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doi: 10.2522/ptj.20110183Originally published online March 30, 2012

2012; 92:898-910.PHYS THER.and Kathleen A. Sluka

Amendola, Miriam Bridget Zimmerman, Deirdre M. WalshBlodgett, Josimari Melo DeSantana, AnnunziatoCarol Grace T. Vance, Barbara A. Rakel, Nicole P.Controlled TrialPeople With Knee Osteoarthritis: A Randomized

inStimulation on Pain, Pain Sensitivity, and FunctionEffects of Transcutaneous Electrical Nerve

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Effects of Transcutaneous ElectricalNerve Stimulation on Pain, Pain

Sensitivity, and Function in PeopleWith Knee Osteoarthritis:A Randomized Controlled TrialCarol Grace T. Vance, Barbara A. Rakel, Nicole P. Blodgett,Josimari Melo DeSantana, Annunziato Amendola, Miriam Bridget Zimmerman,Deirdre M. Walsh, Kathleen A. Sluka

Background. Transcutaneous electrical nerve stimulation (TENS) is commonlyused for the management of pain; however, its effects on several pain and function

measures are unclear.Objective. The purpose of this study was to determine the effects of high-frequency TENS (HF-TENS) and low-frequency TENS (LF-TENS) on several outcomemeasures (pain at rest, movement-evoked pain, and pain sensitivity) in people with

knee osteoarthritis.

Design. The study was a double-blind, randomized clinical trial.

Setting. The setting was a tertiary care center.

Participants. Seventy-five participants with knee osteoarthritis (29 men and 46women; 3194 years of age) were assessed.

Intervention. Participants were randomly assigned to receive HF-TENS (100 Hz)(n25), LF-TENS (4 Hz) (n25), or placebo TENS (n25) (pulse duration100microseconds; intensity10% below motor threshold).

Measurements. The following measures were assessed before and after a singleTENS treatment: cutaneous mechanical pain threshold, pressure pain threshold(PPT), heat pain threshold, heat temporal summation, Timed Up & Go Test (TUG),and pain intensity at rest and during the TUG. A linear mixed-model analysis of

variance was used to compare differences before and after TENS and among groups(HF-TENS, LF-TENS, and placebo TENS).

Results. Compared with placebo TENS, HF-TENS and LF-TENS increased PPT at theknee; HF-TENS also increased PPT over the tibialis anterior muscle. There was noeffect on the cutaneous mechanical pain threshold, heat pain threshold, or heat

temporal summation. Pain at rest and during the TUG was significantly reduced byHF-TENS, LF-TENS, and placebo TENS.

Limitations. This study tested only a single TENS treatment.

Conclusions. Both HF-TENS and LF-TENS increased PPT in people with kneeosteoarthritis; placebo TENS had no significant effect on PPT. Cutaneous pain mea-

sures were unaffected by TENS. Subjective pain ratings at rest and during movementwere similarly reduced by active TENS and placebo TENS, suggesting a strongplacebo component of the effect of TENS.

C.G.T. Vance, PT, MS, GraduateProgram in Physical Therapy andRehabilitation Science, The Uni-versity of Iowa, Iowa City, Iowa.

B.A. Rakel, RN, PhD, College ofNursing, The University of Iowa.

N.P. Blodgett, RN, MS, College ofNursing, The University of Iowa.

J.M. DeSantana, PT, PhD, Depart-ment of Physical Therapy, FederalUniversity of Sergipe, Aracaju,Brazil.

A. Amendola, MD, Department ofOrthopedics and Rehabilitation,The University of Iowa.

M.B. Zimmerman, PhD, Depart-ment of Biostatistics, College ofPublic Health, The University ofIowa.

D.M. Walsh, PT, PhD, Health andRehabilitation Science ResearchInstitute, University of Ulster,Newtownabbey, United Kingdom.

K.A. Sluka, PT, PhD, Graduate Pro-gram in Physical Therapy andRehabilitation Science, The Uni-versity of Iowa, 1-252 MedicalEducation Building, Iowa City,IA 52242 (USA). Address all cor-respondence to Dr Sluka at:[email protected].

[Vance CGT, Rakel BA, BlodgettNP, et al. Effects of transcutaneouselectrical nerve stimulation onpain, pain sensitivity, and function

in people with knee osteoarthritis:a randomized controlled trial. PhysTher. 2012;92:898910.]

2012 American Physical TherapyAssociation

Published Ahead of Print:March 30, 2012

Accepted: March 22, 2012Submitted: June 1, 2011

Research Report

Post a Rapid Response tothis article at:ptjournal.apta.org

898 f Physical Therapy Volume 92 Number 7 July 2012

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Transcutaneous electrical nervestimulation (TENS) is an inex-pensive, noninvasive interven-

tion used to manage a wide variety ofpainful conditions. Previous studies

showed that TENS increases pres-sure and heat pain thresholds in peo-ple who are healthy16 and reducesmechanical and heat hyperalgesia inarthritic animals.7,8 However, arecent systematic review showedthat TENS was not effective for kneeosteoarthritis (OA) pain,9 in directcontrast to an earlier systematicreview that concluded that TENS

was effective for knee OA pain10 anda meta-analysis that showed a signif-icant reduction in knee OA pain with

TENS.11 Several limitations in theincluded trials may explain the lackof effect of TENS; these include smallsample size, poor methodologicalquality, and inadequate randomiza-tion and blinding.

