Prospeedve Randomized Single-blindedContrded CII1CI Mal at PercutaneousNeuromodulation Pain Therapy Device VersusSham for the Ostentritic Knee: A Pilot StudyRichard W. Kang, MD, MS; Paul B. Lewis. MD. MS; Adam Kramer, ATC; Jennifer K. Hayden, RN, MSN:Brian J. Cole, MD, MBA

Osteoanhritie pain can bedebilitating and lead tosignificant and urdesirable life-style changes. Increased empha-sis on addressiag pain has beenfueled by the recent descriptionof pain as the -5Ib vital sign"by the Joint Conunission onAcueditatice of Heakhease Or-ganizatiorn (ICA1110).1 Despiteefforts to deselop arm technolo-

Dm Kans. Lewis. and Cole. MrOmni% ant Ms Hoyden are fromthe Cartage Restoention Cosier aRath. Rash Uneeerslry Medical Cen-tex Cllicago. !IL

Correspondence Jtondd be ad.diVIStS1 to: &San I. Cole. MD.MBA. Departments of Oritiopedies

Anatomy and Cell &Any. Cat,silage RestonstMot Censor as Kash.

Rink Ilitiversay Medkai Centex1725 W Are. Ste 1063.Clonwerk IL 60612.

gies and methods to treat pain.an -analgesic gap- exists."

Currently. the first step insymptomatic 'diet includesanti-inflammatory agents suchas noristeroidalcitatory dnigs (NSAIDs) orcyclooxygenase (COX)-selec-tive chips in conateaction withlifestyle modifications. Often.these measures are not sun-Scion to completely alleviatethe pain, which pushes patientsto seek other alternatives suchas depot oosticosterold injec-tions, narcotics. and surgery.However, narcotics are capableof producing adsesse effects in-cluding =pinata), depression.sedation. nausea. vomiting,and even behavioral problems.'Corticoneroid injections aremore invasive can only be re-

pealed on a limited basis (ie. upto 3 times each year). and hawan associated risk of infectionand pm-steroid flare-upi Forthese re130113. other Itealniallmethods are needed to helpclose the treatment gap andthus reduce patient morbidity.

In addition to phannacologictreatments, other nonpharma-cologic alternatives have beenused including acupuncture.cooling, physical therapy. chi-ropractic manipulation. and

11811813011BOUS electrical nerve

stimulation has been used tor 3 decades ina variety of situations te relieve pain.

transeutaneous electrical nervestimulation. Unfortunately.these alternatives fall shortwith respect to duration andmagnitude of analgesia.

Transemancous electricalaerie stimulader has been usedfor 3 decades in a variety of sho-wiest% to relieve pain. "̒ Using

• the cutting edge

transculancous electrical nervestimulation is junified by thegate control theory, whichstate% that the brain recognizesa limited amount of neural in-put from a given poMt in thebody at any given moment.This impulse may be super-seded by another more power-fid and conducive neural input.Although transculaneous eke-ideal nerve stimulation hasbeen shown to be useful forsuperficial tissues. it lacks the

ability to penetrate into deepertissue.

A manly developed deeptissue percutancous neuromod-ulation pain therapy device,Deeinvave (Biowave Corp.Norwalk. CA:1111). is a viablealternative lot narrowing theanalgesic gap in treating maw-

Reprinted from ORTHOPEDICS. June 2007. Copyrighte 2007. SLACK Incorporated. All rights reserved.

JUNI 2007 I Volume 30 • Number 439

This pilot study presents the initial results for a percutaneous neuromodulation pain therapy device (BiowavePRO with Deepwave Percutaneous Electrode Arrays) that is associated with no morbidity, good pain relief, and increased function in patients with knee osteoarthritis.

• the curling edge

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arthritic pain. Unlike trartscuta-neous electrical nerve stimula-fiat. the Deepwave device candeliver a precise electricalnal to a specific volume of tis-sue in the body dud Meets thetransmission of pain impulses.The electrical signal created inthe body is theorized to have asecondary effect of releasingendorphins and serolonin. andtherefore leafing to a localizedanalgesia at the treatmem site.This analgesic effect dependson the &nation and amplitudeof treatment.

