrambler Therapy is effective in alleviating 
discomfort associated with RLS/WED, this may represent a novel nonpharmacologic 
modality of managing symptoms.  Negative results will also be clinically useful in 
guiding strategies in the treatment of RLS/WED. 
 
Proposed Study Design: Prospective, interventional, pilot study 
 
Inclusion criteria: 
• Male patients age 18 and over and post-menopausal women (or women who are 
not of child-bearing potential) diagnosed with RLS/WED by a board certified 
sleep medicine physician within the Mayo Clinic Center for Sleep Medicine.  
• Patients must have moderate to severe symptoms which have been present for ≥ 
3 months. Patients must endorse discomfort as part of their typical RLS/WED 
symptomatology. 
• Patients must experience daily symptoms and must experience daily symptoms 
during afternoon hours (12-5 PM) 
• Patients on no medications for RLS/WED, or those who have refractory 
symptoms despite RLS/WED medications will be enrolled.  Patients on alpha-2-
delta ligands (pregabalin, gabapentin) will be asked to discontinue these 
medications two weeks prior to starting treatments and remain off these 
medications throughout the study protocol.   
• Informed consent to participate in this study needs to be obtained 
 
Exclusion criteria: 
• Research authorization not provided 
• Patients who are asymptomatic (either by verbal report or completion of severity 
scale) at time of initiation of Scrambler Therapy treatment 
• Patients who have made changes in medication regimen during the 2 weeks 
prior to study initiation (including initiation of iron supplementation) 
• Prior use of Scrambler Therapy 
• Female patients of child-bearing potential (those who are not post-menopausal or 
post-hysterectomy) 
• Patients with implantable drug delivery systems, heart stents, or metal implants 
(including pacemakers and defibrillators) 
• Patients with history of epilepsy or other medical conditions that in the opinion of 
the investigators should be excluded 
• Patients with skin conditions or wounds in or around the area of electrode 
application (lower extremities) 
• Patients treated with alpha-2 delta ligands (gabapentin, pregabalin), who cannot 
discontinue the medications as above 
 
 
 

 
Proposed Methods: 
A total of up to 10 eligible subjects will be recruited who have been diagnosed with 
chronic RLS/WED in the Mayo Clinic Center for Sleep Medicine. Subjects must 
experience daily symptoms and must typically be symptomatic during the timeframe in 
which Scrambler Therapy will be utilized (12-5 PM).  Each patient will complete the 
International Restless Legs Syndrome Rating Scale (IRLS), a validated scale which 
assesses severity of RLS symptoms16 at baseline (pre-treatment) and before and 
directly after each session of Scrambler Therapy. 
 
Patients will receive Scrambler Therapy (Appendix VI) on a daily basis for up to 10 
consecutive weekdays. Electrodes will be placed proximal to the area of RLS 
symptomatology, with gradual downward localization until the entire area of RLS 
symptoms has been treated. Treatment will initially take place on one leg. Treatments 
will be administered by a technician trained in using the Scrambler device.  A physician 
or nurse (with familiarity of Scrambler therapy) will be available throughout each 
treatment session. 
 
Patients will complete questionnaires regarding discomfort or other side effects 
encountered during or after treatment.  They will also complete surveys assessing for 
any changes (benefits or worsening) in RLS symptomatology between treatments. 
 
Patients will be monitored for any adverse events associated with the study procedures. 
Any reported adverse events will be expediently classified by the study group as to 
severity level, whether it relates to the treatments in the study protocol, and whether the 
event was expected or unexpected. This information will allow determination of whether 
or not the adverse event should be reported as an expedited report or part of the 
routinely reported outcomes data. All adverse events which meet criteria for expedited 
reporting will be reported to the institutional IRB as well as external agencies as 
required.  
 
If there is no evidence of clinical benefit with the first 2-4 patients, then further patients 
may not be recruited.   

