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Home , Allodynia, Electroanalgesia, Low back pain, Visual analogue scale

Vol. 43 No. 1 January 2012 Journal of and Symptom Management 87

Original Article Scrambler Therapy May Relieve Chronic More Effectively Than Guideline-Based Drug Management: Results of a Pilot, Randomized, Controlled Trial Giuseppe Marineo, PhD, Vittorio Iorno, MD, Cristiano Gandini, MD, Vincenzo Moschini, MD, and Thomas J. Smith, MD Delta Research & Development (G.M.), Centro Ricerche Bioingegneria Medica, University of Rome ‘‘Tor Vergata,’’ Rome, Italy; Centro di Medicina del Dolore ‘‘Mario Tiengo’’ (V.I., C.G., V.M.), IRCCS Fondazione Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy; and Division of Hematology/Oncology and Palliative Care (T.J.S.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

Abstract Context. Neuropathic pain is common, disabling, and often difficult to treat. Objectives. To compare guideline-based drug management with Scrambler therapy, a patient-specific electrocutaneous stimulation device. Methods. A with patients randomized to either guideline-based pharmacological treatment or Scrambler therapy for a cycle of 10 daily sessions was performed. Patients were matched by type of pain including postsurgical neuropathic pain, postherpetic , or spinal canal stenosis. Primary outcome was change in (VAS) pain scores at one month; secondary outcomes included VAS pain scores at two and three months, pain medication use, and . Results. Fifty-two patients were randomized. The mean VAS pain score before treatment was 8.1 points (control) and 8.0 points (Scrambler). At one month, the mean VAS score was reduced from 8.1 to 5.8 (28%) in the control group, and from 8 to 0.7 points (91%) in the Scrambler group (P < 0.0001). At two and three months, the mean pain scores in the control group were 5.7 and 5.9 points, respectively, and 1.4 and 2 points in the Scrambler group, respectively (P < 0.0001). More relapses were seen in polyradicular pain than monoradicular pain, but retreatment and maintenance therapy gave relief. No adverse effects were observed. Conclusion. In this pilot randomized trial, Scrambler therapy appeared to relieve chronic neuropathic pain better than guideline-based drug management. J Pain Symptom Manage 2012;43:87e95. Ó 2012 U.S. Relief Committee. Published by Elsevier Inc. All rights reserved.

Address correspondence to: Giuseppe Marineo, PhD, Hopkins, 600 North Wolfe Street, Blaylock 369, Delta Research & Development, Via di Mezzocam- Baltimore, MD 21287-0005. E-mail: tsmit136@ mino, 85 00187 Rome, Italy. E-mail: g.marineo@ jhmi.edu mclink.it, or Thomas J. Smith, MD, Duffy Palliative Accepted for publication: March 15, 2011. Care Service, Sidney Kimmel Cancer Center, Johns

Ó 2012 U.S. Cancer Pain Relief Committee 0885-3924/$ - see front matter Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2011.03.015 88 Marineo et al. Vol. 43 No. 1 January 2012