The Deepwave device sendsa premixed modulated enve-lope of two high frequencyelectronic wave forms (-feed

signals") into deep tissue viaa larger feed electrode anda smaller pain site electrodecalled a pestetaneous elec•tmde may. The percutaneouselectrode array facilitateslivery of the feed signals intodeep tissue by providing adirect conductive pathway forcurrent through the enitenuostlayers of skin.

Peretnameous electrode ar•rays are comprised of 1014inicroneedles. each or which is033 mm in length and housedwithin a 2.5•isch diameterhydrogel•based electrode. Po-larized structures in the bodycause an electric field to formwith a low frequency comp°.

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Rpm I; Damn Ilion* Oman* ilortailk, Corte)moans:es al Wien Oa inquency conduction bind( Nor-ma eromettito cd pais Opal Moro can fibers (Cfixes)(A). Cietwamt itelde field lumen sodumtpclassiumkin melange. limey ishbittio le etM trom thancOnoparty an Wincing transmission of pais isnguiSat 4B).

nerd mital to the difference inhequency between the two feedsignals. Formation of the lowfrequency field occurs in theram of a modulated electricfield envelope with a locationdependent on the placement ofthe two electrodes. The volumeof tissue affected is dependenton electrode size and place-ment as well as the amplitudeof the feed signals. With thecoofiguration used in this study.the electric field is believed toform immediately adjacent toand beneath the perculaneouselectrode array over the painsite. along the path between theopposing feed electrode andthe etteutancous electrode ar-ray. The low frequency electricfield is believed to demodulatenerve cells, remadag in an al-leged Na+1)(1-As a result, the membrane po-tential of the nerve cell is sta-bilized (hyperpolarized) and istherefore unable to transmit ac-tion potentials and thereby painimpulses (Figures I and 2).

The use of Deepwave as asingle therapy is efficaciousavid safe in reducing the sever-ity of acute and chronic painin knee osseoardwitis patients.

This study investigated the ef•ficacy of Deepwave in reduc-ing knee pain experienced byour patient population. and re-auction of drug consumptionover the 1-week period follow-ing the treatment.

MATERIALS AND METHODSManta

This is an Institutional Re-view Board•appmved. single-blinded, randomized pilotstudy of 70 paderns over art11-month period. The studybegan in March 2005 and thedata from the last patient wascollected in December 2005.Patients were blinded to eitherlive or sham treatment groups.All patients presented to theclinic with knee pain second-ary to osteoardwitis. The di-agnosis of knee osseoarthritiswas made based on the Ameri-can College of Itheumatologyguidelines, which include kneepain with radiographic changesof osteophyle formation and atleast one of the following pa-tient age >50 years. morningstiffness lasting 30 minutes.or =pinks on motion." In-formed consent was receivedon 70 patients. Seven patientswere lost to follow-up. Of the63 completed patients. 28 pa-tients were randomly assignedto the sham group and 35 pa-tients were randomly assignedto the live treatment group. Ta•ble I presents the demograph-ics for these two groups.

Inclusion criteria consistedof any man or woman who metthe following conditions: agedbetween 18-85 years. diagno-sis of osteoarthrids. knee painsecondary to osteoardwitiswith a visual analog pain scale

440 ORTHOPEDICS www.ORTI tOSuperSne.com

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Eadasion criteria excludedany patient with an allergy orIntolerance to adhesive mate-rials; surgical intervention orinjection of a corticosteroidor viscosupplementthe prior 30 days of the Vest-ment of the painful knee orits underlying etiology; his-tory of any substance abuse ordependence within the past 6months: history of pacemakeruse: existence of implantableelectronic devices; any clini-cal evidence oil-cardiovascular,pulmonary. renal. psychologi-cal. hepatic. neurological, he-matologic or endocrine abnor-malities; and having receivedan investigational drug or de-vice in the past 30days.

Pain Therapy DeviceThe Biorasve deep tissue

neuromoduladon pain therapydevice (Dmpwave) was used.