Test schedule: 
 
 
 
 
Tests and procedures 
≤30 days  
prior to 
registration 
Day 1, 
Prior to 
therapy 
Daily for 10 
consecutive week 
days beginning on 
Day 1 of active 
therapy 
On last day of 
therapy 
1 Week after last 
Session 
Clinical visit with history and exam, 
Eligibility questions, Consent 
X 
 
 
 
 
Baseline severity question confirming 
moderate to severe symptoms 
X 
 
 
 
 
 
IRLS severity questionnaire regarding 
the prior week (Appendix I) 
 
X 
 
X 
X 
Patient Questionnaire: Just Before Each 
Treatment (Appendix II) 
 
X 
X 
 
 
Patient Questionnaire: Just After each 
treatment (Appendix III) 
 
 
X 
 
 
Patient Questionnaire After each therapy  
and during weekly follow-up: Global 
Impression of Change and Patient 
Preference (Appendix IV) 
 
 
X 
 
 
Daily Treatment Log and Adverse 
Assessment (Appendix V) 
 
 
X 
 
 
Coordinator phone call to discuss therapy 
and any concerns, record any adverse 
events that are reported and to remind 
the patient to complete questionnaire 
and mail back 
 
 
 
 
X 
 

Funding: 
Small Grant Award through CCATS and Division of Pulmonary Medicine – for research 
coordinator support and subject remuneration 
 
References: 
 
 
1. 
American Academy of Sleep Medicine. The international classification of sleep disorders : 
diagnostic and coding manual. 2nd ed. Westchester, Ill.: American Academy of Sleep Medicine; 
2005:xviii, 297 p. 
2. 
Stevens MS. Restless Legs Syndrome/Willis-Ekbom Disease Morbidity: Burden, Quality of Life, 
Cardiovascular Aspects, and Sleep. Sleep medicine clinics. 2015;10:369-373, xv-xvi. 
3. 
Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of 
primary medical care patients in western Europe: Prevalence and characteristics. Sleep 
medicine. 2010;11:31-37. 
4. 
Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG. Willis-Ekbom Disease 
Foundation revised consensus statement on the management of restless legs syndrome. Mayo 
Clinic proceedings. 2013;88:977-986. 
5. 
Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb 
movement disorder in adults--an update for 2012: practice parameters with an evidence-based 
systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice 
Guideline. Sleep. 2012;35:1039-1062. 
6. 
Garcia-Borreguero D, Kohnen R, Silber MH, et al. The long-term treatment of restless legs 
syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice 
guidance: a report from the International Restless Legs Syndrome Study Group. Sleep medicine. 
2013;14:675-684. 
7. 
Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control 
disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. 
Sleep. 2010;33:81-87. 
8. 
Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless 
legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest. 
2009;135:74-80. 
9. 
Vance CG, Dailey DL, Rakel BA, Sluka KA. Using TENS for pain control: the state of the 
evidence. Pain management. 2014;4:197-209. 
10. 
Rushton DN. Electrical stimulation in the treatment of pain. Disability and rehabilitation. 
2002;24:407-415. 
11. 
Majithia N, Smith TJ, Coyne PJ, et al. Scrambler Therapy for the management of chronic pain. 
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in 
Cancer. 2016. 
12. 
Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology. 
1996;47:1435-1441. 
13. 
Michaud M, Soucy JP, Chabli A, Lavigne G, Montplaisir J. SPECT imaging of striatal pre- and 
postsynaptic dopaminergic status in restless legs syndrome with periodic leg movements in 
sleep. Journal of neurology. 2002;249:164-170. 
14. 
Wetter TC, Eisensehr I, Trenkwalder C. Functional neuroimaging studies in restless legs 
syndrome. Sleep medicine. 2004;5:401-406. 
15. 
Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by 
pramipexole: a double-blind randomized trial. Neurology. 1999;52:938-943. 
16. 
Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome 
Study Group rating scale for restless legs syndrome. Sleep medicine. 2003;4:121-132. 
17. 
Marineo G. Untreatable pain resulting from abdominal cancer: new hope from biophysics? JOP. 
2003;4:1-10. 
18. 
Sabato AF, Marineo G, Gatti A. Scrambler therapy. Minerva Anestesiol. 2005;71:479-482. 