Key Words Chronic neuropathic pain, , refractory pain, Scrambler therapy,

Introduction Methods Neuropathic pain is common, chronic, dis- Study Population abling, and often difficult to effectively treat.1 Patients were eligible if they had chronic Common types of neuropathic pain include neuropathic pain rated as 6 or more on a visual postsurgical pain, analogue scale (VAS) on at least four days each (PHN), stenosis (SCS) (also known week, for the prior three months despite treat- as narrow canal syndrome), and chemotherapy- ments including , anticonvul- induced .2 Although sants, and . Patients were treated at conventional treatments such as opioids, neu- Ospedale Maggiore, Policlinico Mangiagalli roleptics, and other drugs help, all have side and Regina Elena of Milan at the Centre for effects and limited effectiveness.3 Pain Medicine ‘‘Mario Tiengo.’’ Most of the re- Scrambler therapy is a novel approach to cruited patients were already undergoing treat- pain control that attempts to relieve pain ment in this facility and had been given the by providing ‘‘nonpain’’ information via cuta- standard treatment for neuropathic pain by neous to block the effect of pain infor- their physicians. The inclusion and exclusion mation. Scrambler therapy synthesizes 16 criteria are listed in Table 1. different types of nerve action potentials simi- The monitoring of patients during and after lar to endogenous ones, assembles them into treatments always took place at the same facil- sequences, and uses algorithms to determine ity, the Centre for Pain Medicine in Milan. Two a patient-specific cutaneous electrostimulation research assistants performed the Scrambler to reduce pain. Scrambler therapy has relieved therapy under the direction of the treating refractory in uncontrolled clini- physicians. These two research assistants col- cal trials. In the pilot trial, 11 cancer patients lected the pain assessments in both arms of with received 10 daily one- the study. hour treatment sessions.4 Pain was reduced Informed consent was obtained from all pa- from 8.6 to 2.3, on a numeric rating scale tients. The Scrambler therapy device had been from 0 to 10, after the first treatment and to granted Ministry of Health approval for hospi- <0.5 (P < 0.0001) at the end of 10 sessions. tal and ambulatory use. The hospital’s sci- In the second trial, 226 patients with neuro- entific and health unit, acting as the pathic pain, including failed back surgery institutional review board, approved and mon- pain, brachial plexus neuropathy, and others, itored the study. were treated.5 Eighty percent of patients had greater than 50% pain relief. Smith Randomization and Stratification et al.6 treated 16 patients with refractory For this trial at one center, the patients who chemotherapy-induced neuropathic pain with were eligible (pain $6 for at least three 10 daily hour-long sessions to the painful areas. months, despite treatment according to local Pain scores were reduced by 58% from the practice) were classified according to their start of treatment to the end. No toxicity has pain diagnosis (postsurgical, PHN, SCS). been observed in any trial. However, all these They were then assigned to a treatment group: trials were single-arm trials with no control alternative drug therapy according to the group. European Federation of Neurological Socie- The purpose of this study was to directly com- ties (EFNS) guidelines and in standard prac- pare management of chronic refractory neuro- tice at this center, or Scrambler therapy with pathic pain by Scrambler therapy with no change in the ineffective drug regimen. management using current guideline-based They were assigned consecutively in the order drug treatment7 in a randomized controlled they were enrolled in the trial, for example, trial. the first PHN patient to drug treatment, the Vol. 43 No. 1 January 2012 Scrambler Therapy for Chronic Neuropathic Pain 89

Table 1 Inclusion and Exclusion Criteria Inclusion Exclusion

Presence of mainly neuropathic pain Cancer-related pain VAS pain intensity $6 in the preceding Presence of serious psychiatric disorder (schizophrenia, manic- three months depressive psychosis, primary major ) Failure to respond to currently used pharmacologic Presence of dermatologic conditions that preclude application of treatment of neuropathic pain (antidepressants, skin electrodes anticonvulsants, and opioids) Absence of significant responses to TENS or other Uncontrolled seizures similar electroanalgesic methods In addition to pain, presence of related sensitivity Use of antiseizure medications symptoms: allodynia, , hyperesthesia Presence of pain for at least six months Any form of medical ‘‘metal’’ device (e.g., pacemakers, defibrillators, vascular clips or stents, cardiac valve or joint replacements) Frequency of pain more than four days per week Age >18 years Consent to Scrambler therapy treatment second PHN patient to Scrambler therapy, the a potentially more effective one (typically third PHN patient to drug treatment, and so , clonazepam, and ). forth. The assignment was done in order by Low-dose clonazepam is classified as an anti- the research assistants, with no exceptions. convulsant, has documented efficacy in case e Allocation was not concealed (Fig. 1). series,8 10 and is the standard practice at this center when has not been Standardized Control Treatment effective. The control group patients were managed by the same team of pain specialists using the Standardized Scrambler Treatment most up-to-date EFNS guidelines. The most The Scrambler attempts to deliver ‘‘non- common baseline therapy (typically amitripty- pain’’ information to the area in pain by simu- line, gabapentin, and ) before ran- lating five external artificial . Action domization, which had resulted in a baseline potentials that resemble normal nerve im- VAS pain score of 8.1, was switched to pulses are digitally synthesized, assembled into packets of information strings, and deliv- ered using standard silver gel electrodes simi- All patients, n=56 Assessed for eligibility lar to electrocardiogram electrodes. Each new packet is created with an algorithm that takes into account the previous outputs, dynamically modifying four main variables.

