Neurourology and Urodynamics 28:58–61 (2009)

Validation of a Sham for Percutaneous Tibial NerveStimulation (PTNS)

Kenneth Peters,1,2 Donna Carrico,1,2* and Frank Burks1,2

1Beaumont Hospital, Department of Urology, Royal Oak, Michigan2Ministrelli Program for Urology Research and Education (MPURE), Beaumont Hospital, Royal Oak, Michigan

Aim: Percutaneous tibial nerve stimulation (PTNS) supposedly demonstrates 50–60% improvement in OABsymptoms with no sham-controlled trials reported. This study determined the efficacy of a sham for PTNS.Methods: Thirty healthy volunteers (15 women; 15 men) in this blinded pilot study were randomized into two equalgroups: one group had PTNS on the right and sham on the left; the other group had PTNS on the left and sham onthe right. A drape obscured their lower extremities. The sham utilized a placebo needle placed at the PTNS sitealong with a transcutaneous electrical nerve stimulator (TENS) pad on the ipsilateral foot. The unit was activateduntil stimulation was felt. PTNS was performed on the opposite leg, with the grounding pad mimicking the shampad placement. PTNS stimulation was given until the subject felt stimulation in the foot. Subjects had1 simultaneous 15 min testing of the PTNS vs. sham. Subjects then completed a questionnaire stating which legthey thought had the sham and PTNS (or ‘‘unknown’’). The primary endpoint of the study was the ability toaccurately identify the sham. Results: In total, 10/30 (33%) of the shams were identified correctly. We wouldexpect 50% to be identified by guessing, but only 33% were correctly identified. Females identified the shamcorrectly more often than males (40% vs. 27%). This procedure was validated as a feasible sham for PTNS.Conclusions: This is the first validation of a sham for PTNS that may be used in future placebo-controlledresearch. Neurourol. Urodynam. 28:58–61, 2009. � 2008 Wiley-Liss, Inc.

Key words: electrical stimulation; overactive bladder; placebos; sham; tibial nerve

INTRODUCTION

Neuromodulation of the sacral, pudendal and posteriortibial nerves continues to be investigated in relation tooveractive bladder (OAB) and voiding dysfunction. In October2000, the FDA approved the use of percutaneous tibial nervestimulation (PTNS) without any randomized clinical trialsto evaluate placebo effect.1 However, most drug or devicestudies investigating voiding dysfunction have a large placeboeffect.2–4 Thus, a scientific and clinical need to test PTNS in acontrolled clinical trial against a realistic sham treatment wasidentified. We conducted a randomized, blinded control studytesting a proposed realistic sham against PTNS on healthysubjects.

The first use of suprapubic transcutaneous electrical nervestimulation (TENS) was reported by Fall et al.5 Two carbonrubber electrodes were positioned suprapubically 10–15 cmapart and stimulation was given up to 2 hr twice a day at theintensity tolerated by the patient. In 1981 sacral nervestimulation (SNS) in humans was first investigated to treaturgency, frequency and incontinence. A wire electrode wassurgically placed in the sacral foramen, usually S3, andconnected to an external stimulator. If symptoms improved,a second surgical procedure was carried out to implant apermanent stimulator.6

McGuire et al.7 published a report using an adhesiveelectrode to do transcutaneous tibial nerve stimulation(TNS). They evaluated 22 patients—11 with detrusor insta-bility, 5 with interstitial cystitis (IC), 1 with radiation cystitisand 5 with neurogenic bladder related to spinal cord injury. Allbut two patients showed improvement and the device waswell tolerated. The posterior tibial nerve contains mixedsensory-motor nerve fibers that originate from L4 through S3

and modulate the innervation to the bladder, urinarysphincter and pelvic floor. The specific mechanism of actionof neuromodulation is unclear, although the most likelymechanisms involve improved blood flow and change inneurochemical balance along the neurons.8 In PTNS, the areacalled ‘‘sanyinjiao’’ or ‘‘spleen-6’’ (SP-6) acupuncture pointoverlies the posterior tibial nerve. Stimulation of this pointhas shown improvement in urinary symptoms.9

In 1987, Stoller adjusted this technique by using apercutaneous needle electrode and placing a ground electrodeon the ipsilateral extremity. This device, the Stoller AfferentNerve Stimulator (SANS), stimulates the posterior tibial nervewith a 34-gauge needle placed bilaterally at SP-6. Stollerused weekly session of PTNS for 10–12 weeks, then decreasedsessions to every 3–4 weeks, then every 4–6 weeks as longas symptoms were controlled. If sessions were stoppedfor a period of time, the symptoms relapsed.8 Since Stoller,several publications reported promising early results regard-ing urgency, frequency, urge incontinence, and pelvic painreduction.10–17

MATERIALS AND METHODS

We conducted a randomized, blinded control IRB-approvedstudy testing a proposed realistic sham against PTNS on

No conflict of interest reported by the author(s).Chris Winters led the review process.Grant sponsor: Ministrelli Program for Urology Research and Education (MPURE).*Correspondence to: Donna Carrico, NP, MS, William Beaumont Hospital, 3535 W.13 Mile Road Suite 438, Royal Oak, MI 48073. E-mail: dcarrico@beaumont.eduReceived 26 November 2007; Accepted 11 February 2008Published online 31 July 2008 in Wiley InterScience(www.interscience.wiley.com)DOI 10.1002/nau.20585

� 2008 Wiley-Liss, Inc.