19. 
Smith TJ, Coyne PJ, Parker GL, Dodson P, Ramakrishnan V. Pilot trial of a patient-specific 
cutaneous electrostimulation device (MC5-A Calmare(R)) for chemotherapy-induced peripheral 
neuropathy. Journal of pain and symptom management. 2010;40:883-891. 
20. 
Abdi S, Lakkimsetty VM, Barrera J, Candiotti K, Lubarsky D. The Use of “Scrambler Therapy” for 
Failed Back Surgery Syndrome. Pain Physician. 2011;14:E465-491. 
21. 
Marineo G, Iorno V, Gandini C, Moschini V, Smith TJ. Scrambler Therapy May Relieve Chronic 
Neuropathic Pain More Effectively Than Guideline-Based Drug Management: Results of a Pilot, 
Randomized, Controlled Trial. Journal of pain and symptom management. 2011. 
22. 
Ricci M, Pirotti S, Scarpi E, et al. Managing chronic pain: results from an open-label study using 
MC5-A Calmare(R) device. Supportive care in cancer : official journal of the Multinational 
Association of Supportive Care in Cancer. 2011. 
23. 
Ghatak RK, Nandi SN, Bhakta A, Mandal GC, Bandyopadhyay M, Kumar S. Prospective study of 
application of biological communication (cybernatics) in management of chronic low back pain--a 
preliminary report. Nepal Medical College journal : NMCJ. 2011;13:257-260. 
24. 
Sparadeo F CK, S D'Amato. Scrambler Therapy: An Innovative and Effective Treatment for 
Chronic Neuropathic Pain. Journal of Life Care Planning 2012;11:3-15. 
25. 
Coyne PJ, Wan W, Dodson P, Swainey C, Smith TJ. A Trial of Scrambler Therapy in the 
Treatment of Cancer Pain Syndromes and Chronic Chemotherapy-Induced Peripheral 
Neuropathy. Journal of pain & palliative care pharmacotherapy. 2013. 
26. 
Campbell T, Nimunkar AJ, Retseck J, et al. A randomized, double-blind study of “Scrambler” 
therapy versus sham for painful chemotherapy-induced peripheral neuropathy (CIPN). Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31. 
27. 
Park HS, Sin WK, Kim HY, et al. Scrambler therapy for patients with cancer pain - case series. 
The Korean journal of pain. 2013;26:65-71. 
28. 
Pachman DR, Weisbrod BL, Seisler DK, et al. Pilot evaluation of Scrambler therapy for the 
treatment of chemotherapy-induced peripheral neuropathy. Supportive care in cancer : official 
journal of the Multinational Association of Supportive Care in Cancer. 2014. 
29. 
Sparadeo F, D'Amato S. Scrambler Therapy: Effective use of artificial neurons for the treatment 
of neuropathic pain. Journal of Nurse Life Care Planning. 2014;14. 
30. 
Moon JY, Kurihara C, Beckles JP, Williams KE, Jamison DE, Cohen SP. Predictive Factors 
Associated with Success and Failure for Calmare (Scrambler) Therapy: A Multi-Center Analysis. 
The Clinical journal of pain. 2014. 
31. 
Starkweather AR, Coyne P, Lyon DE, Elswick RK, Jr., An K, Sturgill J. Decreased low back pain 
intensity and differential gene expression following calmare(R): results from a double-blinded 
randomized sham-controlled study. Research in nursing & health. 2015;38:29-38. 
 
 

Table 1 
 
Reports, by first author 
Year 
Pt # 
Condition 
Results 
Trial type 
Comments 
1 
Marineo 17 
2003 
11 
Drug-resistant visceral pain 
Substantial pain reduction 
Prospective trial  
2 
Sabato 18 
2005 
226 
multiple chronic pain 
syndromes 
80% of patients with greater than 
a 50% pain reduction 
Prospective trial  
3 
Smith 19 
2010 
18 
Chemotherapy-induced 
neuropathy 
Over 50% reduction in pain 
Prospective trial (16 evaluable) 
4 
Abdi 20 
2011 
10 
Back pain 
28% reduction in pain. 
Prospective trial Abstract only 
5 
Marineo 21 
2011 
52 
post-herpetic neuralgia, spinal 
canal stenosis, and post-
surgical neuropathic pain 
Pain reduced more in Scrambler 
arm, than the control arm at 1 
month and 3 months ((P<0.0001) 
Randomized, 
controlled 
Open label trial 
6 
Ricci 22 
2012 
82 
Various cancer and non-
cancer pains 
Mean pain scores dropped from 
6.2/10 prior to treatment to 1.6 
just after completing 10 treatment 
days to 2.9, 2 weeks after 
finishing treatment. 
Prospective trial 73 evaluable 
pts. 
7 
Ghatak 23 
2011 
8 
Chronic low back pain 
Pain score drop from 8.12 to 
6.93; Drop in ODI from 49.88 to 
18.44 
Prospective trial Open label 
8 
Sparadeo 24 
2012 
173 
Chronic pain >6 months 
Marked pain reduction 
Clinical practice 
experience 
91 provided 3-6 
months f/u 
9 
Coyne 25 
2013 
39 
Cancer pain syndromes, 
including Chemotherapy-
induced neuropathy 
Significant pain reduction with 10 
treatment days that largely lasted 
for 3 months 
Prospective trial  
10 
Smith 25 
2013 
10 
Post-herpetic neuralgia 
95% pain reduction, that largely 
lasted for 3 months 
Prospective trial 
data 
Some pts were 
the same as in a 
previous trial 18 
11 
Ko 26 
2013 
3 
Post-herpetic neuralgia 
Marked pain reduction 
Clinical practice 
experience 
 
