- Email: [email protected]
Electrical Stimulation of Somatic Afferent Nerves in the Foot Increases Bladder Capacity in Healthy Human Subjects
Electrical Stimulation of Somatic Afferent Nerves in the Foot Increases Bladder Capacity in Healthy Human Subjects Mang L. Chen, Christopher J. Chermansky, Bing Shen, James R. Roppolo, William C. de Groat and Changfeng Tai* From the Departments of Urology (MLC, CJC, BS), and Pharmacology and Chemical Biology (JRR, WCdG), University of Pittsburgh (CT), Pittsburgh, Pennsylvania
Purpose: We determined whether electrical stimulation of somatic afferent nerves in the foot could delay bladder filling sensations and increase bladder capacity in healthy humans without overactive bladder. Materials and Methods: Eight subjects underwent 90-minute foot stimulation using skin surface electrodes connected to a transcutaneous electrical nerve stimulator. The electrodes were attached to the bottom of the foot. Subjects completed a 3-day voiding diary, during which foot stimulation was applied on day 2. Stimulation parameters were pulse frequency 5 Hz, rectangular waveform pulse width 0.2 milliseconds and intensity 2 to 6 times the minimal stimulation current necessary to induce toe twitch. Stimulation intensity was set by each subject to a maximal level without causing discomfort. Subjects were provided with 500 to 1,000 ml of water to drink during stimulation. Results: Average SE volume per void was 350 22 ml during the 24 hours before foot stimulation. This voided volume increased to a mean of 547 52 ml for up to 5 hours after stimulation (p <0.01). Average voided volume returned to 363 21 ml within 36 hours after stimulation. There were no adverse events. Conclusions: Foot stimulation can delay bladder filling sensations and significantly increase bladder capacity in healthy humans without overactive bladder. Although the study group was small, our results support moving forward with clinical trials of foot neuromodulation in patients with overactive bladder.
Abbreviations and Acronyms OAB ¼ overactive bladder T ¼ stimulation intensity threshold Accepted for publication October 3, 2013. Study received University of Pittsburgh institutional review board approval. * Correspondence: Department of Urology, University of Pittsburgh, 700 Kaufmann Building, Pittsburgh, Pennsylvania 15213 (telephone: 412-692-4142; FAX: 412-692-4380; e-mail: cftai@ pitt.edu).
Key Words: urinary bladder; neurons, afferent; electrical stimulation; foot; urination
OVERACTIVE bladder is a syndrome characterized by urinary urgency with or without urge incontinence, often with frequency and nocturia.1 Patients with OAB have significantly impaired quality of life.2 First line therapy involves behavioral treatments such as fluid management, pelvic floor muscle physical therapy and bladder training.3 Pharmacotherapy is offered concomitantly or subsequently if behavioral strategies
fail. Antimuscarinics are the most common drugs used for OAB.4 However, because drug therapy often has low efficacy and significant adverse effects, 70% of patients discontinue therapy within the first year of treatment.4 Food and Drug Administration approved treatment in patients in whom behavioral and antimuscarinic therapies fail include intradetrusor injection of onabotulinumtoxinA, or
0022-5347/14/1914-1009/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2013.10.024 Vol. 191, 1009-1013, April 2014 Printed in U.S.A.
www.jurology.com
j
1009
1010
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
sacral or tibial neuromodulation. OnabotulinumtoxinA requires repeat injections every 6 to 12 months and results in adverse events such as urinary tract infection and urinary retention.5,6 Sacral neuromodulation is invasive, requiring surgery to implant the electrodes and the neurostimulator.7 Furthermore, the costs associated with sacral neuromodulation limit this option to some patients with OAB. Tibial neuromodulation is a minimally invasive, office based procedure that involves inserting a needle electrode near the ankle to stimulate the tibial nerve. The tibial nerve is stimulated for 30 minutes each week for 12 consecutive weeks, followed by 1 stimulation per month to maintain efficacy.8 Although tibial neuromodulation is as efficacious as antimuscarinic drugs and has no major side effects,8 the inconvenience of frequent office visits can be prohibitive for elderly as well as employed patients. Thus, a noninvasive, convenient OAB treatment with no major adverse effects would be attractive to many patients. Our previous studies in cats demonstrated that transcutaneous electrical stimulation of somatic afferent nerves in the foot using skin surface electrodes could inhibit reflex micturition and significantly increase bladder capacity.9,10 Foot stimulation is noninvasive and can be performed conveniently at home without major adverse events. It could be an attractive treatment for a large number of patients with OAB if proved to be effective. However, to our knowledge the effect of foot stimulation on bladder sensation in human subjects is currently unknown. We determined whether foot stimulation could delay bladder filling sensations and increase bladder capacity in healthy humans without OAB.
