Page 1

Rep~inted from

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Volume 84, No.5

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-"tl'

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May 2003

nd" ,

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" _;1

Static Magnetic Field Therapy for Symptom~tic Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Trial Mkhael1. Weintriwb, MD, FACP, FAAN, Gil.l. Wolfe, MD, Richord A. Barohn, MD, Steven P. Cole, PhD,

.'

Gareth J. PatTy, MD, Ghazala Hayat, MD, Jeffrey A. Cohen, MD, Jeffrey C. Page, DPM, Marl< B. Bromberg, MD, Sherwyn L Schwartz, MD, and the Magnetic Research Group

fhIS Issue Sponsored by

, â&#x20AC;˘

AMERICAN ACADEMY OF PHYSICAL MEDIUl\;E AND REHABILITATION

W. B. SAUNDERS


736

Static Magnetic Field Therapy for Symptomatic Diabetic

Neuropathy: A Randomized, Double-Blind,

Placebo-Controlled Trial

Mic1uzell. Weintraub, MD, FACP, FAAN, Gill. Wolfe, MD, Ricluud A.. Barohn, MD, Steyen P. Col#, PhD,

Gareth J. Parry, MD, G/uJ:r.alQ Hayat, MD, Jeffrey A. Cohen, MD, Jeffrey C. Page, DPM, .

Mark B. Bromberg, MD, Sherwyn L Schwartz, MD, and the Magnetic Research Group

ABSTRACI'. Weintraub MI. Wolfe 01. Barohn RA. Cole SP. Parry OJ. Hayat G, Cohen JA, Page JC, Bromberg MB, Schwartz SL, and the Magnetic R..earch Group. Static magnetic field therapy for symptomatic diabetic ncuropalby: a randomized, double-blind, placebo-controlled trial. Arch Phys Med Rehabil 2003;84:736-46. Objective: To detennine if constant wearing of multipolar. static magnetic (4500) shoe insoles can reduce neuropathic pain and quality of life (QOL) scores in symptomatic diabetic peripheral ileuropathy (OPN). Design: Randomized. placcbo-control, parallel study.

Setting: Forty-eight centers in 27 states.

PartidpaDIS: 1brcc hundred seventy-five subjects with

DPN stage n or ill were randomly assigned to wear constantly magnetized iDsoles for 4 months; the placebo group wore similar, uumagnetizcd device. InterventioD: Nerve conduction and/or quantified sensory testing were performed serially. Main Outcome Measures: Daily visual analog seale scores for numbn..s or tingling and buming and QOL issu.. were tabula~ over 4 months. Secondary measures included nerve conduction chang.., role of placebo, aod safety issu... Anal­ ysis of variance (ANaYA), analysis of covariance (AN­ COYA), and chi-square analysis were performed. ResullS: There were statistically significant reductions dur­ ing the Ibird and fourlh monlbs in burning (mean change for magnet treatment, -12%; for sham. -3%; P<.05, ANCOYA), numbn..s and tingling (magnot, -10%; sham, + I %; P<.05, ANCOYA), and exercise-induced foot pain (magnet, -12%; sham, -4%; P<.05, ANCOYA). For a subset of patients wilb baseline severe pain, statistically significant reductions oc­ curred from baseline through the four!h monlh in numbn... and tingling (magnot, -32%; sham, -14%; P<.OI, ANaYA)

From Ihc [)repanmenI of NcuroIDIY. New Yod: Medical CoIJep, Valballa,. NY

(Weintnlllb); UIliYmrity ofTeJllI, Soulhwcstcm McdtCIII Ccnb:r. Dallas. TX (Wolfe,

BIlI'Ohn); Rcseardl Oc:sign lDc, Yortaown Heigflts, NY (Cole); University at Minne­

sota, MinnapoJis. MN (Parry): SL Louis University. 51. LoWs. MO (Haya1); Kaiser­

Permanente Medical Group. Denver, CO (Cohen); California College of Podiabic

Medicine. San Francisco. CA (Page); University of Ugh, Salt J...al,;e City. trr CBrom­

~J; and Diabetes and G~_p'?!!!~ _qi~.~ ~ Antonio, TX (SchWBJ1Z).

'Su~'by-'N~:MaiR~ 11K: ~d Nikkca Inc.

Prestnce:d in pan aJ the JoiDl ConfaeJaCC of 1hc AmenCll"l Congraa of RdLabili­

IlLIian Medicine and che American Sociely of Neurorchabilitation, October 5. 200'l.

PhiIDdclpbia, PA.

No conunctei.ll pattY IlllYiI¥. din:c1 financial interesl in the ruults of the I"C:SC:lU'Ch

suppurtinB this article hal or will confer- I bcnefh upon the aulhur(s) or uJDI any

organiUdion widl which Ihc author(s) islate associuted

Rcprinl requests to Michacll Weintraub, MD. Dept 01 Neurology and Medicine. New York Medical College, 32.5 S Highland Ave:. Briarcliff ManlX. NY J0510. e-mail: ".i~uro@poW'. 0003-99931OJJ8405.7836530.00'0

doi; IO. J016lS0003-9993(031XJ106-0

Arch Phys Med Rehab" Vol 84. May 2003

and fool pain (magnot, -41 %; sham. -21%; P<.OI. ANaYA). Concluslous: Static magnetic fields can p e _ up 10 20mm and appear to target the octopic firing nociccptors in tbc epidennis and dennis. Analgesic benefilS were achieved over time. Key Words: Diabetic neuroplllhics; Magnetics; Rehabilita­ tion. © 2003 by lhe American Congress of RelrDbiliUllion Medi. cine and lhe American Academy of P/rysical Medicine and RelrDbiJiloJion

