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Hypoalgesia in Response to Transcutaneous Electrical Nerve Stimulation (TENS) Depends on Stimulation Intensity
The Journal of Pain, Vol 12, No 8 (August), 2011: pp 929-935 Available online at www.sciencedirect.com
Hypoalgesia in Response to Transcutaneous Electrical Nerve Stimulation (TENS) Depends on Stimulation Intensity Fidelma Moran,*,y Tracey Leonard,*,y Stephanie Hawthorne,*,y Ciara M. Hughes,*,y Evie McCrum-Gardner,*,y Mark I. Johnson,z,x Barbara A. Rakel,{ Kathleen A. Sluka,# and Deirdre M. Walsh*,y *Health and Rehabilitation Sciences Research Institute, and ySchool of Health Sciences, University of Ulster, United Kingdom. z Centre for Pain Research, Faculty of Health, Leeds Metropolitan University, United Kingdom. x Leeds Pallium Research Group, Leeds, United Kingdom. { College of Nursing, and #Graduate Program in Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, Iowa.
Abstract: Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS na€ıve healthy individuals (18–64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P < .0001) at the forearm; Transient Placebo TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r2 = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. Perspective: This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. ª 2011 by the American Pain Society Key words: Transcutaneous electric nerve stimulation, placebo, therapeutic human experimentation, pain threshold, pain.
Received August 26, 2010; Revised February 4, 2011; Accepted February 22, 2011. Supported by the Research & Development Office, Northern Ireland (UK) and Strategic Priority Grant, Department for Employment and Learning, Northern Ireland (UK). The TENS units and electrodes were donated by Empi (USA) and TensCare (UK). Conflicts of interest: delivery of occasional workshops on TENS sponsored by TENS and pharmaceutical companies (Mark Johnson); consultant and research contract with Medtronic and consultant for Regeneron (Kathleen Sluka). Address reprint requests to Prof. Deirdre M. Walsh, Health and Rehabilitation Sciences Research Institute, University of Ulster, Shore Road, Newtownabbey, Co. Antrim BT37 0QB, UK. E-mail: [email protected] 1526-5900/$36.00 ª 2011 by the American Pain Society doi:10.1016/j.jpain.2011.02.352
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he use of transcutaneous electrical nerve stimulation (TENS) for pain relief involves applying a low voltage electrical current through the skin using surface electrodes in order to stimulate afferent nerve fibres. The stimulation parameters of the electrical current (frequency, pulse amplitude, pulse duration) may be manipulated in order to achieve the desired therapeutic effect. While the basic science underlying the mechanism of action of TENS has been well researched,13,21 the optimal stimulation parameters for pain management remain elusive.14 TENS has been administered at a variety of intensities in clinical practice and research investigations;10,11,16 929
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intensities include below sensory detection threshold (ie, not perceptible), just above sensory detection threshold (ie, barely perceptible), between sensory detection and pain threshold (ie, strong but comfortable or strong nonpainful) and above pain threshold (ie, maximal tolerable). For postoperative pain, a key meta-analysis found larger reductions in postoperative analgesic consumption when TENS was applied using adequate intensities, ie, strong, nonpainful intensity.2 Similarly, adequate intensities have been confirmed as essential for reductions in postoperative pain in a clinical trial on postoperative pain.19 In experimental pain studies, increases in pressure pain thresholds (PPTs) were observed with the highest intensities of TENS.20 However, no previous study has systematically investigated the dose response for intensity of TENS. Adequate blinding is an inherent difficulty in TENS research,12,22 as it is impossible to fully blind individuals to sensations generated by TENS. We recently reported successful blinding of participants using a sham TENS device that delivers current at a perceptible intensity for less than 1 minute.9,20 The aim of the current study was to establish the dose response for TENS intensity using pressure algometry in healthy participants. In addition, the effectiveness of blinding across different intensities was assessed.