A key factor that may explain thelack of effect of TENS is that pain atrest was the main outcome routinelyexamined in earlier studies.9 How-ever, TENS has a greater effect on

movement-evoked pain and subse-quently results in improved func-tion.12 Evoked stimuli are used to

measure painlike behaviors in animalstudies and commonly used to exam-ine responses at the site of injury (ie,primary hyperalgesia) and outsidethe site of injury (ie, secondary

hyperalgesia). Primary hyperalgesiaand secondary hyperalgesia are sur-rogate measures for sensitization ofthe peripheral nervous system (atsite of injury) and central nervoussystem (outside site of injury),respectively. It is possible that theeffectiveness of TENS varies byoutcome.

Dosing also is critical to the effective-ness of TENS.1215 Animal studiesshow that both high-frequency TENS

(HF-TENS, 50 Hz) and low-frequency TENS (LF-TENS, 10 Hz),delivered at an intensity of 90% ofthe motor threshold (strong sensoryintensity), reduced pain sensitivity inarthritic animals.1620 Several studies

of HF-TENS in people who arehealthy show that higher intensities,generally described as strong butcomfortable, resulted in greater painreduction.2,6,13,14,21,22 Similarly, stud-ies of postoperative pain show that

adequate intensities are necessary toproduce analgesia and that lowintensities are ineffective.12,15 It is

unclear whether the frequencies andintensities used in animal studies willhave similar effects in people.

The purposes of this study were:

(1) to determine the efficacy ofHF-TENS and LF-TENS for knee OApain and (2) to determine whichoutcome measures (pain at rest,movement-evoked pain, pain sensi-tivity, and function) are most likelyto be affected by HF-TENS andLF-TENS in people with pain toinform the design of future studies.

We compared the effect of TENS,

applied with parameters used in ourearlier animal studies,13,14,16,2228

with the effect of a new placebo

TENS on pain at rest, movement-evoked pain, pain sensitivity mea-sures, and function in people withOA. We hypothesized that bothHF-TENS and LF-TENS would reducepain during movement but not pain

at rest, decrease pain sensitivity, andincrease function.

MethodDesign OverviewThis study was a double-blind, ran-

domized clinical trial that included75 people who had knee OA and

were randomly allocated to 1 of 3groups (HF-TENS, LF-TENS, and pla-cebo TENS). Outcome measure-

ments were obtained before and dur-ing a single TENS treatment.

Available With

This Article atptjournal.apta.org

Discussion Podcast with authorsKathleen Sluka and MyrtoDounavi and Meryl Gersh,Co-chair of the Electrotherapy/Therapeutic Technologies Group,

APTA Section on ClinicalElectrophysiology and WoundCare. Moderated by StevenGeorge.

The Bottom Line

What do we already know about this topic?

A substantial body of literature shows that TENS produces analgesia in

both animal and human subjects with a variety of pain conditions by using

endogenous opioid pathways. Systematic reviews of TENS for knee OA

offer conflicting positions. Although prior studies routinely examine rest-ing pain as their main outcome, TENS may work more effectively for pain

at rest, movement-evoked pain, and pain sensitivity.

What new information does this study offer?

This study evaluated the effect of TENS, applied with parameters used in

prior animal studies, with a new placebo TENS on a variety of outcomes

including resting and movement pain, pain sensitivity, and function in

subjects with OA. There was a significant reduction in evoked pain

measures but not in resting pain with TENS.

Transcutaneous Electrical Nerve Stimulation and Osteoarthritis

July 2012 Volume 92 Number 7 Physical Therapy f 899

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Setting and ParticipantsStudy participants were recruitedthrough flyers and active screening

by experimenters in the orthopedicand sports medicine department ofa large midwestern tertiary carecenter. Inclusion criteria were asfollows: diagnosis of medial-compartment knee OA (radiographi-cally and symptomatically diagnosedby an orthopedic surgeon), 18 to95 years of age, able to ambulate

to mailbox and back, stable medi-cation schedule for 3 weeks beforetesting, and pain rating of greaterthan 3 of 10 during weight bearing(on a verbal rating scale). Lateral-compartment knee OA wasexcluded to standardize the test sitesfor pain sensitivity measures. A painrating of less than 3 of 10 was

needed to derive a clinically mean-ingful change attributable to theintervention.

Initial screening was performed bythe recruiter, or telephone screening

was conducted by the project coor-

dinator to determine inclusion.Exclusion criteria were as follows:uncontrolled diabetes mellitus orhypertension, dementia or cognitiveimpairment, neurological disorder,permanent lower-extremity sensoryloss, earlier TENS use, knee surgeryin last 6 months, or knee injection inlast 4 weeks. To avoid interactions

with medications, participants weregiven instructions not to take anyanalgesic medication 4 hours beforethe testing session. At the first visit,

we obtained a complete list of med-ications currently being taken andassessed bilateral recognition ofsharp versus dull pressure at theL3S2 dermatomes and propriocep-

tion of the great toe to rule out lossof sensation (an exclusion criterion).

All testing was conducted in 1 of 2

dedicated research spaces at TheUniversity of Iowa.

Figure 1 shows the CONSORT dia-gram for this randomized con-trolled trial. As illustrated, 311 peo-ple were assessed for eligibility,and 87 declined to participate. We

were unable to make contact with31 people, and 116 were excluded.Seventy-five of the remaining 77people were allocated to treat-

ment groups and completed the test-ing. Two people were excluded inthe secondary screening processbecause of reduced sensation and lat-eral joint pain.