Randomized; These variables include the following: 1) type stratified by type of to use (16 different possible of pain combinations); 2) packet-associated frequency (from 43 to 52 Hz); 3) packet time duration (0.7e10 seconds); and 4) the amplitude of modulation. The system quickly tries different Control Group, n=26 Scrambler Group, n=26 combinations until pain relief is achieved. Start new drugs, e.g., Start Scrambler therapy; (The technology details are described in pat- amitriptyline, stay on prior drugs clonazepam, oxycodone ent number PCT/IT2007/000647.) The im- pulses are transmitted by surface electrodes placed on the skin in the areas

Control Group, Scrambler Group, of pain above and below the dermatome. Evaluable n=26 Evaluable n=26 The electrical charge used in Scrambler ther- apy is low, and the U.S. Food and Drug Admin- istration has approved it as safe. At the highest Fig. 1. Assignment of patients to treatment groups. setting, ‘‘70’’ on the dial from 10 to 70, the 90 Marineo et al. Vol. 43 No. 1 January 2012

amperage (A) is 3.50e5.50 mA, and the PHN, and ‘‘polyradicular pain’’ if they had maximum current density is only 0.0002009 multiple areas of pain.13 Allodynia was tested W/cm2. with von Frey elements by the research assis- Each Scrambler therapy patient was given tants and recorded as ‘‘present’’ or ‘‘not pres- a 45-minute daily treatment for 10 consecutive ent.’’ The sample size of 26 in each arm was days, Monday through Friday. The determined using an anticipated effect size of was increased to the maximum intensity indi- 1.59, with a starting VAS pain score of 6 vidually bearable by the patient that did not and a standard deviation of 2 to give a 5% cause any additional pain or discomfort. The alpha error margin and 80% power. All statisti- principal investigator (V. I.) chose the best cal calculations were done with StatMate 2 treatment areas during the first visit, which (GraphPad Software, Inc., La Jolla, CA; were then replicated daily. The Scrambler ther- http://www.graphpad.com/StatMate/statmate. apy group maintained their starting drug htm). treatment with no changes. Normally the elec- For the primary endpoint of pain, a repeated- trodes are never applied directly on the pain- measures analysis of variance (ANOVA) was ful area but in the dermatomes above and done with the VAS score as the dependent vari- below the pain affected area. For example, if able and time (baseline, one month, etc.), treat- the pain involves L3, the first electrode is posi- ment (treated or control), and treatment by tioned close to but outside of the painful area time interaction terms as the independent vari- in dermatome L2 or L3 and the other on the ables. The repeated-measures model accounts opposite side of the pain area in zone L3 or for the correlations that might arise from the L4. Once the electrodes are positioned, the same individuals being observed over time. Sec- operator slowly raises the stimulation level un- ondary endpoints included change in pain til pain relief is obtained; if not obtained, the scores by the type of pain and mono- or polyra- operator can add or move channels to increase dicular nature of the pain, change in allodynia, the coverage. There are a total of five chan- and change in medication use and doses; all nels, or paired sets of electrodes. If pain is were measured at entry, one, two, and three not relieved, the electrode placement or stim- months. Changes in pain intensity over time ulus is changed. were analyzed with one-way ANOVA and the Tukey-Kramer Multiple Comparisons Test. The difference in medication type and in dos- Data and Statistical Considerations age, and in allodynia, was evaluated using The primary endpoint was the change in repeated-measures ANOVA. pain VAS scores11 from entry to the scores at one, two, and three months. Pain intensity was measured by an unmarked 10-cm long VAS.12 The patients were classified as having Results ‘‘monoradicular pain’’ if they had one domi- The randomized patients were similar in nant area of pain, for example, one area of both groups, as shown in Table 2. The study