MATERIALS AND METHODS This study was approved by the University of Pittsburgh institutional review board. Foot stimulation was tested in 5 males and 3 females 25 to 60 years old who were healthy and without OAB (see table). Subjects were instructed to Daytime volume per void before and after 90-minute foot stimulation Mean SE Vol/Void (ml) SubjectdSexdAge No. 1dMd46 2dMd49 3dFd41 4dMd40 5dMd25 6dFd48 7dMd47 8dFd60
24 Hrs Before 368 436 206 406 444 173 323 538
63 25 26 71 26 11 54 78
About 5 Hrs After (No. voids/hrs:mins) 667 755 200 577 600 195 530 800
106 33 0 15 25 15 80 0
(3/1:50) (3/2:50) (2/4:45) (3/5:00) (2)* (2/1:30) (2/2:10) (1/1:35)
* One 30 minutes into and another 10 minutes after stimulation.
About 36 Hrs After 465 388 175 469 368 238 263 581
69 18 28 55 30 19 26 74
Figure 1. Sites on right foot where 2 pad electrodes were placed to stimulate somatic afferent nerves of foot.
record daytime voided volumes during a 3-day period without restriction on daily food and water intake. They were also instructed to void in response to the usual bladder sensations and note any void that was withheld or induced early due to unexpected situations. Voiding volumes that resulted from unexpected situations were excluded from study. Foot stimulation was applied for 90 minutes in the morning (10:00 to 11:30 a.m.) on day 2 with the subject sitting. During stimulation the subject was asked to drink 1 to 2 bottles of water (500 to 1,000 ml) so that a void could occur soon after stimulation. Two skin surface electrodes (LGMedSupply, Cherry Hill, New Jersey) were attached to the bottom of the foot. A large cathodal electrode (2 3.5 inches) was placed on the front of the foot to cover as much skin area as possible and a small anodal electrode (2 2 inches) was placed between the inner foot arch and the heel (fig. 1). The electrodes were connected to an LG TEC EliteÔ transcutaneous electrical nerve stimulator, which provided constant current, rectangular pulses of 5 Hz frequency and 0.2 millisecond pulse width. The subject controlled the stimulator to determine the minimal current needed to induce a toe twitch. Stimulation intensity was then increased to the maximal level (25 to 60 mA) comfortable for the subject for the entire 90-minute stimulation, which ranged between 2 to 6 times the minimal intensity necessary to induce a toe twitch. Volume per void was averaged among subjects during 3 periods, including 1) 24 hours before foot stimulation, 2) up to 5 hours after stimulation and 3) up to 36 hours after stimulation. The second period always included the first void after stimulation. However, if voided volumes remained increased in the following 1 to 2 voids, they were also included in the second period (see table). Therefore, the second period was variable, ranging up to 5 hours (see table). The third time period included voids up to 36 hours after stimulation, excluding voids counted in the second time period. One-way ANOVA followed by the Dunnett multiple comparison was used to detect statistically significant differences (p <0.05) between voided volumes before and after stimulation.
RESULTS Average SE volume per void was 350 22 ml during the 24 hours before foot stimulation, which increased to 547 52 ml for up to 5 hours after stimulation (p <0.01, see table and fig. 2). Average
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
*
Bladder Volume/Void (mL)
600 500 400 300 200 100
) H ou rs 6 (~ 3 tim
Af te rS
tim rS Af te
Be
fo re
St im
(2
(~ 5
4
ho ur
ho ur s
s)
)
0
Figure 2. Mean bladder volume per void measured in 8 subjects during 24 hours before foot stimulation (Stim), and within 5 hours and during 36 hours after foot stimulation 90 minutes in duration at 5 Hz frequency, 0.2 millisecond pulse width and 25 to 60 mA intensity (2 to 6 times threshold intensity to induce toe twitch). Asterisk indicates significantly different vs voided volume before stimulation (p <0.01).