Randomization and InterventionAn allocation concealment protocolwith sequentially numbered,

opaque, sealed envelopes and per-muted blocks of 3 and 6 was used torandomize participants to groups.29

Figure 1.CONSORT diagram. Most people were excluded from the initial screening because of earlier transcutaneous electrical nervestimulation (TENS) use or minimal pain. However, all participants allocated to a group completed the study. CNScentral nervoussystem, CVAcerebrovascular accident, OAosteoarthritis.



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Allocation envelopes were kept in alocation separate from the testinglocation and were not available tothe data collection examiner. Thefoil-lined envelopes were signed,

dated, and opened by the allocationexaminer immediately before TENSapplication and after the data collec-tion examiner left the room.

A commercially available TENS unit(Rehabilicare Maxima, DJO Inc,

Vista, California) was used to deliverTENS. The unit uses an asymmetri-cal, biphasic waveform, the pulse

duration was set at 100 microsec-onds, and the intensity was 10%below the motor threshold. We

chose to modulate frequency andkeep all other parameters the sameto test whether there is a frequency-dependent effect on outcomes. Thesame parameters were previouslyused in preclinical animal and

human studies of TENS in our labo-ratory.13,14,16,2328 The placebo TENSunit (DJO Inc) was identical inappearance to the TENS unit, andplacebo TENS was applied in thesame manner as active TENS (100

Hz, 100-microsecond pulse duration,and intensity 10% below motorthreshold). The new transient pla-

cebo TENS unit delivered a currentfor the first 30 seconds and thenramped down to zero over 15 sec-onds. The transient placebo is validand has no effect on pain measuresin healthy controls.13 Neither theTENS allocation examiner nor thedata collection examiner could dif-ferentiate between active TENS and

placebo TENS and, importantly, allparticipants received the same set ofinstructions. Blinding was assessedat the end of TENS treatment andbefore participants left the clinic.Participants were asked if theythought they received active TENSor placebo TENS.

Transcutaneous electrical nervestimulation was applied with 4 self-adhesive electrodes (5 5 cm

[2 2 in]; DJO Inc) to bracket theknee with OA and to apply paresthe-sia encompassing the painful knee.Two electrodes were placed abovethe knee, and 2 were placed below.

The current was delivered across thejoint through 2 channels. One chan-nel was connected to an electrodeabove the knee medially and belowthe knee laterally; the second chan-nel was connected to an electrodeabove the knee laterally and belowthe knee medially. The specific elec-trode sites were determined by theallocation examiner using points of

least impedance.30 To locate thepoints, the participant and the exam-iner each held a gelled electrode in

his or her hand. The examiner com-pleted the circuit by placing a water-dipped finger on the participantsskin and increasing the intensity tothe experimenters sensory thresh-old. The examiner then glided her

finger over the area to locate thepoints of least impedance (ie, pointsat which increased sensationoccurred for the examiner). Thepoints were always located withinthe frontal plane and within 25 to 75

mm of the midpatella. The pointswere cleaned with water, and theelectrodes were applied.

The TENS units were turned on for20 minutes before testing to reachthe peak effect and were turned off

when testing was completed, for atotal application time of 40 to 50minutes. The greatest effects ofTENS occur when the unit is on. Allof our measurements were obtained

in the same order so that quantitativesensory testing was done immedi-ately after 20 minutes and functiontesting (Timed Up & Go Test[TUG]) was performed last. There-fore, we were comparing the effec-tiveness of the same length of TENStreatment across participants.

Outcome Measures andFollow-upSubjective pain intensity. Partic-ipants were asked to rate their painon a horizontal 100-mm visual analog

scale (VAS). The anchors were nopain and worst imaginable pain.The VAS is valid and reliable com-pared with other pain rating scales(r.71.78, intraclass correlationcoefficient [ICC].71.99).31,32 Pain

was assessed at rest, during the TUG,and during heat temporal summation(HTS).

Pain sensitivity. Pain sensitivitywas measured with the quantitativesensory tests outlined below. Three

sites were marked 1 cm apart at themedial joint line bilaterally. Another3 sites were marked 2.5 cm apart onthe tibialis anterior muscle bilater-ally, with the top site being marked7.5 cm below the inferior border of

the patella. All pain sensitivity mea-surements were obtained at all 6sites, except for the heat pain thresh-old (HPT) and HTS (see below),

which were obtained over the mid-dle point of the knee and tibialis

anterior muscle because of the largersize of the thermode stimulatorprobe. All sites were assessed

bilaterally.

Cutaneous mechanical painthreshold (CMPT). The CMPT

was assessed with a set of 20 vonFrey filaments (North Coast Medical,Gilroy, California) applied to the testsites in ascending order (0.008300g). The tip of the filament was

applied perpendicular to the site andpressed until bending occurred. Onetrial per filament was done. TheCMPT has excellent test-retest reli-ability (r.97).32

Pressure pain threshold (PPT).The PPT was assessed with a hand-held pressure algometer (Somedic

AB, Farsta, Sweden) applied at 40kPa/s (1-cm2 circular tip). Partici-pants were instructed to press the



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handheld response switch when the

sensation first became painful. Par-ticipants were familiarized with the

procedure by performing a practicetest on the forearm. The PPT hasexcellent test-retest reliability(r.70.94) and is a valid measurefor deep-tissue hyperalgesia, as indi-cated by earlier studies showingdecreases in chronic pain compared

with the responses in healthycontrols.33

HPT. The HPT was assessed by use

of a TSA II NeuroSensory Analyzer(Medoc Ltd, Ramat Yishai, Israel)

with a 5-cm2 probe. The probe wasplaced at the middle of the 3 marksat each site. The temperature wasinitially set at 37C and increased1C/s to a maximum of 52C. Partic-

ipants indicated when they first feltpain (1/10) by pushing a button thatterminated the stimulus.