Methods Participants Ethical approval was obtained from the University of Ulster’s Research Ethics Committee. One hundred and thirty TENS na€ıve healthy volunteers (65 males, 65 females, age range 18 to 64 years old, mean age 23 years, 113 right handed) were recruited from the staff and student population of the University by poster, e-mail and classroom advertisement. Participants were screened for relevant contraindications including injury or nerve damage to the upper limbs, current pain, pregnancy, chronic illness, cardiac pacemaker, epilepsy, allergies to the TENS electrodes, currently taking pain medication, skin conditions, or deficient skin sensation in the area of electrode placement. After giving informed written consent, participants were randomly allocated to one of 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and, Transient Placebo TENS. No participants withdrew from the study and all participants were included in the analysis. Randomization to groups was performed using a computer generated random number list compiled by a statistician (EMcC-G) not involved in data collection; randomization was stratified for gender thus ensuring equal numbers of males and females in each group. Group allocation was concealed by writing the group allocation onto cards and sealing them in consecutively numbered opaque envelopes. PPT readings from the 2 recording sites were also taken in a random order; this randomization was also performed using a computer-generated random number list compiled by a team member (DW) not
involved in data collection. This random order for PPT readings was also written onto cards and sealed in the same opaque envelopes as described above. The envelopes were locked in a secure cabinet with restricted access and opened after the participant gave consent.
Sample Size Sample size was calculated using a mean difference of 11.97 N (between 2 active TENS groups) and standard deviation of 12.63 N obtained from a recent study on PPT and TENS by 1 of the research team.5 At a significance level of .05, power of 80%, and 5 groups, it was calculated that 26 participants were required in each group (Minitab, v.15, State College, PA), giving a total number of 130 participants for the study.
Intervention Groups An investigator (TL), who was aware of group allocation, applied the TENS intervention. Active or Placebo TENS were applied to the dominant forearm using Select TENS units (Empi, USA) with a balanced asymmetrical waveform at 80 Hz frequency for 30 minutes (see details below). In all groups, 2 self-adhesive electrodes (50 50 mm; TensCare, UK) were positioned on the lateral aspect of the forearm: the distal electrode was placed 1 cm proximal to the proximal border of the anatomical snuffbox and the proximal electrode was placed at a distance of 3 cm from the distal electrode. Participants in all TENS groups (active and placebo) were told they may or may not feel a sensation during the intervention. The pulse duration increased (to a maximum of 400 ms) as the current amplitude increased and ranged between 60 and100 ms. The TENS units were calibrated using an oscilloscope (Model 1602, Gould Electronics, UK) prior to the study commencing. The interventions were as follows: 1) Strong Non Painful TENS. Current amplitude was slowly increased until a level was reached that participants reported was the maximum level they could tolerate below pain threshold. Participants were asked every 3 minutes if the intensity of TENS they were feeling had decreased, and if so, the investigator increased current amplitude until participants reported the same intensity level again; 2) Sensory Threshold TENS. Current amplitude was slowly increased until sensory threshold was reached (ie, barely perceptible). Participants were asked every 3 minutes if the intensity of TENS they were feeling had decreased, and if so, the investigator increased the current amplitude until participants reported that sensory threshold was reached again; and 3) Below Sensory Threshold TENS. Current amplitude was slowly increased until sensory threshold was reached and then decreased to just below this level (ie, not perceptible). The current amplitude remained at this initial setting. Participants in this group were asked every 3 minutes if they were comfortable. Two placebo TENS were delivered: 1) No Current Placebo TENS. A sham device delivered no current (ie, not perceptible). An Empi Select device was used but no current was delivered. Participants in this group were asked every 3 minutes if they were comfortable. Any questions
Moran et al about the lack of TENS sensation in either placebo group were dealt with by the investigator saying that some types of TENS treatments are ‘‘barely perceptible’’; and 2) Transient Placebo TENS. A sham device delivered current for less than 1 minute at a barely perceptible intensity (Select device, Empi, USA) as previously described and validated.9,20 Stimulation was delivered at sensory threshold for 42 seconds (burst stimulus, 80 Hz frequency, 5 seconds cycle time) after which the TENS amplitude reset to 0 mA. These parameters were chosen as they produced a comfortable sensation which lasted long enough for the participant to be aware of it but was too brief to have any definite physiological effect. Participants in this group were asked every 3 minutes if they were comfortable.