The active percutaneous elec-trode placed over the pain sitewas a Li-inch diameter roundpercutaneotss electrode armyembedded within a 2.5-inch*meter round carbon/silver eke-tmde (Unipatch.Wabash. Minn).The feed elecuode placed oppo-site the pain site was the Classic2404. 4x2-inch self adhesiveelectrode (Unipatch).

Visual Analog Pain ScaleA visual analog pain scale

was used to determine pre- andpost-treatment pain levels (im-mediate. 6 hours. 24 hours. and48 hours pora-unatmem). A100-turn scale was used to 'aukthe patient's subjective pain. Atthe far left oldie scale was "nopain" and on the far sight was'Vona pain imagirablelle vi-sual analog pain scale has beenpromo to be a said and reliableantrament of pain.*

TreatmentFor all patients, the ac-

tive percutarmons electrode

was positioned on their siteof maximum knee pain whilethe feed electrode was placeddirectly across the joint line(medial and lateral or anteriorand posterior). Treatment du-ration was 30 minutes in bothgimps. Patients were instruct-ed to sit in a chair with theirbacks to the Biowave machine.Live treatment group patientswere ittameted to tell the ex-aminer when they had achievedthe highest tolerable intensity.The intensity levels then weremassessed and increased as tol-anted by the patient after 5. 10.and 15 minutes from initiationof the 'remittent session. Themean intensity levels for thebtu group were 16%. 19%.21%. and 23% at the ON 5-.10-. and IS-minute time points.respectively.

The sham treatment groupwas instmeted that becausethe percutaneous electrode hasmicroneedles that penetrate'Ismaili the outer skin layers.they would not perceive thenormal "pins and needles"

tonally associated with elec-trical stimulation. Throughoutthe entire sham treatment themachine was not turned onalthough the appmpriate in-temity buttons were messed tosimulate the live treatment.

Subjective OutcomesAdditionally. the Western

Ontario and McMaster Os-teoasthritis Index (WOMAC)questionnaire was completedby each patient prior to reeeiv-ing the treatment and againat 48 hours post-treatment.The WOMAC questionnairehas proven %Mild in assessingpain. stiffness, and functionof the osteoarthritic patient."Posttest data identical to thepretest data was collected im-mediately post-treatment (0hours) by the team At 6. 24.and 48 hours, post-treatmentdata were recorded by the pa-tient and all study materialswere mailed to the investigatorat the completion of the study.A phone call to each patient atthe 6-. 24-, and 48-hour time

KINIE 2007 I Volume 30 • Number 6

• dm add% edge

441

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Rpm Pain Mama% dMerenoe (values noted as centimeters on Mug map pain scale) for ihe lye and sham groups.

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Alan 4: Summed pan Intensity dillontom Maros noted as coodmateis on visual waled pain stale) Mr the bro andsham groom

points was performed to en.hance patient compliance. Theimmediate.. 6-. and 24-hourpost-treatment data consistedof a visual analog pain scaleand perceived overall improve-ment (0%-100%). The 48-how

data included the visual analogpain scale. perceived improve-ment follow-up knee survey.and subjective questions re-garding pain control and relief.Finally. a 1-week phone wrveywas conducted with subjective

questions regarding adverseeffects and medication use.

SIIIISIkal AOSPISISNormally distributed con-

tinuous variables were ana-lyzed with an analysis of vari-

ance (ANOVA) model withrepeated measurements. Con-tinuous variables that werenormally not distributed wereanalyzed using the Wilcosontest for pairwise comparisons.Categorical variables were an-alyzed with a chi-square test.Significance levels were set atP<.03.

RESULTSCoaled and Saida

No serious adverse eventswere noted in either the live orsham groups. As seen in Table2. there were no significant dif-ferences between the and shamgroups with respect to comingsor adverse effects. One patientreported a mild erythematousmaculopapular rash wherethe percumneous electrode ar-ray was placed. This rash hadresolved on its own within 24hours. Three patients ( I live. 2sham) reported mild tinglingthat resolved on its own within6 hours of onset.