Table 2 Demographic Comparison of the Groups Patient Description Control Group (n ¼ 26), n (%) Scrambler Therapy Group (n ¼ 26), n (%)

Sex Male 10 (38.46) 9 (34.61) Female 16 (61.53) 17 (65.38) Age, mean (SD), years 53 (16.14) 56 (16.26) Diagnoses Postsurgical neuropathic pain 14 (53.84) 14 (53.84) PHN 8 (30.76) 8 (30.76) SCS 4 (15.38) 4 (15.38) Pain score at entry, after six months 8.11/10 1.03 8.01 1.12 of standard treatment SD ¼ standard deviation. Vol. 43 No. 1 January 2012 Scrambler Therapy for Chronic Neuropathic Pain 91

sample statistical validity was confirmed with Table 3 the normality test of Kolmogorov and Smirnov Mean Variation in Pain Intensity (by VAS) Over (P > 0.1). Time Group The primary endpoint results are shown in Time of Assessment Fig. 2. The VAS pain score in the control group (months) Control Scrambler Therapy fell by 28% at one month. Average VAS pain T0, entry 8.11/10 1.03 8.01 1.12 intensity in the Scrambler therapy group T1, one month 5.84/10 1.34 0.78 1.78 decreased from entry to T1 (one month), T2, two months 5.76/10 1.40 1.49 2.39 T2 (two months), and T3 (three months) T3, three months 5.91/10 1.44 2.03 3.14 (ANOVA P < 0.0001). The treatment by time All results statistically significant, P < 0.001 by ANOVA. interaction term was significant (P < 0.0001) suggesting that the decline in the VAS score group, as shown in Fig. 4. These pain relapses over time in the treated group was significantly at three months were statistically significant in steeper than the control group (Fig. 2.) The the Scrambler therapy group (P < 0.001, comparison between the two arms of the study Tukey-Kramer Multiple Comparisons Test) at monthly intervals confirmed this signifi- but not in the control group (P > 0.05). This cance (P < 0.001, Tukey-Kramer Multiple relapse was observed only in patients with poly- Comparisons Test). Results shown in Table 3 radicular neuropathy, compared with those document that pain scores were reduced sig- with mononeuropathy (P < 0.001, ANOVA nificantly with Scrambler therapy compared test by Tukey-Kramer Multiple Comparisons with the control group (all results P < 0.001 Test). The control group changes had no dif- by ANOVA). Pain was reduced in all groups: ference in the relapse rate when comparing postsurgical neuropathic pain (P < 0.0001 by the type of pain (P > 0.05). ANOVA), PHN (P < 0.0001), and SCS Scrambler therapy appeared to have a posi- (P ¼ 0.0108). Fig. 3 shows the effect in the dif- tive effect on allodynia. Allodynia was reduced ferent diagnoses. at one and three months in the Scrambler Scrambler therapy appeared to be effective therapy group (Fig. 5). The changes were sta- in both mono- and polyradicular pain, but tistically significant comparing the Scrambler more patients relapsed in the polyradicular therapy group with the control group at one month (P ¼ 0.0017, Fisher’s Exact Test), two months (P ¼ 0.0094), and three months (P ¼ 0.0644). However, given the simple method of assessment (‘‘yes’’ or ‘‘no’’) done in this pilot trial, further work is needed to confirm this effect. Scrambler therapy was associated with signif- icant pain medication dose reductions, as shown in Fig. 6. The percentage reduction was calculated compared with the initial dose at entry, then reassessed at times T2 and T3.