Outcome Measure Pressure pain threshold (PPT) was assessed as the primary outcome measure using a pressure algometer (Type II; Somedic Inc, Sweden) which has been shown to be a valid, reliable, and sensitive analgesic assay in the evaluation of hypoalgesic effects of electrophysical agents.1,7 The algometer was applied at a rate of 50 kPas1 with a 1-cm2 probe tip. The outcome assessor (SH) was blinded to treatment group. PPT measurements were assessed at 2 different sites on the dominant upper limb: 1) 3 cm distal to the distal end of the anatomical snuff box in the midline of the belly of the first dorsal interosseous muscle; and 2) on the anterior aspect of the forearm, 7.5 cm proximal to the distal wrist crease. These sites were chosen to examine the effects of TENS within the area of stimulation and in a distal area that was supplied by the stimulated nerve (superficial radial). Participants were asked to say ‘‘stop’’ when the sensation they were feeling turned to pain (distinct from pressure or discomfort); the algometer was then immediately removed and the measurement recorded. Two PPT measurements, taken 10 seconds apart, were recorded at each time point. In a preliminary reliability study (Hawthorne et al, 2009, unpublished data), the outcome assessor (SH) demonstrated excellent intrarater reliability for PPT measurements (Intraclass Correlation Coefficient values: hand, .956; forearm, .974). During the study, PPT was recorded before TENS (Pre-TENS, from hand and forearm), at 15 minutes (during TENS from forearm only), at 30 minutes (immediately after TENS was switched off, from hand and forearm), and at 60 minutes (30 minutes after TENS was switched off, from hand and forearm). It was not possible to record PPT at 15 minutes from the hand as this area was concealed to maintain blinding while the outcome assessor recorded PPT.
Blinding Attempts were made to blind group allocation for participants in the placebo and active TENS groups as follows: the sham TENS device looked similar to the active TENS device; all participants were told verbally that they may or may not feel a sensation; all participants were asked not to discuss any sensations experienced with the outcome assessor; and all participants were
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TENS na€ıve. Further, the outcome assessor (SH) was unaware of the TENS group and a separate investigator applied TENS (TL). At the end of data collection, the effectiveness of blinding was assessed by TL asking the participant which TENS intervention did they think was delivered with 3 options for the answer: ‘‘real’’, ‘‘placebo’’, or ‘‘don’t know’’. After the participant had left the room, the outcome assessor was asked the same question.
Data Analyses Data were analyzed independently by 2 members of the team (CH and FM) who were blind to group allocation using SPSS (v.15.0): an average of the 2 PPT scores recorded at each time point was used for analyses. Shapiro-Wilk tests showed that data were normally distributed; therefore, parametric tests were used to analyze the data. PPT difference scores (variation from baseline values) were analyzed using between-within groups ANOVA, 1-way ANOVA,and post hoc Scheffe tests. To test dose-response effects, the area under the curve was calculated for the 60-minute testing period and correlated with the maximum current amplitude using a Pearson’s correlation coefficient test. Current amplitudes between the groups were compared using 1-way ANOVA and post hoc Scheffe tests. Significance was set at P # .05. Data are presented as the mean 6 S.E.M.
Results The current amplitude (mA) for each amplitude unit on the Select device was calculated by measuring the peak-to-peak voltage of the waveform across a 1 kU resistor on an oscilloscope (Model 1602; Gould Electronics, UK). The mean maximum current amplitude used during the 30 minutes was recorded for each group as follows: Strong Non Painful TENS, 39.13 6 1.27 mA (n = 26); Sensory Threshold TENS, 22.46 6 .84 mA (n = 26); and Below Sensory Threshold TENS, 11.49 6 .74 mA (n = 26) (mean 6 SEM). The current amplitudes of each group were significantly different from each other (P = .0001), showing we were able to apply TENS at several different doses using intensity as dose.