HTS. The HTS was measured with

a TSA II NeuroSensory Analyzer. Atonic heat stimulus of 45.5C was

applied for 20 seconds. After the first5 seconds of the heat stimulus appli-cation, participants rated pain every5 seconds for 15 seconds. A differ-ence between the pain rating (firstrating) at 5 seconds and the painrating at 15 seconds was used foranalysis. Thermal measures havegood test-retest reliability (ICC.77)

in people with knee OA.32

TUG. The TUG is a standardizedtest in which people arise from achair with no arm rest, ambulateapproximately 3 m (9.8 ft) as quicklyas possible, turn, ambulate back,turn, and return to sitting in thechair.34 Participants were timed in a

standardized fashion from themoment the upper back left thechair until return to the full sittingposition with the back in contact

with the chair. We previously used

the TUG in people with OA andfound a reduction in TUG walking

time, demonstrating the sensitivityof the TUG to a single joint mobili-zation treatment.35 The TUG hasgood reliability (ICC.92.99) inelderly populations34,36,37 and hasgood construct validity and signifi-cant correlations with gait speed(r.61.75), the Berg Balance Scale(r.81), and step length

(r.77).36,37

Test protocol. A time line of thetest protocol is shown in Figure 2.

All testing was performed with thesame equipment and by the sameexaminer. At the testing session,informed consent was obtained andsensory screening was done. If the

sensory examination results werenormal, testing began. First, partici-pants completed a demographicquestionnaire, and height and

Figure 2.Time line for the 3-hour testing session. CMPTcutaneous mechanical pain threshold, HFhigh frequency, HPTheat painthreshold, HTSheat temporal summation, LFlow frequency, PPTpressure pain threshold, TENStranscutaneous electrical nervestimulation, TUGTimed Up & Go Test, VASvisual analog scale.




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weight were recorded. Pain at restwas measured before pain sensitiv-ity. The order of the following mea-surements remained consistent forall participants: CMPT, PPT, HPT,and HTS. The testing order for each

of the 4 areas and 3 test sites wasrandomized to prevent an orderingeffect of testing. Participants thencompleted the TUG and rated theirmaximum pain during this test.

Once testing was completed, thedata collection examiner left theroom and the allocation examiner

allocated TENS. The allocation exam-iner stayed with the participant for20 minutes, at which time the data

collection examiner reentered andrepeated the testing as describedabove. The same blinded examinerobtained all outcome measurementsbefore and after TENS. Once the sec-ond testing session was completed,

the TENS allocation examinerreturned to remove the TENS unitand assess participant blinding.

Data AnalysisSample size calculations were made

with preliminary PPT data to com-pare HF-TENS and LF-TENS againstplacebo TENS. Pain thresholds are

commonly used in studies of animalsand people who are healthy.1,7,13,16,25

The study sample size of 25 partici-

pants per group was determined onthe basis of an expected PPT differ-ence of 100 kPa, a standard deviationof 110, a significance level of .05,and a power of .80. For the otheroutcome measures, the detectable

differences were at least 10 mm(out of 100 mm) on the VAS (SD0.9) and 1.4 seconds on the TUG(SD1.5). Therefore, the sample size

was powered to detect clinically sig-nificant differences in all variables,given that pain ratings and impair-ments are minimal in early OA.38

Mean and standard error of the meanwere calculated for all variablesbefore and after TENS and for the

Table 1.Demographic Characteristics of Study Participants and Outcome Measures Before Transcutaneous Electrical Nerve Stimulation(TENS)a

Variable High-Frequency TENS Low-Frequency TENS Placebo TENS P

Demographic characteristic

Age, XSEM 5711.8 5514.4 5710.9 .756

Men, n (%) 11 (44) 9 (36) 9 (36) .492

Women, n (%) 14 (56) 16 (64) 16 (64) .492

Body mass index, kg/m2, XSEM 33.67.7 36.26.0 39.27.0b .027

Pain on screening (010), XSEM 5.61.9 5.51.7 5.62.3 .95

Knee pain duration (mo), XSEM 108.8113 121.6141.2 83.586.4 .743

Analgesic medication use, no. (%) 18 (72) 20 (80) 18 (72) .757

Nonopioid 17 (68) 20 (80) 17 (68) .556

Opioid 4 (16) 4 (16) 3 (12) .900

Baseline ipsilateral outcome measures,

XSEM (95% CI)

Pain at rest (100-mm scale) 17.75.0 (7.428.0) 29.55.3 (18.640.5) 21.25.1 (10.831.7) . 251

P ai n duri ng T UG (100 -mm sca le) 24 .24.4 (15.233.3) 28.34.6 (18.837.9) 27.54.4 (18.436.5) . 792

TUG walking time (s) 12.10.81 (10.413.8) 14.71.66 (11.318.2) 13.41.0 (11.215.5) . 315

CMPT (g) 1,394111 (1,1651,623) 1,10513 1 (83 5 1,37 6) 1,0231 50 (71 31 ,33 3) .11 9

PPT of knee (kPa) 315.727.0 (259.9371.4) 247.820.2 (206.1289.6) 259.520.6 (217.0302.0) .087