Pall Intensity DISersecaPain intensity difference

was the primary measure old-limey. Pain intensity di flerenceis defined as the difference invisual analog pain scale not-ed at pretreatment (baseline)versus the visual analog painMae noted at each post-treat-meat period. In this respect.figure 3 demonstrates that thelive group had significantlygreater efficacy than the shamgroup in the immediate post-treatment period (P=.0361).The live grours pain intensitydifference was greater thanthe sham groups pain inten-sity difference by 93 min. 3.0atm. 9.0 mm. and 7.0 min for

442 ORTHOPEDICS I www.ORTHOSuperSitc.com

iiJUNE 2007 I Volume 30 • Numbes 6

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figure tie Raw *seal aralog pain scahr SONS menial Ice lh and sham Figaro t lIstribaton of pain control asetend at 48 hours post-trealment Thegroups. Significance is naiad at the isenediale post-trartmeril putt Ice grow hos siorMeardkr fader pen mad Own Ito sham group (fh.-.039).

the immediate. 6-. 24-. and 48-hour pog-treatment periods.respectively. Additionally. atrend was noted in improve-ment of the pain intensity dif-fine= in the live group ascompared to the sham group>48 hours post-treatment.

An overall assessmeet ofpain intertrity difference wasmade by detemining the medi-an pain intensity difference overall post-treatment periods. Themedian pain intensity differencefor the live and sham groups was14.5 nun and 6-5 rum. fame-thely. This 8-111111 vat Union inmedian pain intensity differencewas significant (P= A)071 ).

Figure 4 demonstratesthe live group% significantlygreater efficacy compared tothe sham group when evaluat-ing the median of summed painIntensity difference scores forthe immediate post-treatmentperiod (P=.0161). In this caseas well, a trend was noted inimpmvement in the live groupas wavered to the sham groupover 48 hours post-treatment.Differences in summed painintensity difference were 9.5

mm. 14.5 mos. 23.5 mm. and30.5 mm for the immediate.6-. 24-. and 48-hour post-treat-ment periods, respectively.

Visual Make Pain ScaleThe raw scores for the "cur-

rent pain" reported as a visualanalog pain scale score arcsummarized in Figure 5. Thelive group had a significantly!educed visual analog painscale score compared to thesham group at the ignmedi-ate posttreatment period (livescore=3.2; sham soore=4.9;P=.0494). At later time points,a uend was noted toward great-er reduction in visual analogpain scale scores in the livegroup as compared so the sham

Pain Ceske! and Pain ReliefPain control reported at 48

hours post-treatment was sig-nificantly better for the livegroup than the sham group(P=.039). Figure 6 demon-strates die distribution of thepatients' asserancist of paincontrol. The live group had35% and the sham group had

7% of patients with pain con-Ifell described as either "well"or "complete"

When asked to grade theirpain relief on a 0%-1 00% scaleat 48 hours post-treatmega, thelive group had 42% pain reliefand the sham group had 11%pain relief. This difference of31% between the two groupsis significant (P= .0103).

Palled SalisladienWhen aged •'How

better do you keir patients inthe live group had significantlyhigher taiga:don swim thanthe sham group for all post-treat-ment periods abbe: 'Me live

group was hkgter than the thangroup by 33% (Pa•.0128). 20%(P m .0459). 35% (P= .0287). and50% (P=.0007) for the inunedi-ate 6-, 24-. and 48-hour pout-treatment periods. respstively.

Al I -week follow-ups pa-tient satisfaction was signifi-cantly higher* (P<.000 1) for thelive group than the sham group(Figure 7). The live group had77% and the sham group had11% of their patients report asatisfaction level of "good.""very good." or "excellent."

Medication UseAt I-week follow-up. the live

group reported significantly less

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Hews t Change In WOMAC score from crettmessent to 48 hours post-trial-mint The lira group ass statisticalti signiticaMty different from the shamgroup for the When assessment.

(P<.0001) medication use thanthe sham group to treat theirknee pain (Figure 8). The thegroup had 54% of its patientsreport a decrease in mace-tion use, while the sham groupreported no decreases.