Changes in PPT with TENS The average (mean 6 SEM) baseline PPT of the hand was 221.25 6 8.91 kPa and of the forearm was 264.96 6 11.01 kPa and was not significantly different between groups. Fig 1 illustrates the variation in PPT from baseline for all intervention groups (differences data) at the hand (A) and forearm (B). Statistical analyses of the PPT differences data showed significant differences: over time at the forearm recording points (P = .008); between groups at the hand (P = .005) and forearm (P = .002); and a significant interaction between time and group at the forearm (P = .001). In the hand, the Strong Non Painful TENS group showed a significant hypoalgesic effect compared to the Transient Placebo TENS and No Current Placebo TENS groups at 30 minutes (P = .001, Fig 1A). There was no significant difference between Sensory Threshold TENS and any of the other groups.
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Time (minutes) Figure 1. (A). Hand PPT (kPa) Differences from Baseline (*Indicates Strong Non Painful TENS significantly different to Transient Placebo TENS and No Current Placebo TENS, P = .001). (B). Forearm PPT (kPa) Differences from Baseline (*Indicates Strong Non Painful TENS significantly different to Below Sensory Threshold TENS, No Current Placebo TENS, and Transient Placebo TENS, P < .0001; **Indicates Strong Non Painful TENS significantly different to Below Sensory Threshold TENS, P = .003). In the forearm, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to the Below Sensory Threshold TENS, No Current Placebo TENS, and Transient Placebo TENS groups at 30 minutes (P < .0001, Fig 1B). At 60 minutes, PPT continued to be elevated in the Strong Non Painful TENS group compared to the Below Sensory Threshold TENS group (P = .003). Similar to the hand data, there was no significant difference between Sensory Threshold TENS and any other group.
Relationship Between Current Amplitude and Hypoalgesia To examine the relationship between current amplitude and hypoalgesia, we assessed the effects of active
TENS at different intensities by comparing the area under the curve for changes in PPT at the forearm for the 60-minute period. Fig 2A is a scatter plot of the maximum pulse amplitude (mA) used for each participant and the area for the change in PPT (kPa) in the forearm for the 3 active TENS groups (r2 = .33, P = .003). The summary of the area for each individual group is represented in Fig 2B showing the greatest effect occurring with the highest intensity group.
Blinding Data The outcome assessor responded that she did not know group allocation for all 130 participants, thus showing adequate blinding. The number of participants who correctly guessed their allocated intervention was
Moran et al
Figure 2. (A). Scatter plot of the maximum pulse amplitude (mA) used and the area for the change in PPT (kPa) in the forearm for the 60-minute period for each participant in the Strong Non Painful TENS (Δ), Sensory Threshold TENS (-), and Below Sensory Threshold TENS (Ο) groups (n = 78). (B). Mean area for the change in PPT (kPa) in the forearm for the 60-minute period for Strong Non Painful TENS (C), Sensory Threshold TENS (B), and Below Sensory Threshold (A) TENS groups (n = 78). For comparison, areas for the 2 placebos (Pl) are shown in open symbols (V = Transient Placebo; Δ = No Current Placebo). *Indicates significantly different from Below Sensory Threshold and both Placebo TENS groups.
as follows: Strong Non Painful TENS, 17/26 (65%); Sensory Threshold TENS, 18/26 (69%); Below Sensory Threshold TENS, 14/26 (54%); No Current Placebo TENS, 7/26 (27%); and Transient Placebo TENS, 4/26 (15%). Analysis of these responses showed a significant difference between groups with the Transient Placebo TENS group showing the least number of correct responses (chi-square test, P < .0001). Overall, these data show adequate blinding of the placebo groups as well as the active TENS groups.