30 healthy subjects. The objective of this study was todetermine the efficacy of a sham for percutaneous tibial nervestimulation (PTNS). A convenience sample of 15 women and15 men, were randomized as to which intervention theyreceived on the right and left ankle and foot. No one had animplanted neuromodulation device.

The hypotheses tested was that subjects would not beable to discern a difference between the PTNS stimulationand sham stimulation, that is, that the proportion correctlyidentifying the sham will not be more than 75%. Ourunderlying assumptions of this pilot study were that guessingalone will allow subjects to identify the sham with a 50%probability with an alpha ¼ 0.05 (probability of type I error)and beta ¼ 0.2 (probability of type II error) yielding 80%power. We assumed that a success rate of 75% of guessingPTNS correctly would be significant. The primary endpointwas the number of subjects correctly identifying the shamversus PTNS stimulation.

The subjects had one session of simultaneous testing of thePTNS versus sham (interventions were randomized to side—right or left) that included 15 min of stimulation as notedbelow. The subjects’ legs and feet were draped to keep thesubject blinded and we simulated placement of a needle at thestandard tibial nerve site using a validated Streitbergerplacebo needle.18 This two-piece needle comprised of a needlehandle and blunt-tip shaft and causes the sensation of a slightprick when touched to the skin. However the shaft retracts asit appears to enter the skin and no puncturing takes place. TheStreitberger needle specifically activates the dorsolateralprefrontal cortex which is associated with the placebo effect,19

in contrast to the ipsilateral insula activated with anacupuncture needle.20 Next, instead of the inactive groundingpad used on the PTNS leg, the sham had an active adhesive padplaced on the bottom of the foot just below the smallest toe.This spot was chosen since it is not part of the acupressure oracupuncture nerve pathway connected to the bladder, pelvisor any major organs (Fig. 1).

Electrical current was delivered to this pad via a TENS unitso all subjects felt some stimulation. Our pre-testing of fivepeople with this sham compared with PTNS found thatthis was a realistic sham based on the responses of the testsubjects. All subjects felt some stimulation in their foot witheither method. All therapies were implemented by a NursePractitioner (NP), experienced in PTNS.

PTNS Intervention

Subjects were blinded, with their legs and feet draped. Theywere in a supine position with the knees abducted and flexed.The medial aspect of the lower extremity was palpated anda needle insertion site was identified approximately 5 cmcephalad from the medial malleolus. Between the posteriormargin of the tibia and the soleus muscle, a 34-gauge

acupuncture-like needle (Urgent1 PC catalog #250-12) wasinserted approximately 3–4 cm deep to the tibial nerve (Fig. 2).An adhesive grounding pad was placed on the bottom of thefoot just below the smallest toe. An inactive adhesivegrounding pad was placed on the top of the foot just abovethe small toe to be consistent with the sham pad placement.The needle and grounding pad were connected to thestimulator and the stimulation was increased from 0 to10 mA as tolerated. Flexion of the greater toe and sensorystimulation in the bottom of the foot confirmed proper needleplacement. The needle was taped in place. The electricalcurrent was set at an intensity that was well tolerated by thesubject and the mA recorded on the case report form. A 15 minstimulation session was given at 20 Hz. At the end of theprocedure, the needle and grounding pad were removed anddiscarded.

Sham Intervention

Since subjects with PTNS will feel foot stimulation, thesham was devised to mimic this feeling without the tibialnerve being stimulated. The leg and foot were draped andout of view from the subject. The medial aspect of thelower extremity was palpated and the tibial nerve site wasidentified approximately 5 cm cephalad from the medialmalleolus. A Streitberger needle was used at the tibial nerveinsertion site (Fig. 3) as described above to simulate needleplacement without puncturing the skin. The needle was tapedin place as in the PTNS procedure. The ‘‘grounding pad’’ was agel electrode pad from a TENS unit device that was placed on

Neurourology and Urodynamics DOI 10.1002/nau

Fig. 1. Detailed reflexology chart.

Fig. 2. PTNS.

Sham Validation for Tibial Nerve Stimulation 59

the bottom of the foot just below the smallest toe. Another gelelectrode was placed on the top of the foot just above the smalltoe for conduction. Care was taken to avoid reflexology areasfor major organs as the electrode pads were placed (Fig. 1). TheTENS electrode was connected by lead wires to the Biostim1

M7 TENS unit set at 20 Hz (as in PTNS). The TENS unit wasturned on and stimulation was slowly increased to thesubject’s first sensory level. Once the subject sensed localizedstimulation in the bottom of the foot or toe, the TENS unit wasleft on for the 15 min test period. Then the TENS unit wasremoved.