1ABETIC'PERlPHERAL NEUROPAlHY (OPN) is II and often disabling complication of diabetes mellitus (OM). Depending on crileria, DPN is estimated 10 occur in 50% to 90% ofindividuals wilb diabetes for more than 10 years.'" As many as half of the 16 million diabetics in the Uni~ Stat.. will experience neuropathic paio at some point iD Ibeir liv.....• DPN begins insidioualy, presenting as a symmet­ rical scosory polyncuropalhy that follows a stocking-glove patu:rn. Selective involvement of unmyelinated C fiber!; and small myelina~ A delta fiber!; produces pain of Ibe burning dyseslhetic type and is often accompanied by hyperalgesia and allodynia in the feet1.'0-'2 Neuropathic pain symptoma fluctu­ ate and can be described as superlicial, deep, aching. lancinat· ing, constant, or episodic. Complaints arc often worse at night Although initial symplOms and the course of DPN vary, once neuropsthic pain is ..lahlished, it is almost always progressive. leading to increased discomfort and disability."'>-'s Further­ more, individuals with DPN arc at augmented risk for foot trauma and infections that may necessitate amputative procc­

Dcommon

dUres:.'Z.I6

From a pathophysiologic standpoint, Ibeso symptoms are Iiclieved to be secoodary 10 cc10pic firing of nociceptive affer­ ent nons that are undergoing degeoeration."'·'2 This ectopic depolarization appears 10 be related 10 dysrcgulated expressioo of sodium and calcium channels"·" and a deficit in Ibe p0tas­ sium-internal rectifying channel.20-22 NelD'Ons at the level of the dorsal root ganglion (DRO) also become hyperexcitable after periphcra1 nerve injury, presumably beea... of loss of periph­ eral inhibitory influences. 2S Currently, then: are no treatmeots Ibat reverse or arrest progressive diabetic polyncuropalby." A variety of standard oral therapies used for symptomatic neum­ palbic pain include tricyclic antidepressants,2S antiepileptic medications,'" and narcotic analgesics. 71 .2ll Additionally, topi­ cal products such as capsaicin2'''' have bcco applied and have produced incomplete pain relief and significant side effects. Overall, the results have been disappointing and associated with significant side effects.'s'>''>2 The search for reliable, safe, and effective mainstream lrealmenlS for the neuropathic pain of

DPN remains a major challengc. 13•IS.2.5--Z'.JI.u and. not surpris­ ingly, patients have explored a variety of alternative ap­ proaches, including homeopathy. acupunctun:, and magnetic


MAGNE11C FIELD lHERAPV FOR DIABE11C NEUROPAlHV, Welntnlub therapies. Spurred on by anecdotal reports, the use of penna­ nent magnets for relief of pain has become extremely popular in recent years, with consumer spending exceeding $500 mil­ lion in the United States and Canada and $5 billion world­ wide."'" The idea that magnetic energy from commelCiaily available, weak magnets applied locally to the feet oould in­ ftuence chronic neuropathic pain may seem absWl!, and yet this approach is not new."'" In the absence of randomized, place­ bo-conlrOlled trials, the medical conununity has been under­ standably skeptical, which has limited the acceptance of mag­ nets as a valid option for pain relief.''''' However, 2 prior pilot studies successfully showed reduced neuropathic pain in 75% and 90% of patients with refractory OPN over a 4-month period, with constant application of oommercial multipolar foot magnets (4500)."'" These surprising and unexpected favor­ able results prompted the present study_ nadonwide, ran­ domized placebo-<:onlrOlled investigation into the legitimacy of static magnetic fields in the relief of pain from OPN.

METHODS Enrollment Criteria

737

minute ~~e~on such as walking or o.ther physical activity. After ehglbl11ty was confirmed and wntten informed consent accepted, subjects were randomized consecutively (I: I via

computer assignment) to receive an active magnetic shoe insole or a sham insole of similar appearance. Randomization was Slratified by center and gender. Neither the subject nor the research staff was aware of the treatment allocation. If correc­ tive trimming of the device Was necessary to provide a c0m­ fortable fit in the shoe, a noninvolved secretary or nurse would trim them along identifiable lines arOund the margins. The sUbjects and site investigators were not present if trimming willi necessary. All data were submitted to a centnll data bank under

the sUpeMsion of the statistician who was aware of the assign.. ments. Magnetic Devices The devices used in the present study are comprised of a reinforced and ftexible magnetic rubber compound pressed into a sheet and cut into the shape of a shoe insole for men and women. Strontium ferrite powder 'il; mixed into this rubbec binder and magnetized with' a patented palW1l of alternating magnetic poles. Each pole is adjacent to and contiguous with another triangular-shaped magnetic pole of opposite polarity on each of the 3 sides of the triangle. This pattern produces a continuous array of alternating magnetic poles in every direc­ tion across the insole (fig I). The strength of the magnetic field is 4500, ax measured widt a conventional gauss meter on the surface of the insoles at the center of the triangle (I O,OOOG= I 1'). The field depdt of pen_ etration is 20nun and is reduced inveraely with the square of the distance. By far, the simple, most direct method of deler. mining field strength at various distances from the insole sur­ face is by instrwnent measurement For example. using a Lakesbore 420 gauss meter with a llat traosverne probe' has an accuracy of :!:.25%. The effective field of the magner from the insole surface is 20nun. Beyond 2Omm, the magnetic field measures in the range of the ambient magnetic field of the earth at about 0.5G. The mllJ<imum surface field strength of the magnetic insole is 4500. At a I-mm distance from the surface, the field strength drops to 2490. At2mm, the field strength is measured at 1500. At 3mm (approximately 'Aiin) the field snength is 900. Flux density at the target area be more clinically relevant than the magnetic reading at the surface of the magnet. The specific ftux density, however, at the target area is unknown. At 13mm above the surface of the magnetized insole, the reading is only 1.5G. The sham insole's gauss meler readings did not exceed the 0.5G of the earth's magnetic field. Both sham and active magnetic shoe insoles could not be distinguished in rerms of appearance, consistency, or weighL The magnetic insoles used in the present study were manufac­ tured by Nu-Magnetics Inc," and are commercially sold under the brand narne of Magsteps- by Nikkon Inc.'