Discussion The current study showed, for the first time, a doseresponse effect for TENS. Specifically, using intensity as dose, we have shown that the highest intensities of TENS (Strong Non Painful, Sensory Threshold) produce greater hypoalgesia than lower intensities (Below
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Sensory Threshold) or placebo. Further, the degree of hypoalgesia produced by TENS was significantly correlated with the amplitude of TENS currents and therefore shows that TENS should be delivered at the highest tolerable intensity. These data agree with prior studies that show intensity of stimulation correlates with hypoalgesia in healthy controls,20 and that intensity is a critical factor for postoperative pain reduction.2,19 Our study showed no hypoalgesia with TENS delivered just below sensory threshold, further supporting the notion that TENS should be delivered at a strong intensity. Surprisingly, however, there was no statistically significant difference between the Strong Non Painful (highest intensity) and Sensory Threshold (middle intensity) TENS groups. Further, the Sensory Threshold TENS group was not significantly different from Placebo or Below Sensory Threshold TENS groups. This is a similar pattern seen in typical pharmacological studies with multiple doses. This pattern could be because we continuously increased the current amplitude throughout the application to maintain the target intensity level and could therefore have achieved an adequate intensity towards the end of the stimulation to produce hypoalgesia in some subjects. In a recent study, we showed that increasing current amplitude to maintain the same level of intensity throughout TENS application produced a greater hypoalgesia than keeping the intensity at the initial level.18 Our data agrees with this study and suggests that even starting at sensory threshold intensity and continuously increasing current amplitude to maintain this intensity is enough to produce hypoalgesia. Previous TENS laboratory studies have been conducted to investigate frequency,4 electrode site,3 segmental versus extra segmental stimulation,6 type of electrode,9 and stimulation intensity hypoalgesic effects of TENS.8,15 It is difficult to interpret effects of stimulation intensity in such studies since several variables were varied at the same time. For example, Chesterton et al6 showed that 30 minutes of low frequency (4Hz) extrasegmental stimulation TENS (applied to the leg), at ‘‘maximum tolerable’’ intensity, produced a rapid onset hypoalgesic effect (significant compared to control and sham groups) in the hand. In contrast, high frequency (110 Hz) segmental TENS (applied to the forearm) at ‘‘strong but comfortable’’ intensity produced comparable hypoalgesic levels. Direct comparisons of intensity have been done in several studies using 2 levels. PPT significantly increased with intensities of ‘‘strong but comfortable nonpainful’’ but not ‘‘sensory threshold’’ with high frequency TENS (100 Hz) for 20 minutes.1 Similarly, an intensity described as ‘‘to tolerance without pain’’ showed greater hypoalgesia when compared to ‘‘strong but comfortable’’ intensity with low frequency (2 Hz).15 By definition, these 2 levels of intensity should be very similar, if not identical; this highlights the importance of semantics when describing intensity of TENS. In the future, it would be wise to describe TENS intensity by referring to perceptual thresholds (ie, above or below sensory detection or pain threshold). The second objective of our study was to compare 2 types of placebo TENS: a no-current placebo and a novel
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transient placebo. An adequate placebo is an essential component of trial design in pain research and has proven challenging for TENS due to the perceived sensations of active TENS. While TENS-na€ıve participants are usually recruited for laboratory and clinical studies, the problem remains of how to produce a realistic placebo that mimics the perceived sensations of the active device but produces no analgesia. Typically, clinical trials utilize inactive TENS units that deliver no current, or more recently, subsensory levels of stimulation.17,22 The current study used a new placebo unit, termed Transient Placebo TENS, that delivers a short duration of stimulation. Our group has previously validated this transient placebo20 when delivered at maximal tolerable intensity showing both a lack of hypoalgesia and adequate blinding of both the investigator and the participant. In the current study, the transient placebo TENS was delivered at a sensory threshold intensity level in an effort to further improve blinding. Our prior study20 assessed blinding by asking participants ‘‘Do you think you received an active or placebo treatment?‘‘ and showed that 60% of participants in the transient placebo group correctly identified the intervention as placebo. In the current study, the degree of blinding was higher in