PPT of tibialis anterior muscle (kPa) 349.537.9 (271.4427.7) 319.030.9 (255.2382.7) 319.430.1 (257.2381.5) .757

HPT of knee (C) 45.50.45 (44.546.4) 43.20.71b (41.744.6) 44.5.52 (43.545.6) . 020

HPT of tibialis anterior muscle (C) 46.30.52 (45.247.4) 45.40.67 (44.046.8) 45.5.57 (45.345.7) . 66

HTS (5 s) (100-mm scale) 24.74.7 (1434.4) 37.35.1 (26.848) 27.64.4 (18.636.7) . 15

HTS (10 s) (100-mm scale) 28.85.5 (17.540.1) 35.65.3 (24.746.5) 31.14.7 (21.640.8) . 64

HTS (15 s) (100-mm scale) 30.66.0 (18.342.9) 37.45.6 (25.949.0) 28.34.3 (19.337.2) . 46

a CIconfidence interval, TUGTimed Up & Go Test, CMPTcutaneous mechanical pain threshold, PPTpressure pain threshold, HPTheat painthreshold, HTSheat temporal summation.b Significantly different from values for other groups.




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difference score before and after

TENS within individual groups. Inaddition, 95% confidence intervals

were calculated for primary out-come measures. A linear mixed-model analysis for repeated mea-sures was used to compare mean

changes among treatment groups(HF-TENS, LF-TENS, placebo TENS)in the outcome measures for the

site (knee, tibialis anterior muscle),side (affected, contralateral), andtime (before, after) (within-subjectseffects). The model included base-line values and body mass indexesas covariates because body massindexes differed between groups(Tab. 1). For specific comparisonsof interest, a test of mean contrasts

based on the fitted method wasperformed. To account for the mul-tiple tests performed in relation toa specific hypothesis, P values

were adjusted with the Bonferronimethod. The Kruskal-Wallis test wasused to detect differences in non-parametric data.

Role of the Funding SourceThis study was supported by theNational Institutes of Health (R03-

NR010405), a Marsha and Ralph

Congdon Faculty Development Fel-lowship in Acute Care for the Chron-ically Ill, and The University of IowaCarver College of Medicine.

Results

Table 1 shows the demographicinformation for all treatment groupsas well as the baseline values foreach measure. There were no signif-icant differences between groups in

demographic characteristics, withthe exception of body mass indexes(P.027). Therefore, body massindexes were controlled for in theanalyses. All baseline measures weresimilar between groups, with theexception of HPT (P.02). Baseline

measures were also controlled for inthe analyses. Eleven participants

(15%) were taking opioid medica-tions for pain control, and 54 (72%)

were taking nonopioid medications.There were no significant differ-ences between groups in the num-bers of participants taking analgesicmedications (Tab. 1).

TENS Amplitude and BlindingThe pulse amplitudes required toachieve the desired TENS treatmentintensities were similar betweengroups; the mean amplitudes were27.4 mA (SD1.70) for HF-TENS,24.1 mA (SD1.8) for LF-TENS, and

24.5 mA (SD1.6) for placebo TENS.Of the participants receiving placeboTENS, 57% correctly identified the

treatment as a placebo, whereas 43%believed that they received the activetreatment. Participants receivingactive TENS correctly identified thetreatment as active 92% of the time.

Pain SensitivityHigh-frequency TENS increased PPTat the affected knee (P.002) and

over the anterior tibialis muscle ofthe affected leg (P.0001) com-pared with pre-TENS values (Tab. 2,Fig. 3). Low-frequency TENS signifi-cantly increased PPT at the ipsilateralknee only (P.05). Placebo TENSdid not significantly change PPT(Fig. 3). Pairwise comparisons of thetreatment groups revealed a signifi-

cant difference in the mean changesin PPT between HF-TENS and pla-cebo TENS (P.026); there was no

Table 2.Primary and Secondary Measures Expressed as Difference Scoresa

Variable

Difference Score, XSEM (95% Confidence Interval)

High-Frequency TENS Low-Frequency TENS Placebo TENS

PPT of knee (kPa) 65.8117.05b (30. 6 t o 101.0) 51. 5020.65b (8.9 to 94.1) 22.613.66 (5.6 to 50.8)

PPT of tibialis anterior muscle (kPa) 82.1418.90b (43. 1 t o 121.1) 44. 2015.50 (12.2 to 76.2) 20.6716.27 (12.9 to 54.2)

TUG walking time (s) 0.40.29 (0.13 to 1.06) 0.720.46 (0.23 to 1.66) 0.520.36 (0.22 to 1.23)

Pain at rest (0100 mm) 10.324.00 (2.05 to 18.59) 16. 145.23 (5.34 to 26.94) 16.844.81 (6.09 to 26.78)

Pain during TUG (0100 mm) 9.442.56 (4.15 to 14.73) 8.703.93 (0.58 to 16.82) 14.183.55 (6.86 to 21.50)

CMPT of knee (g) 15395 (18 to 324) 25983 (87 to 431) 1983 (152 to 191)

CMPT of tibialis anterior muscle (g) 271101 (68 to 479) 14466 (7.8 to 280) 2487 (204 to 156)

HPT of knee (C) 0.060.36 (0.68 to 0.8) 1.30.55 (0.18 to 2.4) 0.20.28 (0.78 to 0.38)

HPT of tibialis anterior muscle (C) 0.50.34 (0.2 to 1.2) 0.090.36 (0.65 to 0.83) 0.080.46 (0.87 to 1.0)

HTS of knee (100-mm scale) 1.31.6 (4.5 to 1.9) 0.30.36 (2.3 to 2.9) 3.92.3 (8.7 to 0.89)

HTS of tibialis anterior muscle

(100-mm scale)

1.11.9 (4.8 to 2.6) 0.81.0 (2.9 to 1.3) 0.081.2 (2.4 to 2.6)

a TENStranscutaneous electrical nerve stimulation, PPTpressure pain threshold, TUGTimed Up & Go Test, CMPTcutaneous mechanical painthreshold, HPTheat pain threshold, HTSheat temporal summation.b Significantly different from placebo value.