voided volume returned to 363 21 ml within 36 hours after stimulation. Volume per void remained increased for several hours after stimulation in 3 consecutive voids in subjects 1, 2 and 4, and after 2 consecutive voids in subjects 6 and 7 (see table). These subjects did not void during stimulation. However, subject 5 voided 625 ml 30 minutes into the stimulation period. He again voided 575 ml 10 minutes after completing the 90-minute stimulation (average 600 25 ml) (see table). Each voided volume was much larger than the mean voided volume of 444 26 ml before stimulation. The T needed to induce a toe twitch varied from 10 to 16 mA in the 8 subjects. The intensity used for the 90-minute stimulation session varied from 2T to 3T (24 to 36 mA) in 7 subjects. In subject 8 a stimulation intensity of 6T (60 mA) was used. All subjects tolerated stimulation without discomfort. There was no observable change in the toe twitch during stimulation and no immediate (ie local skin reaction) or long-term adverse events.
DISCUSSION This study demonstrates that transcutaneous electrical stimulation of somatic afferent nerves in the foot can delay bladder filling sensations and significantly increase bladder capacity more than 50% or
1011
by about an average of 200 ml in healthy humans without OAB (fig. 2). Our previous studies in cats showed that transcutaneous electrical stimulation of somatic afferent nerves in the foot inhibited reflex micturition and significantly increased bladder capacity.9,10 The current study suggests that the same mechanisms might occur in healthy humans and this technology has the potential to be an effective new treatment for patients with OAB. Since stimulation electrodes were placed on the skin surface rather than directly on nerves, it is difficult to know which nerves were activated. However, it is highly likely that foot stimulation activates afferent axons in the lateral and medial plantar nerves of the foot because the 2 skin surface electrodes were placed along the passage of these nerves (fig. 1). The tibial nerve runs from the inner ankle down to the bottom of the foot and branches into the lateral and medial plantar nerves at the location of the small electrode. These 2 nerves further branch into multiple small nerves that run toward the toes. The large electrode placed at the front of the foot allows for stimulation of these small nerve branches. Additional studies will help determine whether the current electrode positioning is most effective for activating the lateral and medial plantar nerves (fig. 1). Since all subjects were comfortable with the stimulation intensities used in this study, small Ad and C-fiber afferents that induce painful sensations were unlikely to be activated by stimulation. Consequently, transcutaneous foot stimulation must activate the large somatic afferent nerve fibers. In this study foot stimulation was applied acutely for 90 minutes rather than chronically during days or weeks. We chose a stimulation period of 90 minutes as a time convenient for subjects to sit and rest between 10 and 11:30 a.m. just before lunch. Despite this brief stimulation period average voided volume remained increased in 6 of 8 subjects up to 5 hours after stimulation, indicating that the inhibitory effect of foot stimulation persisted into the post-stimulation period. Post-stimulation inhibition was expected since foot stimulation activates the branches of the tibial nerve and tibial nerve stimulation elicits changes in bladder function that last for weeks.8 In addition, our previous study in cats showed that foot stimulation induced post-stimulation inhibition of reflex bladder activity lasting 1 to 2 hours.9 If this poststimulation effect occurs in future clinical trials, foot neuromodulation would not have to be applied continuously to treat OAB. Furthermore, subject 5 voided a larger volume after only 30 minutes of stimulation, indicating that 90 minutes of stimulation might not be needed to induce the inhibitory effect. Since this study included only a few subjects,
1012
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
results must be viewed as observational. More studies with larger subject numbers are required to determine the optimal stimulation duration/pattern and further elucidate the post-stimulation effect. In open label studies there is always the possibility of a placebo effect. However, this is unlikely in our study for several reasons. 