References 1. Aarskog R, Johnson MI, Demmink JH, Lofthus A, Iversen V, Lopes-Martins R, Joensen J, Bjordal JM: Is mechanical pain threshold after transcutaneous electrical nerve stimulation (TENS) increased locally and unilaterally? A randomized placebo-controlled trial in healthy subjects. Physiother Res Int 12:251-263, 2007 2. Bjordal JM, Johnson MI, Ljunggreen AE: Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic consumption. A meta-analysis with assessment of optimal treatment parameters for postoperative pain. Eur J Pain 7:181-188, 2003 3. Brown L, Tabasam G, Bjordal JM, Johnson MI: An investigation into the effect of electrode placement of transcutaneous electrical nerve stimulation (TENS) on experimentally induced ischemic pain in healthy human participants. Clin J Pain 23: 735-743, 2007 4. Chen CC, Johnson MI: An investigation into the effects of frequency-modulated transcutaneous electrical nerve stimulation (TENS) on experimentally-induced pressure pain in healthy human participants. J Pain 10:1029-1037, 2009
Hypoalgesic Effects of TENS Intensity the Transient Placebo TENS group with only 15% of participants correctly identifying that they received placebo. These data support this transient placebo as a useful model since no hypoalgesic effects were observed, and if used at a sensory threshold intensity level, it produces a very high level of participant blinding. In conclusion, this experimental pain study demonstrated a dose response for the intensity of TENS with higher intensities producing a superior hypoalgesic effect than the lower intensities or placebo groups. It is accepted that this study has limitations as it was conducted on healthy participants and future studies will need to be performed on clinical pain conditions to support this observation. The clinical implication of this study is that, ideally, TENS should be delivered at a strong nonpainful intensity level in order to produce maximum pain relief. Finally, this study also provided further data to support the use of a transient placebo TENS as opposed to a no-current placebo TENS in clinical trials.
Acknowledgments Tracey Leonard and Stephanie Hawthorne are equal contributors to this paper.
8. Claydon LS, Chesterton LS, Barlas P, Sim J: Effects of simultaneous dual-site TENS stimulation on experimental pain. Eur J Pain 12:696-704, 2008 9. Cowan SJ, McKenna J, McCrum-Gardner E, Johnson MI, Sluka KA, Walsh DM: An investigation of the hypoalgesic effects of TENS delivered by a glove electrode. J Pain 10: 694-701, 2009 10. Coyne PJ, MacMurren M, Izzo T, Kramer T: Transcutaneous electrical nerve stimulator for procedural pain associated with intravenous needlesticks. J Intraven Nurs 18: 263-267, 1995 11. De Angelis C, Perrone G, Santoro G, Nofroni I, Zichella L: Suppression of pelvic pain during hysteroscopy with a transcutaneous electrical nerve stimulation device. Fertil Steril 79: 1422-1427, 2003 12. Deyo RA, Walsh NE, Schoenfeld LS, Ramamurthy S: Can trials of physical treatments be blinded? The example of transcutaneous electrical nerve stimulation for chronic pain. Am J Phys Med Rehabil 69:6-10, 1990 13. Kalra A, Urban MO, Sluka KA: Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther 298:257-263, 2001
5. Chen CC, Johnson MI: An investigation into the hypoalgesic effects of high- and low-frequency Transcutaneous Electrical Nerve Stimulation (TENS) on experimentally-induced blunt pressure pain in healthy human participants. J Pain 11:53-61, 2010
14. Khadilkar A, Odebiyi DO, Brosseau L, Wells GA: Transcutaneous electrical nerve stimulation (TENS) versus placebo for chronic low-back pain. Cochrane Database of Systematic Reviews, Issue 4, 2008
6. Chesterton LS, Barlas P, Foster NE, Lundeberg T, Wright CC, Baxter GD: Sensory stimulation (TENS): Effects of parameter manipulation on mechanical pain thresholds in healthy human subjects. Pain 99:253-262, 2002