From August 1999 through January 2001, 375 subjects with symptomatic symmetrical sensory and motor diabetic periph­ eral neuropathy (OPN stages norm), as defined by Dyck et al,..~, were r=uited from 48 sites in 27 states. Consecutive patients from neurologic, podiatric, and diabetic clinics or private practice were enrolled A few centers advertised their participation in this nationwide study to attract eligible volun­ teers. The primary providers were skilled clinicians who had previously participated in pharmacologic studies of diabetes andlor pain management. Enrollment criteria required thai all subjects have at least 2 abnonnalities on neurologic examina­ tion (sensory, motor, reftex), moderate (II) to severe (HI) neuropathic pain, abnormal nerve conduction or quantitative sensory testing, andlor symptoms of autonomic dysfunction. Symptoms had to be constant and present over 6 months and refractory to various medications. Subjects included penons with insulin-<lependent diabetes mellitns (lOOM) and those who were not iIUiulin dependent (NIDOM). Subjects were excluded if other systemic diseases oould potentially esplain their symptoms. As a safety precaution, pregnant women and subjects who had mechanical insulin pumps or canliac pace­ makers were also excluded. Subjects tabulated validated"'''' daily pain scores and similar, but unvalidated, quality of life (QOL) scores for 4 months and agreed that they would not attempt to break blinding of the foot devices. They also asreed to wear the devices constaDt1y, 24 hows per day. Moderate pain was defined as scores of 5.0 to 6.99 and severe pain was defined as 7 and higher. No new analgesic drugs were allowed during the study, but individuals could remain on (or reduce) their current regimen of neuropathic pain medication. The randomized, placebo-conlrOlled, parnllel design study was fully Outcome Measures explained to all subjects and voluntary withdrawal was allowed Pain was measured On an II-point numeric pain raring scale without prejudice. (VAS; scale range: O. no pain; 10, worse possible pain). 'The primary efficacy measure was the reduction in neuropathic pain Randomization scores at week 16 compared with baseline scores. We also Demographic data (age, height, weight, gender, race, glyco­ compared month-to-month changes. We looked specifically at sylated hemoglobin [lIb A"I, family history, duration of OM, 2 of the most common pain symptom scores of numbness or complications of OM,lrealment of OM) were collected at each tingling and burning. Each symptom was recorded 3 times site. Subjects completed a 2-week baseline Likert visual analog daily so to reduce any new variables (VAS range, 0-10). scale (VAS) quantification of their pain symptoms 3 times Similarly, QOL issues were considered primary efficacy mea­ daily to establish a reliable mean pain soore. QOL scores were sures with reduction of exelCise-induced foot pain and sleep recorded once daily to measure (I) sleep disturbance scoondory interruption secondary to pain r:v AS range, 0-10). These were to foot pain and (2) exelCise-indoced foot pain after a 10­ recorded once daily. Secondary outcomes compared baseline

may

An:h Phys Mod Reh.bll Vol 84, Mey 2003


· 738

MAGNETIC AELD lllERAPY FOR DIABETIC NEUROPAnly. W.lntnub

and 16-week values of neurologic examinations, nerve condue· tion velocity (NCV), quantitative sensory testing (QST) thresh­

01<1s (Neurometer'"'' or C..e IV"), and other elecrrophysi· ologic tests."'" Safety measures with tabulation of adverse events were monitan:<! as w.. cau.. for dropouts. Additionally, an interim study performed before the end of this study at selected sites ....ssed m..king and bi.. by asking patients and investigators whether they believed that a placebo or active device was used or whether they had no opinion. Sites There were 48 investigative sites in 27 states. They included II university-based centers and 37 private practices. A neuro­ logic examination was performed before entrY to identify the presence of a ..nsory peripheral polyneuropathy in the feet that met the Dyck" criteria of moderate (II) to severe (III) DPN. Nevs of the peroneal and/or posterior tibial (motor) and sural Derves (sensory) were performed in a standardized manner to confinn the presence of neuropathy. Selected sites perfonned forced-choice QST by using Neurometer (CYI') or Clise IV equipment and other neurophysiologic tests, such as biothesi­ omO\TY and sympathetic skin respon.. (SSR). Because no stan­ dard, validated device exists and controversy about their merits surrounds the various deviees~ we let each site use their stan­ dard analysis technique. Investigational Review Board Phelps Memorial Hospital Investigational Revi~ Board (JRB) reviewed and approved the protocol, as did IRBs at individual university centers. Phelps Memorial served as a central JRB for many investigative sites and appropriate safety and progress data were submiDed to this JRB in a timely fashioD.. A11 patients provided written informed consent to participllle in this study.

Ag 1. Megn.de field vltuellutlon. wtth superimposed mesne-view film. The mJcroencapsullted colloldel nickel plrtJcles congregate In alignment with the mlgnetlc flux lines produdng 8 2-dlmenlionel image of the pole plItteITI.