1) Average voided volume increased more than 50% or about 200 ml (fig. 2). This large response is unlikely to have been mediated by a placebo effect alone.11 2) Placebo effects are less often observed in objective measurements such as blood pressure.12 Voided volume is also an objective measurement.13 3) Placebo effects usually last for weeks.14 We observed that average voided volumes returned to prestimulation levels 5 hours after stimulation. It would be difficult to design a placebo controlled study for foot stimulation since simply turning off stimulation would easily be recognized by the subject. In a previous study of tibial neuromodulation the placebo control was designed using a Streitberger 2-piece needle and an inactive skin electrode to simulate tibial neuromodulation procedures.15 Two small skin electrodes were also placed at the bottom and top of the foot close to the small toe to maximally avoid stimulating the tibial nerve while mimicking the foot sensation induced during tibial neuromodulation. However, the placebo control unexpectedly produced a significant inhibitory effect on bladder overactivity. Based on the results of our current study this specific placebo control for tibial neuromodulation may have possibly stimulated a small branch of the tibial nerve innervating the foot. Designing a placebo control for bladder neuromodulation currently remains challenging. Notably, subjects drank 500 to 1,000 ml of water during the 90-minute stimulation session to increase the bladder filling rate. Previous studies show that a fast, nonphysiological bladder filling
rate (50 to 100 ml per minute) during cystometry could significantly increase bladder capacity.16,17 However, the maximal urine excretion rate by the kidney after a large fluid intake is only about 15 ml per minute.16 In this study the mean voided volume after 90-minute stimulation was about 540 ml (fig. 2), indicating that the mean urine excretion rate must have been less than 6 ml per minute. Therefore, it is unlikely that the comparatively slow physiological bladder filling rate could have delayed the bladder filling sensation and caused a significant increase in bladder capacity. It is even more unlikely that such a large increase in capacity (more than 50% or about 200 ml) could have occurred due to physiological filling (fig. 2). Study subjects were instructed to note any void that was withheld or induced early due to unexpected situations. No subjects reported any situation when voiding was withheld. However, subject 6 intentionally initiated voiding early before night sleep on days 1 and 2, and produced small 75 ml voids. These small voids were excluded from data analysis.
CONCLUSIONS This study shows that foot stimulation delayed bladder filling sensations and increased bladder volume in healthy humans without OAB. Although only a few subjects were tested, our results support moving forward with clinical trials of foot stimulation in patients with OAB. If foot stimulation proves to be effective for treating OAB, it would provide several potential advantages over tibial neuromodulation therapy. Foot stimulation is noninvasive and can be performed safely at home. Thus, daily stimulation becomes possible with a potential benefit of higher efficacy than tibial neuromodulation, which is only performed once per month during maintenance therapy.
REFERENCES 1. Abrams P, Cardozo L, Fall M et al: The standardization of terminology of lower urinary tract function: report from the Standardization Subcommittee of the International Continence Society. Neurourol Urodyn 2002; 21: 167. 2. Girman CJ, Jacobsen SJ, Tsukamoto T et al: Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology 1998; 51: 428. 3. Gormley EA, Lightner DJ, Burgio KL et al: Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. J Urol, suppl., 2012; 188: 2455.
4. Chapple CR, Khullar V, Gabriel Z et al: The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008; 54: 543. 5. Mohee A, Khan A, Harris N et al: Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder. BJU Int 2013; 111: 106. 6. Nitti VW, Dmochowski R, Herschorn S et al: OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 2013; 189: 2186.
7. van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP et al: Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007; 178: 2029. 8. Peters KM, Macdiarmid SA, Wooldridge LS et al: Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol 2009; 182: 1055. 9. Chen G, Larson JA, Ogagan PD et al: Poststimulation inhibitory effect on reflex bladder activity induced by activation of somatic afferent nerves in the foot. J Urol 2012; 187: 338.
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
10. Tai C, Shen B, Chen M et al: Suppression of bladder overactivity by activation of somatic afferent nerves in the foot. BJU Int 2011; 107: 303. 11. Hunsley J and Westmacott R: Interpreting the magnitude of the placebo effect: mountain or molehill? J Clin Psychol 2007; 63: 391. 12. Hrobjartsson A and Gotzsche PC: Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New Eng J Med 2001; 344: 1594.
13. Daan NMP, Schweitzer KJ and van der Vaart CH: Associations between subjective overactive bladder symptoms and objective parameters on bladder diary and filling cystometry. Int Urogynecol J 2012; 23: 1619. 14. Coryell W and Noyes R: Placebo response in panic disorder. Am J Phychiatry 1988; 145: 1138. 15. Peters KM, Carrico DJ, Perez-Marrero RA et al: Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment
1013
of overactive bladder syndrome: results from the SUmiT trial. J Urol 2010; 183: 1438. 16. Klevmark B: Volume threshold for micturition. Influence of filling rate on sensory and motor bladder function. Scan J Urol Nephrol, suppl., 2002; 210: 6. 17. Robertson AS, Griffith CJ, Ramsden PD et al: Bladder function in healthy volunteers: ambulatory monitoring and conventional urodynamic studies. Br J Urol 1994; 73: 242.