Fig. 2. Effect of treatment on pain scores over time. A repeated-measures ANOVA with the VAS score as the dependent variable and time (baseline, one month, etc.), treatment (treated or control), and treatment by time interaction terms as the indepen- dent variables. The repeated-measures model accounts for the correlations that might arise from the same individuals being observed over time. The treatment by time interaction term was significant (P < 0.0001), suggesting that the decline in the VAS score over time in the treated group was significantly Fig. 3. Effect of treatment by type of pain. steeper than that in the control group. PSP ¼ postsurgical pain. 92 Marineo et al. Vol. 43 No. 1 January 2012

Fig. 4. Effect of therapy by mono- or polyneuropathy.

At T3, opioids were totally eliminated in 11 of include raising the ‘‘gate’’ threshold for pain 17 cases, halved in one case, and unvaried in at the spinal cord, reducing ‘‘wind up’’ (central five cases. Anticonvulsants were eliminated in of the spinal cord and that 17 of 24 cases, reduced in one case, and unvar- amplifies the abnormal feelings), reducing im- ied in six cases. Lastly, antidepressants were pulses from the damaged nerve, and reducing eliminated in nine of 19 cases, reduced in psychological maladaptation to pain.17 Spinal four cases, and unvaried in six cases. Dosage cord stimulation gave a 50% pain reduction variation was statistically significant (repeated- in small nonrandomized series for chronic measures ANOVA: P < 0.0001). pain from complex regional pain syndrome I (median change in VAS 10 to 0e2, P < 0.01, sustained)18 and PHN (median change in Discussion VAS 9 to 1, sustained).19 Spinal cord stimula- In this small, randomized, controlled trial, tion gave over 50% pain reduction in a ran- Scrambler therapy appeared to reduce pain, al- domized trial compared with conventional lodynia, and pain drug use significantly better medical management in patients with failed than guideline-based drug therapy. In 21 of 26 back syndrome (mean scores fell from 7.6 to patients, pain could be relieved entirely. 3.8 or less, sustained for 24 months, < 20 > Scrambler therapy was associated with a 91% P 0.001). This same 50% effect size has pain reduction compared with a 28% reduc- been observed in randomized trials of intraspi- tion using new medications. nal drug delivery systems compared with con- ventional , when opioids Chronic pain syndromes can be helped by 21 patient-specific (adjusted to the tolerance of and local anesthetics can be infused to act the individual patient) direct nerve stimu- directly on nerves. However, spinal cord stimu- e lation.14 16 The mechanisms by which direct lation and intrathecal drug delivery involve patient-specific nerve stimulation reduce pain invasive expensive technology with the possi- bility of serious complications. Scrambler therapy differs from transcutane- ous electrical nerve stimulation (TENS) in

Fig. 5. Effect of treatment on allodynia. Allodynia was assessed as present or absent. The graph shows the percentage of subjects in each arm that had allodynia at each time point. Fig. 6. Effect of treatment on pain medication use. Vol. 43 No. 1 January 2012 Scrambler Therapy for Chronic Neuropathic Pain 93