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significant difference betweenLF-TENS and placebo TENS orbetween LF-TENS and HF-TENS.

Baseline CMPT, HPT, and HTS values

for each group before TENS areshown in Table 1. The HPT, CMPT,and HTS values were unchangedafter all treatments, and there wereno significant differences betweengroups (Tab. 2).

Pain at RestPain at rest decreased significantly inall 3 groups (P.001, P.01, and

P.0001 for HF-TENS, LF-TENS, andplacebo TENS, respectively). How-ever, there were no significant differ-

ences between groups (Tab. 2,Fig. 4).

Function (TUG) and Pain DuringFunctionPain during the TUG decreased sig-

nificantly in all 3 groups (P.001,P.03, and P.001 for HF-TENS,LF-TENS, and placebo TENS, respec-tively). However, there were no sig-nificant differences between groups(Tab. 2, Fig. 5). The time to perform

the TUG did not change significantlyin any of the groups, and there wereno significant differences between

groups (Tab. 3).

DiscussionThe present study showed anincrease in PPT at the knee joint withHF-TENS and LF-TENS and over thetibialis anterior muscle withHF-TENS relative to the resultsobtained with placebo TENS; pla-

cebo TENS had no significant effecton PPT. However, subjective pain atrest and during the TUG decreasedequally with all 3 treatments. No dif-ferences were observed for CMPT,HPT, HTS, or function. These datashow that TENS is effective for deep-tissue pain sensitivity induced byOA. They further show that a single

treatment of TENS has minimaleffects on pain and function relativeto the effects of placebo TENS.

Figure 3.Differences between pressure pain threshold (PPT) before transcutaneous electricalnerve stimulation (TENS) and PPT after TENS for both the knee and the tibialis anteriormuscle both ipsilaterally and contralaterally. Data are expressed as the mean andstandard error of the mean. *significantly different from baseline, significantlydifferent from placebo. HFhigh-frequency TENS, LFlow-frequency TENS, PplaceboTENS.

Figure 4.Difference scores for pain at rest in ipsilateral and contralateral knees during transcu-taneous electrical nerve stimulation (TENS). Significant decreases were observed ipsi-laterally for all 3 groups (placebo TENS [P], low-frequency TENS [LF], and high-

frequency TENS [HF]). Data are expressed as the mean and standard error of the mean.*significantly different from baseline.




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HF-TENS and LF-TENS ReduceDeep-Tissue Pain SensitivityThe present study showed thatHF-TENS and LF-TENS increase PPTat the site of injury; we interpret thisfinding as a reduction in primary

hyperalgesia. Changes in primaryhyperalgesia measures suggestchanges in nociceptor sensitivity39

and parallel changes that we previ-

ously observed in animal studies.25

The present study also showed thatHF-TENS increases PPT over the tib-ialis anterior muscle, an area outsidethe site of injury; we interpret thisfinding as a reduction in secondary

hyperalgesia. Changes in secondary

hyperalgesia measures suggestchanges in central neuron excitabil-ity39 and parallel changes that wepreviously observed in animal stud-ies.19 The increases in PPT are similar

to increases in PPT during activeTENS in healthy controls16,13,14 andin arthritic animal models examininghyperalgesia immediately after TENS

with the same parameters.16,20,24

Transcutaneous electrical nervestimulation reduces the excitabilityof nociceptive neurons in the centralnervous system in arthritic animals,40

and higher intensities produce

greater reductions in excitability.41

Therefore, changes in PPT withTENS are likely mediated by reducedcentral neuron excitability. The pres-ent study is the first to show the

effects of TENS on hyperalgesia inpeople with OA; these effects mayserve as a useful measure of neuronexcitability. The PPT correlates withmovement-evoked pain (Sluka KA,Rakel BA, et al, unpublished observa-tions); both are evoked pain stimuli.Furthermore, palpation tenderness isan essential part of the physicalexamination of patients; PPT mea-

sures may offer clinicians animproved objective measure oftenderness.

The reason for the lack of changes inCMPT, HPT, or HTS may have beenthe fact that these measures are cuta-neous stimuli and are not sensitizedby knee OA. A previous study of OA

showed greater enhanced temporalsummation to pressure in people

with more pain.42 However, a recentstudy showed enhanced HTS in peo-ple with OA.43 Alternatively, TENSmay have minimal effects on cutane-

ous heat pain but be more effectivefor deep-tissue pain. In support ofthis notion, we found no change in

HPT with TENS in people who werehealthy44 but significant reductionsin PPT and temporal summation tomechanical stimulation of muscle.13

Together, these data support theidea that TENS is more effective inreducing deep-tissue hyperalgesia.

Effects of TENS on Pain and

FunctionWe previously showed that activeTENS reduced movement-evokedpostoperative pain relative to theresults obtained with placeboTENS.12 Surprisingly, the presentstudy showed equivalent reductionsin pain during the TUG with bothactive TENS and placebo TENS but

no changes in function. The reasonfor the lack of difference betweenactive TENS and placebo TENS may

Figure 5.