Purpose: We determined whether electrical stimulation of somatic afferent nerves in the foot could delay bladder filling sensations and increase bladder capacity in healthy humans without overactive bladder. Materials and Methods: Eight subjects underwent 90-minute foot stimulation using skin surface electrodes connected to a transcutaneous electrical nerve stimulator. The electrodes were attached to the bottom of the foot. Subjects completed a 3-day voiding diary, during which foot stimulation was applied on day 2. Stimulation parameters were pulse frequency 5 Hz, rectangular waveform pulse width 0.2 milliseconds and intensity 2 to 6 times the minimal stimulation current necessary to induce toe twitch. Stimulation intensity was set by each subject to a maximal level without causing discomfort. Subjects were provided with 500 to 1,000 ml of water to drink during stimulation. Results: Average SE volume per void was 350 22 ml during the 24 hours before foot stimulation. This voided volume increased to a mean of 547 52 ml for up to 5 hours after stimulation (p <0.01). Average voided volume returned to 363 21 ml within 36 hours after stimulation. There were no adverse events. Conclusions: Foot stimulation can delay bladder filling sensations and significantly increase bladder capacity in healthy humans without overactive bladder. Although the study group was small, our results support moving forward with clinical trials of foot neuromodulation in patients with overactive bladder.
Abbreviations and Acronyms OAB ¼ overactive bladder T ¼ stimulation intensity threshold Accepted for publication October 3, 2013. Study received University of Pittsburgh institutional review board approval. * Correspondence: Department of Urology, University of Pittsburgh, 700 Kaufmann Building, Pittsburgh, Pennsylvania 15213 (telephone: 412-692-4142; FAX: 412-692-4380; e-mail: cftai@ pitt.edu).
Key Words: urinary bladder; neurons, afferent; electrical stimulation; foot; urination
OVERACTIVE bladder is a syndrome characterized by urinary urgency with or without urge incontinence, often with frequency and nocturia.1 Patients with OAB have significantly impaired quality of life.2 First line therapy involves behavioral treatments such as fluid management, pelvic floor muscle physical therapy and bladder training.3 Pharmacotherapy is offered concomitantly or subsequently if behavioral strategies
fail. Antimuscarinics are the most common drugs used for OAB.4 However, because drug therapy often has low efficacy and significant adverse effects, 70% of patients discontinue therapy within the first year of treatment.4 Food and Drug Administration approved treatment in patients in whom behavioral and antimuscarinic therapies fail include intradetrusor injection of onabotulinumtoxinA, or
0022-5347/14/1914-1009/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2013.10.024 Vol. 191, 1009-1013, April 2014 Printed in U.S.A.
www.jurology.com
j
1009
1010
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
sacral or tibial neuromodulation. OnabotulinumtoxinA requires repeat injections every 6 to 12 months and results in adverse events such as urinary tract infection and urinary retention.5,6 Sacral neuromodulation is invasive, requiring surgery to implant the electrodes and the neurostimulator.7 Furthermore, the costs associated with sacral neuromodulation limit this option to some patients with OAB. Tibial neuromodulation is a minimally invasive, office based procedure that involves inserting a needle electrode near the ankle to stimulate the tibial nerve. The tibial nerve is stimulated for 30 minutes each week for 12 consecutive weeks, followed by 1 stimulation per month to maintain efficacy.8 Although tibial neuromodulation is as efficacious as antimuscarinic drugs and has no major side effects,8 the inconvenience of frequent office visits can be prohibitive for elderly as well as employed patients. Thus, a noninvasive, convenient OAB treatment with no major adverse effects would be attractive to many patients. Our previous studies in cats demonstrated that transcutaneous electrical stimulation of somatic afferent nerves in the foot using skin surface electrodes could inhibit reflex micturition and significantly increase bladder capacity.9,10 Foot stimulation is noninvasive and can be performed conveniently at home without major adverse events. It could be an attractive treatment for a large number of patients with OAB if proved to be effective. However, to our knowledge the effect of foot stimulation on bladder sensation in human subjects is currently unknown. We determined whether foot stimulation could delay bladder filling sensations and increase bladder capacity in healthy humans without OAB.