many aspects, although both provide stimula- There are limitations to this study. First, this is tion via peripheral nerves. Clinically, TENS ther- a well-balanced, randomized, controlled study apy has been shown effective in postoperative similar to that done comparing implantable pain and musculoskeletal pain, but the number drug delivery systems with guideline-based and quality of randomized controlled trials are care,24 but it is not a ‘‘sham’’ trial. Some re- often inadequate for particular conditions.22 searchers will insist that the only proof of effi- We were not able to find any randomized trials cacy is a randomized, double-blind, believable of TENS for SCS or chronic postsurgical pain. placebo, or sham-controlled trial, but these As reviewed by Niv et al.,23 the TENS effect in may be difficult to perform.25 It has been PHN has been limited in randomized trials hard to devise appropriate blinded studies be- and disappears a few hours after treatment. cause Scrambler therapy requires adjustments TENS provides an on-off biphasic current with- of the electrode placement and dose, titrated out variation, whereas Scrambler therapy pro- to pain relief, before the actual daily treatment vides continuously changing variable nonlinear is begun. Alternative methods to control for waveforms. Recent studies with TENS units placebo effect include two strategies done have used a continuous pulse pattern, pulse here: first, to set a pain relief goal that would width of 200 microseconds, and a pulse fre- likely be unobtainable with placebo, and sec- quency of 80 Hz, increased until the patient feels ond, to allow an effective comparison control a strong sensation. The Scrambler therapy aver- group. Here, the reduction in pain was 91%, age charge per phase is 38.8 microcoulombs, much higher than typically seen with placebo. similar to conventional TENS devices. The phase For example, in a randomized trial of electrosti- duration is 6.8e10.9 microseconds, and the mulation for , the sham group had pulse rate is 43e52 Hz. Because the frequency a 9% reduction in back pain,26 and a study in- delivered by the device never exceeds 52 Hz, volving various nonpharmacological therapies the mean energy delivered per second is gener- in showed that the placebo effect ally less than most standard TENS devices, which was less than two points on a normalized 0e10 deliver a square wave with frequencies greater scale.27 The second alternative to a placebo- than 52 Hz. controlled trial allows an effective control com- How Scrambler therapy causes pain relief parison group. Here, the control group had requires further study, but our observations a 28% reduction in pain by the end of the first may inform mechanisms. First, Scrambler ther- month, consistent with the 14%e20% reduc- apy gives new ‘‘nonpain’’ information such tion seen in worst and usual pain in the that patients report new sensations in the guideline-managed group of a large random- pain area (pressure, itching, ‘‘bee sting’’ sensa- ized trial,28 and the 39% reduction in pain tions, and a flow of impulses). Second, it is not seen in the guideline-managed control group simple C-fiber electrical stimulation, which of a cancer pain trial.20,25 A second limitation would produce pain. Third, Scrambler therapy to the study is the type of treatment provided is not producing paresthesias because the to the control group. Although some clinicians patient does not feel numbness and can still would suggest alternative drug treatments, this feel other noxious stimuli. Fourth, Scrambler was the current practice at this Italian pain cen- therapy analgesia occurs quickly, suggesting ter, and the control group had a very reasonable that the receptors are transmitting the 28% reduction in pain. A third limitation is the ‘‘nonpain’’ information. Fifth, the sustained small sample size, but the study was powered to pain relief for days or months suggests either detect a relatively large difference in pain con- resetting of calcium channels (as with zicono- trol and accomplished this. tide) or remodulation of the pain system’s There are strengths to this study, in addition response. Finally, the patient feels the sensa- to the limitations. The patients were well bal- tion throughout the dermatome, not just anced in the two arms. The patient-reported under the electrode patch, suggesting the outcomes are all standard, reproducible, spread of ‘‘nonpain’’ information along the and valid. The magnitude of the pain relief lines of nerve transmission. Clearly, more study effect is large, persistent, consistent with the is needed to define the effect and the reduction in pain medication use, and consis- mechanisms. tent with the size of the pain relief in the 94 Marineo et al. Vol. 43 No. 1 January 2012