Difference scores for movement-evoked pain during the Timed Up & Go Test (TUG)in ipsilateral and contralateral knees during transcutaneous electrical nerve stimulation(TENS). Significant decreases were observed ipsilaterally for all 3 groups (placebo TENS[P], low-frequency TENS [LF], and high-frequency TENS [HF]). Data are expressed as themean and standard error of the mean. *significantly different from baseline.

Table 3Timed Up & Go Test (TUG) Walking Times Before and During TranscutaneousElectrical Nerve Stimulation (TENS)a

Group

TUG Walking Time, s (XSEM)

Baseline

During

TENS Difference

Placebo TENS 13.41.0 12.90.98 0.520.36

Low-frequency TENS 14.71.6 14.01.4 0.720.46

High-frequency TENS 12.10.8 11.60.83 0.470.29

a There were no differences among TENS groups.




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be the fact that the TUG minimallyincreased pain above that at rest(10 mm/100 mm), suggesting thatthe TUG did not produce enoughpain in our participants to evaluate

movement-evoked pain. In contrastto the present study, which involveda single visit, 2 weeks of active TENSreduced TUG walking times in peo-ple with symptomatic knee OA rela-tive to the results obtained with pla-cebo TENS.45We previously showeddecreases in TUG walking times inpeople with OA after a single jointmobilization,35 demonstrating the

capacity of a single treatment tomodify TUG walking times. It is pos-sible that the difference between

studies with improvements in theTUG and the present study is relatedto the severity of functional limita-tions. For instance, in earlier OAstudies showing a positive effect onthe TUG, the times were 20 to 24

seconds,35,45,46 whereas the times inthe present study were 12 to 14 sec-onds, close to normal (10 sec-onds).34 Therefore, for less severesymptomatic OA, the TUG may notbe an appropriate measure for exam-

ining movement-evoked pain andfunction. Future studies should use afunction test that produces greater

pain, such as stair climbing.

We previously showed no significanteffect of TENS on pain at rest (VAS)relative to the effect of placebo TENSafter abdominal surgery.47 In thepresent study, both placebo TENSand active TENS reduced ratings ofpain at rest by 10 to 18 mm out of

100 mm. These changes are minimaland not clinically important whenpeople have pain ratings below 50 of100 mm on the VAS38; pain ratings inour participants averaged between24 and 28 mm. Therefore, the effectson pain at rest may depend on thepain intensity.

Earlier work showed that high dosesof caffeine can reduce analgesiaproduced by TENS.48 In the present

study, we did not control for caf-feine; therefore, caffeine may haveinfluenced our results. However,our earlier studies of people who

were healthy did not control for caf-

feine and showed positive effectsof active TENS relative to placeboTENS,13,14,22,49 and we showedeffects on PPT in the present study.Opioid intake also may influenceresults; people and animals who aretolerant of opioids showed reducedeffects of LF-TENS but notHF-TENS.23,50 However, the majorityof our participants (85%) were not

taking opioid analgesics, and thenumbers of participants taking opi-oid analgesics were similar between

groups. Additionally, participants didnot take analgesic medications for 4hours before testing to eliminate theeffect of analgesia on the test results.

Intensity Is Critical for TENSEffectivenessEarlier studies of people with OAincluded in the 2009 Cochranereview9 supported the need for high-intensity TENS. Intensities in theincluded studies varied widely.9

High-frequency TENS was given at astrong but comfortable intensity in 7trials,45,46,5155 at sensory threshold

or below in 5 trials,5660 at a noxiouslevel in 1 trial,61 and at an unre-ported intensity in 2 trials.62,63 Low-frequency TENS was applied at amotor intensity in 3 studies6466 anda strong sensory intensity in 1study.45 Trials that reported effectiveTENS generally used higher intensi-ties than those that reported no

effect. In the present study, TENSwas applied at 90% of the motorthreshold, a strong sensory intensity.In recent studies, higher intensitiesof TENS were shown to be moreeffective in reducing pain.1215,22,67

The intensity of stimulation was pos-itively correlated with the change inPPT produced by TENS.13,14 Another

variable that may have influencedour results is the fact that we did notcontinuously adjust the stimulation

over time, as is common in clinicalpractice. Titrating TENS intensityupward during treatment increasedhypoalgesia in healthy controls.67

Finally, LF-TENS may not have beenas effective because we used a lowerpulse duration and a lower intensitythan are commonly used clinically(ie, motor intensity).45,6466 The totalcurrent applied with HF-TENS isgreater than that applied withLF-TENS when the same intensityand pulse duration are used.

Although LF-TENS is traditionally

delivered at motor intensities, ourearlier work showed that LF-TENS ata strong sensory intensity produced

effects equivalent to those obtainedwith HF-TENS at a strong sensoryintensity.16,25 We also showedopioid-mediated analgesia at sensoryintensities with both LF-TENS andHF-TENS.17,20 Therefore, the present

study focused on the effect of fre-quency delivered at a strong sensoryintensity for both HF-TENS andLF-TENS.