WOMAC SUMThe change in WOMAC

mores From pretreatment to48-boor post-treatment for the liveand sham groups are presentedin Figure 9. The five groupdemonstrated greater improve-

meats than the sham groupfor all WOMAC categories ofpain (live =4. sham = I). stiff-ness (live=1, sham=0). andfunction (live =12. sham 2).The live group bad a statisti-cally significant improvementover the sham group with re.speo to the stiffness aas-mcmt .0296).

DISCUSSIONThe Deepwave neuromod-

elation pain therapy devicewith percataneous electrode

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arrays demonstrated safetyand comfort in both the liveand sham poops, with no se-rious adverse events reportedin either group. Moreover,any minor events wcrc toler-able and short-lasting. The livegroup had significamly greaterefficacy over the sham groupwhen evaluating pain intensitydifference scores at the imme-diate post-treatment period.The live group pain intensitydifference scores remainednumerically superior to thesham group's scores as all lasertime points. hut did not readsstatistical siptilicance. Oneconsideration is that a largersample number may lead tonarrower distributions withineach group. and thereby makethe differences more likely toachieve statistical significance.Anther factor to consider isthe improvement in functionin the live group. as noted bythe WOMAC scores, could re-flect a greater level of activityin this group; and when com-bined with the reduction in an-algesic consumption in the livegroup these effects may have

diminished the reduction in vi-sual analog pain scores that thedevice would have achievedat later time points had thoseother variables remained con-stant.

Of pmicular nose is thatseven patients were loss to fol-low-up from the sham groupand none were lost from thelive gimp. Despite our empha-sis on the importance °raisin-ing follow-up information, thepatients lost to follow-up didno respond so our solicitations.It is likely that these patientswere unhappy with the resultsof their treatment and did notFeel compelled to contributeany further to the study. Thus.there is a possibility that ifthe results from these palle105we obtained., the differencesin pain intensity difference be-tween the two groups wouldhave been larger and achievedstatistical significance.

Despite the lack of magi-cal significance with respectto the pain intensity differ-ence at later time points, thedifferences between the liveand sham groups became more

ORTHOPEDICS! www.ORTHOSuperSite-com

apparem when they were as-sessed subjectively. The livegroup had significandy betterglobal assessment of pain re-lief and pain control than thesham group at 48 hours post-treatment. In the live group,35% of the patients reportedat least "well" or "complete'control of pain at the 48-hourtime point. as compared to the7% for the sham group. Addi-tionally. 54% of the patients inthe live group demonstrated adecrease in medication usage,which is overwhelming com-pared to 0% of the patients inthe sham group. These reportsare consistent with the signifi-cant level of satisfaction re-posted by the live group (77%of the patients reported goodto excellent) as compared tothe sham group (11% reponedgood to excellent).

Zubieta ci al reported thatwhen a potential treatment hasimplied analgesic propertiesthere are specific regional alter-ations in the brain leafing to ac-tivation of the mu opiod reev-e:NS pmducing a placebo effect.Indeed, we observed a placeboeffect in our sham group. Thepain intensity difference forthe sham group began at 11.5mm immediately after treat-ment. and declined to 1.0 mmat 48 hours post-treatmern. Thisrange of pain intensity differ-ence is consistent with the av-erage pain Intensity difference(6.5 mm on a 100rmn scale) ina recent systematic review of27 clinical trials involving theueatment of pain."'