At the end of the test session, subjects were asked to completea questionnaire about the location of the sensation, the type ofsensation felt during the test, and to identify which leg had thesham and which one had the PTNS or to state it is unknown.

RESULTS

The demographics of this convenience sample of thirtysubjects are listed (Table I). The majority of this populationhad at least some college and more than half of the group hada post-graduate education.

The data analysis was carried out with SAS1 9.1.3, Cary,NC. We examined the data to see if subjects were able topositively identify the sham. The one-sided exact binomialP value is <0.0001 with a 95% CI being (0.17 to 0.53). This wastesting for HO ¼ 0.75. This tells us that the true proportion ofcorrect tests is <75%.

There were 14 shams total on the right of which 4/14 (29%)were correctly identified. There were 16 shams total on the leftof which 6/16 (37.5%) were correctly identified. In total, 10/30(33%) of the shams were identified correctly. We would expect50% to be identified simply by guessing and proposed that up to75% correct identification would be acceptable. With only 33%being correctly identified, the conclusion from this preliminarystudy is that subjects are unable to identify whether they are

receiving a sham or the PTNS and therefore, the developedprotocol provides a reasonable sham for this proposed study.

We examined females and males separately to see if onegroup was able to identify the sham more often. Althoughfemales tended to identify the sham correctly more often thanmales (40% vs. 27%) this is still below the expected 50% andwell below the acceptable 75% identification rate.

DISCUSSION

The literature suggests that PTNS may be a useful treatmenttool for urinary frequency, urgency, and pain. However,randomized sham-controlled studies were not done. Althoughsome may wonder if this sham will inadvertently stimulateother acupuncture meridians that converge at SP-6 (spleen, liver,kidneys), our research found that none of these meridians travelto the area of the small toe on the foot. It is highly unlikely thatthe placement of the TENS pads in the sham is producingstimulation of SP-6. This sham has proven to be an effectivesham for PTNS, allowing researchers to now study PTNS insham-controlled trials. One limitation of our sample was itshomogeneity. This study could be duplicated in a more diversepopulation to verify our results. Interestingly, half of the menwere physicians, yet only 27% of the men identified the shamcorrectly (only 1 of these was a physician). This supports theeffectiveness of the sham, even in those familiar with needlesand health related equipment. Additional information is stillneeded to assess the effectiveness of the procedure and theoptimal treatment technique in terms of length and frequencyof treatment. PTNS, if proven effective, could improve thequality of life of over 1 million people in the United States aloneaffected by bladder symptoms of urgency, frequency, and pain.The cost savings could be significant (>$10,000 per person) ifPTNS is as effective as sacral nerve stimulation for reduction ofbladder symptoms. Currently, the cost of PTNS is approximately$1,800 for 12 sessions and the cost of Interstim1 sacral nervestimulation is more than $15,000 in the midwestern UnitedStates. In addition, surgeries, emergency room and office visitscould be reduced, resulting in tremendous cost savings for thehealth care system and the client. A future cost analysis studycomparing current surgeries and treatments for interstitialcystitis/painful bladder syndrome and OAB versus PTNS wouldbe beneficial.

CONCLUSIONS

The proposed sham was demonstrated to be an effectivesham for PTNS. Further research is needed testing PTNSagainst a sham in order to discern the true efficacy of thistreatment for voiding dysfunction.

ACKNOWLEDGMENTS

We would like to thank Judy Boura MS for her assistancewith the data analysis. This study was supported by the

Neurourology and Urodynamics DOI 10.1002/nau

Fig. 3. Sham.

TABLE I. Demographics of Study Population

Demographics Males, N ¼ 15Females,

N ¼ 15 P-value

Age 34 � 10 (30) 43 � 9 (44) 0.012

Height (inches) 71 � 2.6 (70) 64 � 2.5 (64) 0.0003

Weight (lbs) 187 � 30 (175) 155 � 33 (145) 0.013

Race

White, not Hispanic 12 (85.7%) 15 (100%) 0.22

Asian 1 (7.1%) 0

Other 2 (14.2%) 0

Education

High School 1 (6.7%) 1 (6.7%) 0.0018

Some College 0 5 (33.3%)

Bachelor’s Degree 2 (13.3%) 5 (33.3%)

Post-graduate (non-MD) 4 (26.7%) 4 (26.7%)

MD 8 (53.3%) 0

60 Peters et al.

Ministrelli Program for Urology Research and Education(MPURE). This is an internal fund made possible by a privatedonor to our Urology Department.

AUTHOR DISCLOSURES

K. Peters is a consultant for Medtronic and AdvancedBionics as well as speaker honorarium for Allergan and trialparticipant for Advanced Bionics, Uroplasty and Pfizer.

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