12 
Park 27 
2013 
3 
Cancer bone metastases 
Marked pain reduction 
Clinical practice 
experience 
 
13 
Campbell 26 
2013 
14 
Chemotherapy-induced 
neuropathy 
No differences between active 
and placebo arms 
Prospective, 
double-blind, 
placebo-
controlled trial 
Abstract only 

 
Reports, by first author 
Year 
Pt # 
Condition 
Results 
Trial type 
Comments 
14 
Pachman 28 
2014 
37 
Chemotherapy-induced 
neuropathy 
Average pain decreased by 53% 
at end of treatment and benefit 
largely remained for 10 weeks 
after completion. 
Prospective trial 
Decrease in 
tingling and 
numbness, too. 
15 
Sparadeo 29 
2014 
91 
Variety of pain syndromes 
Substantial pain reduction 
Clinical practice 
experience 
Consecutive 
patients; Some 
pts were the 
same as in a 
previous trial30 
16 
Moon 30 
2014 
147 
Variety of pain syndromes 
 
Clinical practice 
experience 
 
17 
Starkweather 31 
2015 
30 
Low back pain 
Significant improvements in 
active vs control group for: 1) 
worse pain and pain interference 
states; 2) pain sensitivity 
measures, and 3) differential 
mRNA expression of 17 pain 
genes 
Prospective, 
double-blind, 
placebo-
controlled trial 
 

  
Appendix I 
Algorithm 1: Basic Scrambler Treatment Algorithm 
 
 
 
 
 
 
1. Assess/Locate Area of Pain 
• 
Start with area of most severe pain 
2. Place Electrodes 
 
• 
Place electrodes outside area of pain, in 2 D line of pain (horizontal or vertical), and 
on the same side as pain, preferably 2 fingerbreadths outside of pain area 
• 
The area under electrode should be free of pain and allodynia 
• 
The area under the electrode should have good sensation 
 
*If the above criteria are not met, use Algorithm 2 
3. Begin Treatment (turn on channel) 
 
Ask 3 questions: 
• 
When do you feel something? 
• 
When do you feel a sting? 
• 
When do you feel maximum tolerated intensity without discomfort? 
 
*May need to turn up past sting to treat effectively 
*During process may turn up as quickly as tolerated to the maximum 
tolerated intensity after the sting 
0 pain 
Continue to treat for 30 
minutes 
*May turn up intensity if 
intensity has decreased during 
treatment and if patient 
tolerates  
Decreased pain, but >0 
 
Try again to increase 
intensity. If patient does not 
tolerate further increase 
then return to tolerable 
intensity and add another 
channel (Step 1) to attempt 
zeroing pain 
OR 
If at max on machine and 
pain still>0 add another 
channel (Step 1) to attempt 
zeroing pain 
No change in pain 
 
Zero machine and 
reposition electrodes 
Increased 
Pain/Discomfort 
 
If increase of his/her 
pain, move one 
electrode farther  
(may mean that initial 
electrode placement is 
in area of pain) 
If different/new area of pain 
presents then place new set of 
electrodes using same 
algorithm 
No limit to number of 
electrodes used per area 

 
Algorithm 2: Advanced Scrambler Treatment Algorithm 
(If patient does not meet criteria for proper electrode placement) 
 
 
 
 
 
Option 1: Reduce Area of Pain 
 
Place all electrodes above area of pain  
 
• 
For feet, place electrodes on leg above area of pain, most likely 
minimum of 2 electrode sets, but may use as many as fit and are 
tolerated, or pain/tingling is zeroed 
 
• 
For hands, place electrodes on arm above area of pain, most likely 
minimum of 2 electrode sets, but may use as many as fit and are 
tolerated, or pain/tingling is zeroed 
 
Goal: Replace pain or tingling with new/different tingling sensation in the area 
of pain, in order to reduce area of pain/tingling and allow for proper placement 
of electrodes in next session 
 
Treat for 30 minutes after tingling begins 
 
 
* Patient assessed daily for ability to follow Algorithm 1 
Option 2: Treat in area of pain  
 
When electrode cannot be placed in area of non-pain, an electrode can be placed 
in the area of least pain and then Algorithm 1 can be followed 
 
However, this can cause increased pain and discomfort and therefore this 
technique should be used based on provider experience and patient tolerability