Arcl1 Phys Mod Rohabll Vol 84. May 2003

Statistical Analyses For each of the 4 outcome measures (burning, numbness and tingling, foot pain, sleep scores), a 2 (treatmeut, sham) X5 (baseline, Imo, 2mo, 3mo, 4mo) repeated-m.....ures analysis of variance (ANOYA) was used to assess possible differences between treatment and sham groups over the course of the study. Theae analyses were followed by a 2 (trealment, sham) X2 (2mo, 4mo) analysis of covariance (ANCOYA) with base­ line score as the covariate to explore treatment effects during the last 2 months of the study. Furthermore, for each outcome me..ure,· we grouped patients into 3 categories of severity based on baseline scores: Ratings of 1 to 4 corresponded to mild pain; 5.0 to 6.99. to moderate pain; and 7 to 10, to severe pain." ANOYAs were used to compare the mean changes separately for each severity group. For each of the outcome measures, chi-square tests for independence were used to as­ seas magnet versus sham group differences in the percentage of patients who had at least a 30% reduction in ..vere pain. Finally, ANOY As and ANCOV As were used to as"ss treat­ ment effects for subgroups defined by measures known to previouslY affect outcomes in this population. For all tests, a P value of .05 or less was considered to indicate statistical significance. Subjects with any missing dalll for an endpoint were excluded for that analysis. On the basis of published results of clinical trial placebo responses for painful diabetic neuropathy," at an a level of .05 and a power of .80, with 150 subjects per group, it was estimated that a difference between treatment and sham group responses of 17% or more would be statistically significant."" Analyses were conducted with SPSS:


MAGNmC fiELD THERAPY FOR OIASmC NEUROPAlllY, Weintraub

739

375 SUBJECTS EnroUed & Randomized

.~

I

199 ax

r ----'",

i

Lost to follow-up Allodynia'

2S 1S

ComplicatiODS

6

176 PLACEBO

Lost to follow-up Allodynia Complications

N=44

N=46

Excluded/Missing Data 12

141 ACTIVE ax ANALYSIS

27 13 4

ExcludedIMissing Data 14

118

PLACEBO

ANALYSIS

IDOM

n=49

IDOM

n=40

NIDOM

n=92

NIDDM

n=78

Fig 2. flowch.rt 01 tho rondomlzod pl.cebo...."'"'l tri.r. AbbrevlllllOn: fix. trelrtment.

Adverse Events Potential injury to the sole producing ulcer or abrasion or infection was monitored Mechanical allodynia because of sen­ sitive feet was also tabulBted.

Role

or Funding So.......

This study '1o'!!!iIliJiolly funded by Nu-Magnetics and sup­ plemented by :/I!i~en!Inc. The grant ICCipients had complete independence regarding study design, data analysis, and manu­ script preparation. The study's protocol was approved by the National Institutes of Health, but not funded. .

RESULTS The flow of patients lhrougb the clinical mal is depicted in figure 2. 'I1Iree hundred seventy-five subjects were randomly assigned to treatment and sham groups, and 259 subjects (69%) successfully completed this 4-month mal. Of the 90 dropouts, 74% in the treatment group and 71 % in the sham coholt dropped out before the second month. Of the totAl group, 45% were lost to follow-up, 24% dropped because of alIodynia. and 9% dropped for noostudy complications. Twenty-six subjects were dropped by the stlItistician for missing or questionable

data. Th. baseline characteristics for the remaining 259 sub­ jocl! were similar for treatment and sham groups (table I). The t lesUi far independent samples revealed DO baseline differences between the treatment and sham groups fur the primary end points (table 2). Racial..,thnic proportions at enrollment were a representative cross-sectiun of the US population. In addition, a series of ANDY As revealed no baseline differences or dif­ ferences OVf:t Ibe study period between patients at university centers and in private practice settings.

Primary Outcomes Burning. Burning scores decreased 309& for the lreallIlent group from baseline (mean:: standard deviation, 5.13::2.29) to month 4 (3.61 ::2.44) and decreased 24% for the sham group from baseline (5.27::2.40) to month 4 (4.01:!:281) (P=.OOO, ANOYA; fig 3). There was a larger decrease in mean scores for the treatment group (-12%) from month 2 (4.09::2.38) to month 4 (3.61:!:2.44) than for the sham groop (-3%) from month 2 (4.12:!:2.65) 10 month 4 (4.01=2.81) (P<.05, AN­ COVAl. Numbness and ringling. Numbness and tingling scores decreased 29% for the treatment group from baseline An:h Phys Med Rehabil Vol 84, May 2003


MAGNEllC FIELD THERAPY FOR DIABEllC NEUROPAniv. Wointroub

. 740

·

Table 1: Baseline Ch....ec.ristlcs of the Subjects Tr8ltmeRl Char.tt.,rietic

Group

Sham G"",.

In-141)

In-118)

,----------------,

.~

Ago 1YI 62.6:11.3 36-415 206.7:47,0

Me!n Range ,Weight (lb) Height (in)

67.7::4.05

63.2::11.2 27-85 207.1::41.2 67.9:4.28

66 75

60

So.lnl Female Male

Mean 3

50_

2

68

Roce Inl 107 34 13.0:10.8 7.7::1.8

Wh~o

Nonwhite Years sines onset of diebetes

HB At., Nerv.l conduction vefocfty (nJ

No-nnel

5

Axonel Derny Mb<ed Insulin In)

42

4S

No

92 8'"

, Month

103 15

2_

11.6:!:10.2 7.6=2.1

3 31 14

16 61

Voo NOTE. Values indicated.

---''''''_.....",=.0-.._::_:::::::-_---_-_.. __ __-1

" Months

--

Ag 3. Burning ~en ~.... for treatment and .ham subjecta-.

4S 40 78

msan :±: standard deviation ISO) or

B8

otherwise

Abbreviation: Derny. demytinating.