MATERIALS AND METHODS This study was approved by the University of Pittsburgh institutional review board. Foot stimulation was tested in 5 males and 3 females 25 to 60 years old who were healthy and without OAB (see table). Subjects were instructed to Daytime volume per void before and after 90-minute foot stimulation Mean SE Vol/Void (ml) SubjectdSexdAge No. 1dMd46 2dMd49 3dFd41 4dMd40 5dMd25 6dFd48 7dMd47 8dFd60
24 Hrs Before 368 436 206 406 444 173 323 538
63 25 26 71 26 11 54 78
About 5 Hrs After (No. voids/hrs:mins) 667 755 200 577 600 195 530 800
106 33 0 15 25 15 80 0
(3/1:50) (3/2:50) (2/4:45) (3/5:00) (2)* (2/1:30) (2/2:10) (1/1:35)
* One 30 minutes into and another 10 minutes after stimulation.
About 36 Hrs After 465 388 175 469 368 238 263 581
69 18 28 55 30 19 26 74
Figure 1. Sites on right foot where 2 pad electrodes were placed to stimulate somatic afferent nerves of foot.
record daytime voided volumes during a 3-day period without restriction on daily food and water intake. They were also instructed to void in response to the usual bladder sensations and note any void that was withheld or induced early due to unexpected situations. Voiding volumes that resulted from unexpected situations were excluded from study. Foot stimulation was applied for 90 minutes in the morning (10:00 to 11:30 a.m.) on day 2 with the subject sitting. During stimulation the subject was asked to drink 1 to 2 bottles of water (500 to 1,000 ml) so that a void could occur soon after stimulation. Two skin surface electrodes (LGMedSupply, Cherry Hill, New Jersey) were attached to the bottom of the foot. A large cathodal electrode (2 3.5 inches) was placed on the front of the foot to cover as much skin area as possible and a small anodal electrode (2 2 inches) was placed between the inner foot arch and the heel (fig. 1). The electrodes were connected to an LG TEC EliteÔ transcutaneous electrical nerve stimulator, which provided constant current, rectangular pulses of 5 Hz frequency and 0.2 millisecond pulse width. The subject controlled the stimulator to determine the minimal current needed to induce a toe twitch. Stimulation intensity was then increased to the maximal level (25 to 60 mA) comfortable for the subject for the entire 90-minute stimulation, which ranged between 2 to 6 times the minimal intensity necessary to induce a toe twitch. Volume per void was averaged among subjects during 3 periods, including 1) 24 hours before foot stimulation, 2) up to 5 hours after stimulation and 3) up to 36 hours after stimulation. The second period always included the first void after stimulation. However, if voided volumes remained increased in the following 1 to 2 voids, they were also included in the second period (see table). Therefore, the second period was variable, ranging up to 5 hours (see table). The third time period included voids up to 36 hours after stimulation, excluding voids counted in the second time period. One-way ANOVA followed by the Dunnett multiple comparison was used to detect statistically significant differences (p <0.05) between voided volumes before and after stimulation.
RESULTS Average SE volume per void was 350 22 ml during the 24 hours before foot stimulation, which increased to 547 52 ml for up to 5 hours after stimulation (p <0.01, see table and fig. 2). Average
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
*
Bladder Volume/Void (mL)
600 500 400 300 200 100
) H ou rs 6 (~ 3 tim
Af te rS
tim rS Af te
Be
fo re
St im
(2
(~ 5
4
ho ur
ho ur s
s)
)
0
Figure 2. Mean bladder volume per void measured in 8 subjects during 24 hours before foot stimulation (Stim), and within 5 hours and during 36 hours after foot stimulation 90 minutes in duration at 5 Hz frequency, 0.2 millisecond pulse width and 25 to 60 mA intensity (2 to 6 times threshold intensity to induce toe twitch). Asterisk indicates significantly different vs voided volume before stimulation (p <0.01).
voided volume returned to 363 21 ml within 36 hours after stimulation. Volume per void remained increased for several hours after stimulation in 3 consecutive voids in subjects 1, 2 and 4, and after 2 consecutive voids in subjects 6 and 7 (see table). These subjects did not void during stimulation. However, subject 5 voided 625 ml 30 minutes into the stimulation period. He again voided 575 ml 10 minutes after completing the 90-minute stimulation (average 600 25 ml) (see table). Each voided volume was much larger than the mean voided volume of 444 26 ml before stimulation. The T needed to induce a toe twitch varied from 10 to 16 mA in the 8 subjects. The intensity used for the 90-minute stimulation session varied from 2T to 3T (24 to 36 mA) in 7 subjects. In subject 8 a stimulation intensity of 6T (60 mA) was used. All subjects tolerated stimulation without discomfort. There was no observable change in the toe twitch during stimulation and no immediate (ie local skin reaction) or long-term adverse events.