There woe a few limits-dons to our study. The inherentnatural history of osteoarthriticknee pain allows for daily varia-

dons of lake pain based on timeof day and activity level Thepatients' insauctiorts were tocontinue their daily activities.however some patients weremore active than miters OMthe length of the study. There-fore. time of administration ridchanges in activity level mayrepresent confounding variablesin this pilot study. Also becauseof its logistical feasibikty. onlya single treatment was adminis-feted for each patient. However.it is of general makestandingthat IralIMCIIIS analogous tothe Deepwave percutameonsneuromoduktion pain therapydevice avoid be given on anas needed- basis. The lack of

this option in our study desigamay have coomluted to thefading of the live treatment'seffkacy over time. finally, thisstudy only had 24% power toconclude that the difference inpain intensity difference store at48 hour posttreatment betweenthe two groups %vas statisticallysignificant (0=05). Nonethe-less. given die magnitude of theasperity in pain intensity dr-femme scores between the liveand sham treatment groups. ourresults resit further study forsymptomatic treatment (with aDeepwave pain therapy device)of patients with knee osteoar-

The Deerwave pereutane-ous networandislation paintherapy device has significantpromise as an effective Com-ponent of the tannoperativetreatment algorithm for symp-tomalie osicoarthritis of theknee. The results of this pilotstudy have determined thesafety and efficacy of a singledose LW-BIWA of the Deep-

wave perculancous neummod-ulation pain therapy device.Fume studies should considerincluding administration of thetreatment over a greater timeperiod to mimic clinical appli-cation and assess a potentialCUMUISIiVe dose effect. The re-sults from this pilot phase maybe teed to &sign a broadermulticenter study that will bepowered to provide greaterdata points leading to banderconclusions as to the treaunentefficacy of the perculancousDeepwave device.

REFERB10ESI. Moose ID Jr. An issue of %ma-

ny: Aim! Heirlikr. 2000; 29: la-ts.

2. Aprelhaam IL. Gan Ti. ChenC. Patient perception of post-operative pis experience af-ter outpatient ungery: patinasurvey. Anesthrsiology.93(supplgrA I.

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7. Come la Marshall All, TramSN. Daly IC. Idler M. IVIIISCWmoms do:triad nave stimula-te rearming apeorickectomy:the placebo aka. Mn t CoilScar Eltat. 1986t 68:191-192.

& Coot PI. MacMurrea M. ImoT. Kilmer T. Transemancouselectrical nave stimulator forprecedent pain associated witlasmonam needlesticks, / In-yawn Nam 1995: I 8:263.267.

9. Forster EL. Kramer W. Lucy

Scudds RA. Novick RI Ef-fects of 'rENS on pais. onerfica.dem and pulmonary functionfollowing coronary anay by-pass grail surgery. Oleo. 1994:1061343-1348,Nagnaws A. Lander J. Useof transcuonneous electricalnerve stimulation for postop.amble pain. Nun ReA• 1989;38159.161-;0ms AY. Lee R. HoltagerD. Joon RD. A comparkon ofdifferent electrode placementson the effectiveness of MSS inpint whet for post-cholecystoc-mini patients. Physiogmw.1990; 76.567-570.

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14. Smith CM. Gwalnick MS. Gel-find MM. Jeans ME. The elfiXiSof tanaciatanteus *asked gavesimattion on pomervareaspain. /bin. 1986: 27181-193.

IS. Alma R. Arch 11, Bloch I/, et

al. Driacenneat of criteria forthe datetheatiem and apatiteof ostectueettis. Cbasillesekeof ostecordviin of the knee. Di.*vote and Iliermattle O& Comardate of the AntalcutRheumatism Amoebae& Arafari•tis Rheims.. I916. 291039-1049.Cerkson AM. Amassment ofdienic pain. I- Aspects of therdsahilily ard validity oldie vi-sual analogue scale. Rain. 1983:I 7:777-M.

17. Balsam N. Buckman WW.Goltranit CH. Cwripbell I,Sit LW. Validation study ofWOMAC a tales anus In-smemem for meawning chid.(ally impunity patient relevantmecomets to atublyumatic dragtherapy in patients with atom.Omit of tit. lip or km: Rime-learnt 1988: 15:1833-1840

I& Zublein IK. Dueller IA. JacksonIR. et al. Placebo effects met-Ned by endogamous °Mehl ac-tivity on mu-opioid receptors..1Nermisri. 2005: 25:7754-7762,Hrobjamsom A. Gotmehe PCk the placebo powerless? Ananalysis of clinked Stasis cons.ming placebo with no trots.smut. N Esg J Aka 2001;3441594-1601

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