(5.63:!:2.08) to month 4 (4.02±2.46) and decreased 22\\7 for the sham group from baseline (5.89:!:202) to month 4 (4.57±2.58) (P=.fXXJ, ANOVA; fig 4). Theze was a decn:ose in mean scores fur the treatment group (-10\\7) from month 2 (4.46:!:2.23) to month 4 (4.02:!:2.46) and a small increase for the sham group (+ 1%) from month 2 (4.54:!:2.58) to month 4 (4.57:!:2.58) (P<.05, ANCOVA). For pllIients with severe pain at baseline, numbness and tingling decreased 32% for the treatment group from baseline (8.17:!:.85) to month 4 (5.58:!:2.43) and decreased 14% for the sham group from baseline (8. 12:!:.95) to month 4 (6.97:!:2.38) (P<.OI. ANOVA; fig 5). Of the 38 Ireatment patients with severe pain at baseline. 27 1%) had mild or modeI1lte pain at month 4.10 contrast, of the 40 shwn patients with severe pain at baseline, 16 (40%) had mild or modeI1lte pain at month 4 (P<.OI, x').

n

Foot pain. Foot pain scores decreased 31 % for the treat­ ment group from baseline (5.84:!: 2.33) to month 4 (4.05:!:2.66) and decreased' 25% for the sham group from baseline (5.76:!:2.29) to month 4 (4.31:!:2.80) (P=.fXXJ, ANOVA; fig 6). A larger decrease in mean scores existed for the treatment group (-12\\7) from month 2 (4.62:!:2.53) to monlh 4 (4.05:!:2.66) than for the sham group (-4%) from month 2 (4.47:!:2.68) to month 4 (4.31 :!:2.80) (P<.05, ANCOVA). For patients wilh severe pain at baseline, foot pain decreased 41% for the lreatment group from baseline (8.49:!:1.07) to month 4 (4.97:!:3.IO) and decreased 21% for the sham group from baseline (8.35±.95) to monlh 4 (6..56±2.50) (P<.OI. ANOVA; fig 7). Of the 40 trealment patients with severe pain at baseline, 29 (69%) had mild or modeI1lle pain at month 4.10 contrast, of the 35 sham-device patients with severe pain at baseline, 17 (49%) had mild or moderate pain at month 4. This trend in category change did IlOt reach statistical significance (P=.07,

x').

Sleep. Sleep scores decreased 30% for the treatment 8rouP from baseline (4.83:!:2.66) to month 4 (3.36:!:2.76) and de­ creased 30\\7 for the sham group from baseline (5.19:!:2.79) to month 4 (3.65:!:3.04) (P=.fXXJ, ANOVA; fig 8). There was a nonsignificant trend for a larger decrease in mean scores for the lreatment group (-13%) from month 2 (3.83:!:2.83) to month

Table Z: MHn Sco.... for Primary Endpoints From Baseline to Month 4 n

Blluline

Month 1

Month 2

Month 3

Month 4

133 111

5.1:::2.3 5.3=:2.4

4.3:!:2.3 4.6±2.6

4.1:!:2.4 4.1::!:.2.7

3.9=:2.5 4.1:2.7

4.0:!:2.8

137 116

5.6=::2.1 5.9:::2.0

4.7:!:2.2 4.9:!:2.3

4.5=2.2 4.5:2.6

4.3:t2.4 4.6::2.6

4.0:!:.2.5 4.6±2.7

121 106

5.8=2.3 5.8::!:.2.3

4.9:!:.2.4 4.9:!:.2.4

4.6"'2.5 4.5=2.7

4.2:2.6 4.3=:2.8

4.1:!:.2.7 4.3±2.S

112 98

4.8:!:2.7 5.2=2.8

4.0:!:2.8 4.6:!:2.6

3.8=2.6 3.8=2.8

3.5=:2.7 3.8::3.0

3.4=2.8

OLltcome Meesure

Burning Treatment Sham Numbness and tingling Treatment Sham Foot pain Treatment Sham Sleep Treatment Sham NOTE. Values are mean:!: SO.

Arch PhV' Mod Rono";l Yo! 84. MeV 2003

3.6~2.4

3.7±3.0


741

MAGNrnC FIELD THERAPY FOR DIABETlC NEUROPATHY. Wei"'.oub

.C""~--------, 5

;::;:::::::=_=""J==------:J

.-•..--.....::.......

--"--­

M

.

s.....

2

, 1 MonCh

.........

1 Manlh

ZMantha

.M......

I

Rlndamlzed Growp .-..- Treatment ""21) 'hun (n=101)

fig 4. Numbii&a: end tingling me.n scores fortntltment and .ham subjects.

4 (3.36:t2.76) tban for the sham group (-3%) from month 2 (3.76:t2.83) to month 4 (3.65:t3.04) (P~.08. ANCOVA).

Secondary Outcomes There W8.5 no evidence of deterioration of nerve function

clinically or electropbysiologically in those patients reporting improvement in pain scores. Thus. there was no evidence of clinical wor.enillg. Of the 259 subjects. 61 (24%) had Neu· rometer. Case IV. SSR, or biothesiometty srod!es. No signifi· cant differences existed between sUbjects in the trealmen' group (n~32) and those in the sham group (n=29) from baseline to 4 months on these meuurea. Subgroup Analyses For patients not taking oral antidiabetic agents. a 1arger decrease occum:d in mean burning scores for the treatment group (-14%) from month 2 (3.81:t2.38) to month 4 (3.30:t2.39) than for the sham group (-1%) from month 2 (3.91:t2.87) to month 4 (3.86:t2.85) (P<.OI. ANCOVA). There was a nonsignificant trend for a larger decrease in mean numbness and tingling scores for the treatment group (-to%)

I

Fig I. Foot pal" men &COrea 'or ~ end .h~m aubjech.