DISCUSSION This study demonstrates that transcutaneous electrical stimulation of somatic afferent nerves in the foot can delay bladder filling sensations and significantly increase bladder capacity more than 50% or
1011
by about an average of 200 ml in healthy humans without OAB (fig. 2). Our previous studies in cats showed that transcutaneous electrical stimulation of somatic afferent nerves in the foot inhibited reflex micturition and significantly increased bladder capacity.9,10 The current study suggests that the same mechanisms might occur in healthy humans and this technology has the potential to be an effective new treatment for patients with OAB. Since stimulation electrodes were placed on the skin surface rather than directly on nerves, it is difficult to know which nerves were activated. However, it is highly likely that foot stimulation activates afferent axons in the lateral and medial plantar nerves of the foot because the 2 skin surface electrodes were placed along the passage of these nerves (fig. 1). The tibial nerve runs from the inner ankle down to the bottom of the foot and branches into the lateral and medial plantar nerves at the location of the small electrode. These 2 nerves further branch into multiple small nerves that run toward the toes. The large electrode placed at the front of the foot allows for stimulation of these small nerve branches. Additional studies will help determine whether the current electrode positioning is most effective for activating the lateral and medial plantar nerves (fig. 1). Since all subjects were comfortable with the stimulation intensities used in this study, small Ad and C-fiber afferents that induce painful sensations were unlikely to be activated by stimulation. Consequently, transcutaneous foot stimulation must activate the large somatic afferent nerve fibers. In this study foot stimulation was applied acutely for 90 minutes rather than chronically during days or weeks. We chose a stimulation period of 90 minutes as a time convenient for subjects to sit and rest between 10 and 11:30 a.m. just before lunch. Despite this brief stimulation period average voided volume remained increased in 6 of 8 subjects up to 5 hours after stimulation, indicating that the inhibitory effect of foot stimulation persisted into the post-stimulation period. Post-stimulation inhibition was expected since foot stimulation activates the branches of the tibial nerve and tibial nerve stimulation elicits changes in bladder function that last for weeks.8 In addition, our previous study in cats showed that foot stimulation induced post-stimulation inhibition of reflex bladder activity lasting 1 to 2 hours.9 If this poststimulation effect occurs in future clinical trials, foot neuromodulation would not have to be applied continuously to treat OAB. Furthermore, subject 5 voided a larger volume after only 30 minutes of stimulation, indicating that 90 minutes of stimulation might not be needed to induce the inhibitory effect. Since this study included only a few subjects,
1012
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
results must be viewed as observational. More studies with larger subject numbers are required to determine the optimal stimulation duration/pattern and further elucidate the post-stimulation effect. In open label studies there is always the possibility of a placebo effect. However, this is unlikely in our study for several reasons. 1) Average voided volume increased more than 50% or about 200 ml (fig. 2). This large response is unlikely to have been mediated by a placebo effect alone.11 2) Placebo effects are less often observed in objective measurements such as blood pressure.12 Voided volume is also an objective measurement.13 3) Placebo effects usually last for weeks.14 We observed that average voided volumes returned to prestimulation levels 5 hours after stimulation. It would be difficult to design a placebo controlled study for foot stimulation since simply turning off stimulation would easily be recognized by the subject. In a previous study of tibial neuromodulation the placebo control was designed using a Streitberger 2-piece needle and an inactive skin electrode to simulate tibial neuromodulation procedures.15 Two small skin electrodes were also placed at the bottom and top of the foot close to the small toe to maximally avoid stimulating the tibial nerve while mimicking the foot sensation induced during tibial neuromodulation. However, the placebo control unexpectedly produced a significant inhibitory effect on bladder overactivity. Based on the results of our current study this specific placebo control for tibial neuromodulation may have possibly stimulated a small branch of the tibial nerve innervating the foot. Designing a placebo control for bladder neuromodulation currently remains challenging. Notably, subjects drank 500 to 1,000 ml of water during the 90-minute stimulation session to increase the bladder filling rate. Previous studies show that a fast, nonphysiological bladder filling
rate (50 to 100 ml per minute) during cystometry could significantly increase bladder capacity.16,17 However, the maximal urine excretion rate by the kidney after a large fluid intake is only about 15 ml per minute.16 In this study the mean voided volume after 90-minute stimulation was about 540 ml (fig. 2), indicating that the mean urine excretion rate must have been less than 6 ml per minute. Therefore, it is unlikely that the comparatively slow physiological bladder filling rate could have delayed the bladder filling sensation and caused a significant increase in bladder capacity. It is even more unlikely that such a large increase in capacity (more than 50% or about 200 ml) could have occurred due to physiological filling (fig. 2). Study subjects were instructed to note any void that was withheld or induced early due to unexpected situations. No subjects reported any situation when voiding was withheld. However, subject 6 intentionally initiated voiding early before night sleep on days 1 and 2, and produced small 75 ml voids. These small voids were excluded from data analysis.