single-arm uncontrolled Scrambler therapy 9. Fishbain DA, Cutler RB, Rosomoff HL, studies. The comparison group had good re- Rosomoff RS. Clonazepam open clinical treatment lief of pain from standard guideline-based trial for myofascial syndrome associated chronic pain. Pain Med 2000;1:332e339. measures applied by the expert group, as noted above. The pain relief was well beyond 10. Zakrzewska JM. Medical management of trigem- the 50%29 and 33%30 reductions proposed as inal neuropathic . Expert Opin Pharmacother 2010;11:1239e1254. being clinically important for chronic pain. In conclusion, the pain relief obtained in 11. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs 2005; this small, pilot, randomized trial encourages 14:798e804. further development of both treatment and 12. Dixon JS, Bird HA. Reproducibility along of knowledge regarding Scrambler therapy. a 10 cm vertical visual analogue scale. Ann Rheum This knowledge will provide a better under- Dis 1981;40:87e89. standing of the mechanisms of action and 13. Tan JC. Practical manual of physical medicine new opportunities for the treatment of all and rehabilitation, 2nd ed. Philadelphia, PA: Elsevier forms of pain. It also provides more knowledge Mosby, 2006. of effect size for further randomized placebo- 14. Folletti A, Durrer A, Buchser E. Neurostimula- or sham-controlled trials, which are underway. tion technology for the treatment of chronic pain: a focus on spinal cord stimulation. Expert Rev Med Devices 2007;4:201e214. Disclosures and Acknowledgments 15. de Leon-Casasola OA. Spinal cord and peripheral Dr. Giuseppe Marineo holds property rights nerve stimulation techniques for neuropathic pain. e to the Scrambler Therapy basic research J Pain Symptom Manage 2009;38(Suppl 2):S28 S38. and international patent to its technology 16. Mailis-Gagnon A, Furlan AD, Sandoval JA, development. Taylor R. Spinal cord stimulation for chronic pain. Cochrane Database Syst Rev 2004;(3). CD003783. 17. Jensen MP. A neuropsychological model of References pain: research and clinical implications. J Pain 2010;11:2e12. 1. Botez SA, Herrmann DN. Sensory neuropathies, from symptoms to treatment. Curr Opin Neurol 18. Harke H, Gretenkort P, Ladleif HU, Rahman S. 2010;23:502e508. Spinal cord stimulation in sympathetically main- tained complex regional pain syndrome type I 2. Wolf S, Barton D, Kottschade L, Grothey A, with severe disability. A prospective clinical study. Loprinzi C. Chemotherapy-induced peripheral neu- Eur J Pain 2005;9:363e373. ropathy: prevention and treatment strategies. Eur J Cancer 2008;44:1507e1515. 19. Harke H, Gretenkort P, Ladleif HU, Koester P, Rahman S. Spinal cord stimulation in postherpetic 3. Finnerup NB, Sindrup SH, Jensen TS. The evi- neuralgia and in acute herpes zoster pain. Anesth dence for pharmacological treatment of neuro- Analg 2002;94:694e700. pathic pain. Pain 2010;150:573e581. 20. Kumar K, Taylor RS, Jacques L, et al. Spinal 4. Marineo G. Untreatable pain resulting from ab- cord stimulation versus conventional medical man- dominal cancer: new hope from biophysics? JOP agement for neuropathic pain: a multicentre rando- 2003;4:1e10. mised controlled trial in patients with failed back 5. Sabato AF, Marineo G, Gatti A. Calmare therapy. surgery syndrome. Pain 2007;132:179e188. Minerva Anestesiol 2005;71:479e482. 21. Smith TJ, Staats PJ, Pool G, et al. Intrathecal 6. Smith TJ, Coyne PJ, Parker G, Dodson P, implantable drug delivery systems give sustained Ramakrishnan V. Pilot trial of a patient-specific cuta- pain control, less side effects, and possibly better Ò neous electro-stimulation device (MC5-A Calmare ) survival for six months: results of a randomized clin- for chemotherapy induced peripheral neuropathy. ical trial vs. comprehensive medical management. J Pain Symptom Manage 2010;40:883e891. Ann Oncol 2005;16:825e833. 7. Attal N, Cruccu G, Haanp€a€a M, et al.EFNS Task 22. DeSantana JM, Walsh DM, Vance C, Rakel BA, Force. EFNS guidelines on pharmacological treat- Sluka KA. Effectiveness of transcutaneous electri- ment of neuropathic pain. Eur J Neurol 2006;13: cal nerve stimulation for treatment of hyperalge- 1153e1169. sia and pain. Curr Rheumatol Rep 2008;10: 492e499. 8. Hugel H, Ellershaw JE, Dickman A. Clonazepam as an adjuvant in patients with cancer- 23. Niv D, Maltsman-Tseikhin A, Lang E. Posther- related neuropathic pain. J Pain Symptom Manage petic neuralgia: what do we know and where are 2003;26:1073e1074. we heading? Pain Physician 2004;7:239e247. Vol. 43 No. 1 January 2012 Scrambler Therapy for Chronic Neuropathic Pain 95

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