from month 2 (4.26::2.21) to month 4 (3.84:t2.46) thon for the sham group (-1%) from month 2 (4.78±2.68) to month 4 (4.24:t2.59) (P=.08. ANCOVA). A similar pattern was re­ ported for patients with severe foot pain scores. with reductions of 41 % and 21 % for treabDent and sham groups. respectively. and for numbness and tingling. with reductions of 32% and 23% for the 2 groups. respectively. Results remained signifi­ cant with a Bonferroni correction.'" By using the 30% pain reduction criterion as suggested by a Farrar stratification anal­ ysis." we noted that 50% of patients with magnels had at least a 30% reduction in severe numbness and tinglinl!. compnred with 25% of patients with sham devices (P<.OS. )[). Although the percentages for foot pain (32% vs 19%) and burning (42% vs 29%) were impressive. they were not s18tislically significanL No differences between treabDent and sham groups,were found based on family history of diaberes. baseline nerve conduction,

or Hb Ale scores. Blinding An interim analysis for bias and breaking the blind was performed at those active sites 6 months before study termi­ nated (university and private pnlClice). This analysis was to determine whether the present study was adequately blinded.

.,---------------,

.

s~

1

:=::.::------------1

•..•:::: .....

..._---~-

---------_._---.._.

Mean 5 Score 4 ~

2

• Mean 5 S.......

~

• oL._ _-'Basellnll

Ag 5. Numbnn_ and tingling mean acorea for subjects with be..,... line severe peln.

-'-_ _---L_ _---J

1 Month

2 Manlhl

3 Months

4 Monlhl

Fig 7. Foot pain mean scores for subjects with bas.line severe pain.

Arch Phy. Mod Rehlbll Vol 84. Mey 2003


.742

MAGNETIC FIElD THERAPY FOR DIABE11C NEUROPAniY. W.I......ub

.,------------,

Mean } Score

2

....nne

1 MonlIl

0_-

2MonIh'

R'ndomect Group

Tr.edM'" fn-U2) -

3 ........

anlm ,na'l)

--

Fig 8. Sleep mun KOrea for treatment lind ahem subjects.

-DISCUSSION This is the first multicenter, doUble-blind, placebo-<:ontrolled study to examine the role of static magnetic fields in a homog­ enous cohan of DPN with neuropathic pain. The antinocicep­ tive effect was significantly pronounced during the third and fourth month, indicating that a tonic and chronic exposure must be prescot to inhibit and inftuence sensitized afferent pain fibers. The magnitude of the reduction of burning, numbness and tingling, and exercise-induced fOOl pain, especially in severe and extreme cases. was comparable or superior to that observed in Ibe gabapentin,"" tramadol,'" and lamotrigi1Je'4 studies, but without side effects. Additionally, a change of I.S in tbe 0 to 10 pain scale represents a clinically meaningful difference. This also reaffirms the data from 2 prior pilot studies."'" Subset analysis identified that subjects with severe pain" and those not taking oral hypoglycemic agents re­ sponded more favorably than other symptomatic patients. Al­ though our results sbow a statistically significant reduction in predetUrnined primary· outcome measures, it i. difficult 10

59'"

determine the mechanism of action responsible for these ben­ efilS. It is of interest that in the pharmacologic trials of tram­ Subjects and examining irivestigat011i were asked at the end of the study to identify the treatment provided. Sixty-three percent of the sUbjects responded. Of the 83 lTeatmenl group subjects responding 40 (48%) believed they had active magnets, 31 (37%) beli~ved they had sham msgnets, and 12 (15%) did not know. Of the 80 sham-device subjects responding. 29 (36%) believed they had active magnets. 30 (38%) belieVed they had sham magnets, and 21 (26%) did "?t know. Of 46 investigat~ of treatmenl suhjects, 23 (50%) beheved the subjects had aetlve magnets, IS (33 %) believed they had sham magnets, and 8 (17%) did not know. Of 50 investigat011i of sham-device sub­ jects 22 (40%) believed the subjects had active magnets, IS (30%) believed they had sham magnets, and 12 (26%) did not know. There was no significanl association between the actual treatment received and the belief about Ihe treatmeat received for subjects or investigators. Dropouts The dropouts were evenly represented and did not impact on the prirnmy analysis for efficacy. We did not use the intentioD­ Io-treat (l1T) model for e.timll!es of missing data, because 75% of the dropouts from the lTeatrnent group and 71 % from the sham group droPPtd out before month 2. As shown in our figures, the magnetic effects became apparent after month 2; therefo"" using the model with most estimates based on data before month 2 would severely bias the analysis. Dropouts secondwy to anodynia were equalJy common in both groups. Foot sensitivity is a well-known phenomenon in symptomatic patients with DPN. Thus, il is not surprising that the application of an insole (magnetized or unmagnetized) would be unpleas­ ant to a small but significant group of patients. Th= were 90 dropouts (lost to follow-up, allodynia, complications) equally represented out ofa sample size of 349 (25.8%). There were no mean differences between the 46 treatment and 44 sham-dcVlre patients for age, years since ons~t o~ diabetes, an~ baseline Hb

A , burning, numbness and tlDghng, fOOl pam, and sleep

sc::'res (P> .05. ANOVA). The statistician dropped 26 patients

(equal representationrbec.use of site difficulties obraining data

and unreliable data.