CONCLUSIONS This study shows that foot stimulation delayed bladder filling sensations and increased bladder volume in healthy humans without OAB. Although only a few subjects were tested, our results support moving forward with clinical trials of foot stimulation in patients with OAB. If foot stimulation proves to be effective for treating OAB, it would provide several potential advantages over tibial neuromodulation therapy. Foot stimulation is noninvasive and can be performed safely at home. Thus, daily stimulation becomes possible with a potential benefit of higher efficacy than tibial neuromodulation, which is only performed once per month during maintenance therapy.
REFERENCES 1. Abrams P, Cardozo L, Fall M et al: The standardization of terminology of lower urinary tract function: report from the Standardization Subcommittee of the International Continence Society. Neurourol Urodyn 2002; 21: 167. 2. Girman CJ, Jacobsen SJ, Tsukamoto T et al: Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology 1998; 51: 428. 3. Gormley EA, Lightner DJ, Burgio KL et al: Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. J Urol, suppl., 2012; 188: 2455.
4. Chapple CR, Khullar V, Gabriel Z et al: The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008; 54: 543. 5. Mohee A, Khan A, Harris N et al: Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder. BJU Int 2013; 111: 106. 6. Nitti VW, Dmochowski R, Herschorn S et al: OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 2013; 189: 2186.
7. van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP et al: Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007; 178: 2029. 8. Peters KM, Macdiarmid SA, Wooldridge LS et al: Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the overactive bladder innovative therapy trial. J Urol 2009; 182: 1055. 9. Chen G, Larson JA, Ogagan PD et al: Poststimulation inhibitory effect on reflex bladder activity induced by activation of somatic afferent nerves in the foot. J Urol 2012; 187: 338.
ELECTRICAL STIMULATION OF AFFERENT NERVES IN FOOT INCREASES BLADDER CAPACITY
10. Tai C, Shen B, Chen M et al: Suppression of bladder overactivity by activation of somatic afferent nerves in the foot. BJU Int 2011; 107: 303. 11. Hunsley J and Westmacott R: Interpreting the magnitude of the placebo effect: mountain or molehill? J Clin Psychol 2007; 63: 391. 12. Hrobjartsson A and Gotzsche PC: Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New Eng J Med 2001; 344: 1594.
13. Daan NMP, Schweitzer KJ and van der Vaart CH: Associations between subjective overactive bladder symptoms and objective parameters on bladder diary and filling cystometry. Int Urogynecol J 2012; 23: 1619. 14. Coryell W and Noyes R: Placebo response in panic disorder. Am J Phychiatry 1988; 145: 1138. 15. Peters KM, Carrico DJ, Perez-Marrero RA et al: Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment
1013
of overactive bladder syndrome: results from the SUmiT trial. J Urol 2010; 183: 1438. 16. Klevmark B: Volume threshold for micturition. Influence of filling rate on sensory and motor bladder function. Scan J Urol Nephrol, suppl., 2002; 210: 6. 17. Robertson AS, Griffith CJ, Ramsden PD et al: Bladder function in healthy volunteers: ambulatory monitoring and conventional urodynamic studies. Br J Urol 1994; 73: 242.