Blinding of Active and Placebo

TENSThe present study is the first to vali-date and test the new transient pla-

cebo TENS unit in a group of peoplewith pain. We were able to ade-quately blind the participants receiv-ing placebo TENS, with 57% cor-rectly identifying the placebo; this

value was not significantly differentfrom chance (50:50). If blinding hadbeen ineffective, we would haveexpected the percentage correctly

identifying the placebo to be closerto 100%, like the value obtained forthe active TENS unit. The new pla-cebo TENS unit can completely blindthe experimenter applying TENS,and we previously showed the com-plete inability of the examiner tocorrectly identify active TENS orplacebo TENS.13,14,22Adequate blind-

ing is important because earlierTENS studies used separate instruc-tions for active TENS and placebo




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TENS, and doing so can influencethe expectations of patients andhave a profound effect on treatmentoutcomes.6872 For example, semi-nal work by Levine and Gordon68

revealed significant analgesia with aplacebo drug given in a completelyblinded manner; the placebo pro-duced analgesia equivalent to that oflow-dose morphine. On the otherhand, negative or neutral instruc-tions resulted in less reduction inpain after spinal manipulation thanpositive instructions.72 By giving thesame instructions, we were able to

show that active TENS in peoplewith OA produced pain reductionsimilar to that produced by placebo

TENS, suggesting that TENS has astrong placebo effect on OA pain.

It is possible that the initial placeboeffect that occurs with a single treat-ment is reduced with repetitive

TENS. In support of this notion, 10days of electroacupuncture or 2

weeks of TENS in people with kneeOA resulted in significant improve-ments in pain and function.45,73 Fur-thermore, Marchand et al74 showed a

cumulative effect of active TENS butnot placebo TENS given twice per

week in people with chronic low

back pain. Therefore, future studiesshould examine the effects of repet-itive active TENS and transient pla-cebo TENS when the experimenterapplying TENS also is blinded withregard to group.

In the present study, participantswere able to correctly identify active

TENS 92% of the time. We previouslyreported similar responses to activeTENS in healthy controls.13 Despiteparticipants knowing that theyreceived active TENS, there was nodifference between active TENS andplacebo TENS in subjective pain rat-ing. Blinding of an electrical modal-ity such as TENS has always been

difficult, and few studies havereported blinding of active TENS.

Clinical ImplicationsIn summary, the present randomizedclinical trial examined the effects ofsingle treatments of HF-TENS andLF-TENS on knee OA pain and func-

tion. The use of various outcomemeasures, different frequencies, andan improved placebo providedinsight for the management of kneeOA pain with TENS. We pilot testeda series of outcome measuresdesigned to parallel and validate ani-mal models of TENS and to test theeffects of TENS in a true double-blindmanner. Using PPT as an objective

measure of pain sensitivity, weshowed that both HF-TENS andLF-TENS reduced primary hyperalge-

sia and that only HF-TENS reducedsecondary hyperalgesia in people

with OA. Quantitative sensory test-ing with cutaneous mechanical andheat pain measures was not affectedby HF-TENS, LF-TENS, or placebo

TENS, suggesting that TENS has noeffect on cutaneous hyperalgesia.

Alternatively, it is possible that theparticipants with OA did not havecutaneous mechanical and heathyperalgesia. All treatments had sim-

ilar but minimal effects on subjectivepain measures, suggesting a placebocomponent of the effect of TENS.

None of the treatments had an effecton TUG walking times. The TUGmay not be an appropriate functionaloutcome measure in people withearly symptomatic OA of the kneebecause increases in pain anddecreases in function are minimal.Future studies should expand out-come measures used in TENS studies

to include not only pain at rest, ascommonly assessed, but also painduring physical function tasks anddeep-tissue hyperalgesia measures.The effects of repetitive treatmentsand of higher intensities should betested in people with painful condi-tions to further elucidate the mosteffective use for TENS.

Dr Rakel, Dr Walsh, and Dr Sluka providedconcept/idea/research design. Ms Vance, DrRakel, Ms Blodgett, Dr Walsh, and Dr Slukaprovided writing. Ms Vance, Dr Rakel, MsBlodgett, Dr DeSantana, and Dr Sluka pro-vided data collection. Ms Vance, Dr Rakel, Dr

Amendola, and Dr Sluka provided data anal-ysis. Ms Vance, Dr Rakel, and Ms Blodgettprovided project management. Dr Rakel andDr Sluka provided fund procurement andfacilities/equipment. Dr Amendola providedstudy participants. Ms Vance, Dr Rakel, andMs Blodgett provided clerical support. MsVance, Dr Rakel, Ms Blodgett, Dr DeSantana,Dr Amendola, Dr Walsh and Dr Sluka pro-vided consultation (including review of man-uscript before submission).

The authors thank Shannon Lehman, whoserved as the TENS effectiveness coordina-tor, for assistance with the study. The TENSunits and supplies used in the study weredonated by DJO Inc.

This study was approved by the Human Sub-jects Institutional Review Board at The Uni-versity of Iowa.

This study was supported by the NationalInstitutes of Health (R03-NR010405), a Mar-sha and Ralph Congdon Faculty Develop-ment Fellowship in Acute Care for theChronically Ill, and The University of IowaCarver College of Medicine.

This trial is registered at ClinTrials.gov:NCT01354054.

DOI: 10.2522/ptj.20110183

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doi: 10.2522/ptj.20110183Originally published online March 30, 2012

2012; 92:898-910.PHYS THER.and Kathleen A. SlukaAmendola, Miriam Bridget Zimmerman, Deirdre M. WalshBlodgett, Josimari Melo DeSantana, AnnunziatoCarol Grace T. Vance, Barbara A. Rakel, Nicole P.Controlled TrialPeople With Knee Osteoarthritis: A Randomized

inStimulation on Pain, Pain Sensitivity, and FunctionEffects of Transcutaneous Electrical Nerve

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