m

Safety Measures of safety included constant reporting of adverse events and the cause for dropouts. There were no significant complications. Arch Phys Mad Rehebil Vol 84, May 2003

adol'" and gabapentin,"" the subjects with severe and extreme pain responded better than other subjects. Segal et aI" also ooced in testing bipolar magnetic devices in knee pain'second. ary to rheumatoid arthritis that patients with mild symptoms did not respond as well. DPN pain appears to arise from an increase in afferent signals from degenerating nociceptive af. ferent fibers. It has been shown that early in the course of painful oeuropathies, free nerve endings of nociceptive axons can disappear from the skin but are still present in the suml nerve.'" One possibility may be Ihat Ibe magnetic field of these insoles somehow dire<:t1y or indirectiy intelTUpts and su»' presses the afferent signal traffic of the C-fiber firing pattern of the distal part of the surviving axon thereby producing an antinociceptive effect. A number of studies have shown thai DPN pain could result from depolarization because of dysregu­

laboo of normal

S~Um.I'l·I~,.63

calcium.23.64 and potassiumm

channel activities. It is well known that sodium channels ac­ cumulate in areas of axonal damage'" and static magnetic fields bave been shown to block or reduce action potential via effects on sodium flux...... A number of studies using weak pulsed, time-varying electromaguetic fields have shown biologic changes...·?> Adey and Chopart74 •73 considered the cell mem­ brane as the most likely transducer modifying ion traniipon of protein and adenosineaiphosphatase activity. Membrane lipids witb organized arrays of polar molecules, diamagnetic, have been shown to realign anisotropic molecules as well as to summate and interfere with ionic transport.'76.77 Tnmslational movement or changes in orientation in a magnetic field can influence amplilUde of evoked responses. 78.... Because phos­ pbolipids in cell membranes have both diamagnetic and para­ magnetic properties, it is clear that mechanisms exist that can produce confonnational changes in various channels and struc­ tures. IO•BI However, it is not known if any of this is pertinent to putative biologic effects of static magnetic fields. Based on OUr data, we speculate that the kinetic activity of channelized membrane ions and blood flow in a static magnetic field is sufficientiy strong to stimulate living tissues and to induce a biologic reaction. Signal transduction pathways appeared to be functionally modulated, and this is a restatement of Faraday's law of rime variation. '7o.l:z..L1 It is also known that weak mag­ netic fields can increase the partial pressure of tissue oxygen, Ibereby improving oxygen delivery to tissues." TIli. propeny may be important because of a reported reduction in endoneur­ ial oxygen tension in DPN." Thus, it is biologically plausible


MAGNE1IC FIELD THERAPY FOR DIABE1IC NEUROPAllIY. W.lntroub

743

that static magnetic fields influence diabetic neurons and ceU

for pain control (ie. rostral anlerior cingulate COrlex. brainstem)

membnnes of cUtaDeous nociceptor> by arnplifying the weak electromagnetic signals from the imposed and constant static magnets. thereby inducing changes ia the cellulBJ"'~' and

were somehow activatcd.29

pericellular microenvironmeot. 19,SlO Because these devices have

Although many questions remain about a precise mechanism of action, the present study provides convinCing data confirm­ ing that the constant wearing of static. permanent, magnetic insoles prodllCes statistically significant reduction of neuro­ pathic pain. Considering their safety and minimal cost «SIOO). our data suggest that the iosoles may be used as . adjunctive or monotherapy. Future studies are needed to iden­

a presumed penetration of up to 2Omm-thereby indicating passage through the epidermal" and dennal layers. which contain a rich network of nerves and capillaries-we speculate that, at this site, there is inhibition and/or interruption of ectopic firing of the dwnaged small nnciceptive afferent unmy­ elinated C fibers. The specific magnetic flux density at this Iarget area is not known. Pernaps a gating response with simultaneous stimulation of the A delta fibe'" producing an inhibitory llIltinocicepti ve effect on C fibeJS DCC"",. compatible with Melzak-Wnll hypothesis.'" Another possibility includes rhe n:cruitment of previously passive C flbenl.. PJ•04 Case IV studies of warm andlor cold thermal thresholds did not reveal any ,;erial cbanges from baseline. Thus. at an ionie-membrane level. we can speculate that either the underlying sodium channels can be up- or down-regulated" or. alternatively. rapid

CONCLUSION

tify the optimal time to achieve maximum andnoc:iccptive

effect and to confirm and extend these results. Additional search for biologic marie... (ie. epidermal nerve fiber biopsy, microneurography) will be necessary in future protocols 10 determine if permanent strUctural changes can be produced.

Acknowledgments: We thank Jefm:y Katims. MD. of Neurotron Inc. forthe loan of equipmenI used at the;3 centers. We also thaDk Dr. William -Frishman- for critical n::vicw of the_ lTW1Usc:ript and Susan Pincs-Wolen for data collection. The members of the M.gnetic Research-Di.betic Neuropathy Study repolarization occurs because of stimulation of the potassium Group include the foilowing: MJ. Weintraub. Me (principal invuti­ internal rectifying channels." This phenomenon may also pro­ gator); A.L. Rodunan, MD. sod G.I. Wolfe. MD (co-principal inves­ duce a secondary inhibition of the firing from the DRG neu­ tigatun); sod Steven P. Cole, PhD (chief biostatistician). 1J rons. Site investigalors (listed alphabetically· With the principal investiga­ The major strengths of the present study include random­ lor listed fiBt) include the following: B.T. Adornato. MD. P.C.. ized, placebo design; the cooperative involvement of neurolo­ Cassini. MD. Stanfonl Medical Center. Palo Alto, CA; CN. Apple­ gists. podiatrists. and diabetologists; and the geographic and g.... MD. E. Moore. CNRN. Ozarks Medical Ceo..... West Plains. racial diversity of the study population. These factor> suggest MO; S.W. Asher. MD. Neurological Associates. Boise, ID; T.E. that the observed benefits will be applicable to the general Benorini. MD. J. Karb. LPN. S. Maecarino. R.EDT. Wesley Neurol­ ogy ainic. Memphis. TN; T.W. Bohr. MD. V. Johnson. MD. D. diabetic popUlation. Because pain levels can vary during the Moses. RN, Loma Unda UnivClSity School of Medicine. Loma Unda, day, patients recorded their score 3 timos daily to best derive a CA; M.B. Bromhetx. MD. A.K. Fall<:her. RN. University of Ulah mean daily discomfort level and to reduce recall bias. Simi­ Medical Ceoler. Salt Lake City. lTI'; H.K. Bucholtz, MD. R. Malone. larly, QOL experiences have yet to be standardized and vali­ RN. Edi5oa. NJ; A.C. Chalmers. MD. S. Tipton. Kern County Neu­ dated by large cohorts in DJ'N'4; yet, intuitively. quantification rological Medical Group. BRkenfie1ds, CA: R. Cintron. Neuroscience of exercise-induced foot pain and sleep disturbance represents . Consull8Dts, Reston, VA; J.A. Cohen. ~. F..Ze= RN. MSN. D. importanl functional outcome m.....ures. Another strength Al1I1bruster. RN, Kaiser Pennanente Medical Group, DenVeT, CO; S.P. is the utilization of both academic and private practice centers Cole. PhD. Re&earch Design Anoci81eS. Yorktown Heights. NY; S. thal nol only showed good interobserver reliability. but also Cooper. MD. 018d Breau~. CRC. Medical A..oci.... of GeorJia, Canton. GA; A.C. Coener, MD. O. Molinar. RN. Texas Tech Medical reduced the likelihood of selection bias. Ceoter. E1 Paso. TX: N.W. Culligan, MD. S. Undblom, PT. ABsoci­ Despite this provocative data, several limitations exist. We ated Neurologists PC, Danbury. cr; L. Diamond, MD, New YorI< relied exclusively on patients' self-report for pain and out­ College of Podiatric Medicine. New York, NY; P.B. Dunne. MD. S. come....... Despite favorable statistical reduction of neuropathic Khorami. MD. H. Wong. MD. University of South Florida. Tampa, pain and QOL scores by w~g these devices; only modest Fl.; L.W. EppeBDn, MD. S. Thorp, RN. Al.boma Neurological Clinic, clinical improvement was achieved. 'The slopes of our figures Montgomery. AL; AJ. Esposito, MD. Northeast Alabama Neurolog­ from months 2 to 4 suggest that a more potent clinical benefil ical Services. Anniston. AL; R.A. Fischer. MD, L.M. Leschck­ could be anticipated at 8 to 12 months. and, thus•.long-term Gelman, MD. R. Titus. RN. Neurology Associa"", Wilmington. DE; studies must be performed. Another limitation was that il is a D.E Fleming. MD. M.T. Stock, DPhiI, FNP. EastCarolioa Neurology. Greenville. NC; T. Giancarlo. DO. G. LapadOl, LPN. Midlilan Neu­ physical impossibility to blind these foot devices and to prevent rolOgy Associ..... St. Claire Shores. Ml; M.G. GregOl)l, MD. J. the determination of magoetic activity. Subjects and investiga­ Bishop, RN, ceRC. Nevada Neurological Consultants. Las VegllS, tors were advised of the importance of maintaining the blind, NY; I. Haber. DO. M. Smith, Terre Haute, IN; G. Hayal, MD. J.

and the questionnaire al study termination indicates thaI both

Armbruster. RN. St. Louis Univmity. St. Louis. MO; S.A. Kabbani.

groups remained blinded. Unfortunately. we were unable

MD, T. Jenkins, East Tennessee NeW'Ology Cinie, Knoxville. TN; J. to identify a biologic marker using QST. SSR, and biothesi.

K.walec, PhD. B.D. Caldwell, DPM. A. Palel, MD. Ohio College of ometry. None of the limitations invalidates the statistical an~ podiatric Medicjne, Cleveland, OR; H.t. Kettler, MD, FAAN, Wheel­ tinnciceptive effeelS. lntraepidermal nerve fiber density mea­ ing Clinic. Wheeling. WV; D.A. Konanc, MD. K.L. HuU. MD. A.T. Perkins, MD. S.M. Freedman. MD, P.I'. Bye, RN. CRC. J.K. Do...ns. surements were not performed and may have provided a useful RN, CCRC. T.S. Gam... CRe. Raleigh Neurology A..ociates. pathologic correlate.'o, II has been shown thaI regeneration of Raleigh, NC; K.A. Levin. MD. K.A. CiI8lc. MD. J.T. Nasr. MD, S. nerve fibers can occur within 39 days in the dermis after an Pipala, RN, L. Warnock. RN. Neurology Group of Bergen County. injury and after 4 months in the epidermis.·o,.IOJ The observa­ Ridgewood. NI: M.E. Lipi... DO. L.L. Ford. LPN. J.E. Benton. RN. tion thal both refractory groups improved with lower VAS Blair Medical Associates. Altoona, PA: A. Maloon. MD, D. Hall, scores by 2 months compared with baseline by wearing foot LPN, CCRC. Marietta Neurological Associates, Marietta, GA; R. devices (magnetized. unmagnetized) is provocative and similar Mendjcino, DPM. D. Houpt, RN. Foot and Ankle Institute of Western to thaI seen in pharmaceutical studies and placebo trials; this Pennsylvania, Pittsburgh, PA; C. Miller, MD, B.C. Wouten, MD. suggests either a placebo response or analgesic benefil induced D.D, Mayer. RN, NeuroJo8Y Consultants of Montgomery, Montgom. by foot pressure. It is possible that central regions of the brain ery. AL; J. P.ge. DPM. CH DPM. California College of Podiatric

".97

".'00

An:h Phys Med Rehabil Vol 84. May 2003


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MAGNrnC AELD 'THERAPY FOR DIABrnC NEUROPAniy, Welntnlub

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Static Magnetic Field Therapy for Symptomatic Diabetic Neuropathy - Insoles - Plantillas  

Diabetic neuroplllhics; Magnetics; Rehabilita­ tion. similar, uumagnetizcd device. InterventioD: Nerve conduction and/or quantified sensory...