15. Lazarou L, Kitsios A, Lazarou I, Sikaras E, Trampas A: Effects of intensity of Transcutaneous Electrical Nerve Stimulation (TENS) on pressure pain threshold and blood pressure in healthy humans: A randomized, double-blind, placebo-controlled trial. Clin J Pain 25:773-780, 2009
7. Chesterton LS, Sim J, Wright CC, Foster NE: Interrater reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin J Pain 23: 760-766, 2007
16. Lehmann TR, Russell DW, Spratt KF, Colby H, Liu YK, Fairchild ML, Christensen S: Efficacy of electroacupuncture and TENS in the rehabilitation of chronic low back pain patients. Pain 26:277-290, 1986
Moran et al 17. Nnoaham KE, Kumbang J: Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database of Systematic Reviews, Issue 3, 2008 ~o MA, Laurino MF, Gallego NLG, Cabral CMN, 18. Pantalea Walsh DM, Rakel B, Vance C, Sluka KA, Liebano RE: An investigation of the effect of adjusting pulse amplitude during TENS application. Proceedings of the International Association for the Study of Pain 13th World Congress on Pain, Montreal, 2010. 19. Rakel B, Frantz R: Effectiveness of transcutaneous electrical nerve stimulation on postoperative pain with movement. J Pain 4:455-464, 2003
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20. Rakel B, Cooper N, Adams HJ, Messer BR, Frey Law LA, Dannen DR, Miller CA, Polehna AC, Ruggle RC, Vance CGT, Walsh DM, Sluka KA: A new transient sham TENS device allows for investigator blinding while delivering a true placebo treatment. J Pain 1:230-238, 2010 21. Sluka KA, Walsh DM: Transcutaneous Electrical Nerve Stimulation and Interferential Therapy, in Sluka KA (ed): Mechanisms and Management of Pain for the Physical Therapist, 1st ed, Seattle, WA, IASP Press, 2009, pp 167-190 22. Walsh DM, Howe TE, Johnson MI, Sluka KA: Transcutaneous electrical nerve stimulation for acute pain. Cochrane Database of Systematic Reviews, Issue 2, 2009
Hypoalgesia in Response to Transcutaneous Electrical Nerve Stimulation (TENS) Depends on Stimulation Intensity Fidelma Moran,*,y Tracey Leonard,*,y Stephanie Hawthorne,*,y Ciara M. Hughes,*,y Evie McCrum-Gardner,*,y Mark I. Johnson,z,x Barbara A. Rakel,{ Kathleen A. Sluka,# and Deirdre M. Walsh*,y *Health and Rehabilitation Sciences Research Institute, and ySchool of Health Sciences, University of Ulster, United Kingdom. z Centre for Pain Research, Faculty of Health, Leeds Metropolitan University, United Kingdom. x Leeds Pallium Research Group, Leeds, United Kingdom. { College of Nursing, and #Graduate Program in Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, Iowa.
Abstract: Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS na€ıve healthy individuals (18–64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P < .0001) at the forearm; Transient Placebo TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r2 = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. Perspective: This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. ª 2011 by the American Pain Society Key words: Transcutaneous electric nerve stimulation, placebo, therapeutic human experimentation, pain threshold, pain.
Received August 26, 2010; Revised February 4, 2011; Accepted February 22, 2011. Supported by the Research & Development Office, Northern Ireland (UK) and Strategic Priority Grant, Department for Employment and Learning, Northern Ireland (UK). The TENS units and electrodes were donated by Empi (USA) and TensCare (UK). Conflicts of interest: delivery of occasional workshops on TENS sponsored by TENS and pharmaceutical companies (Mark Johnson); consultant and research contract with Medtronic and consultant for Regeneron (Kathleen Sluka). Address reprint requests to Prof. Deirdre M. Walsh, Health and Rehabilitation Sciences Research Institute, University of Ulster, Shore Road, Newtownabbey, Co. Antrim BT37 0QB, UK. E-mail: [email protected] 1526-5900/$36.00 ª 2011 by the American Pain Society doi:10.1016/j.jpain.2011.02.352
T
he use of transcutaneous electrical nerve stimulation (TENS) for pain relief involves applying a low voltage electrical current through the skin using surface electrodes in order to stimulate afferent nerve fibres. The stimulation parameters of the electrical current (frequency, pulse amplitude, pulse duration) may be manipulated in order to achieve the desired therapeutic effect. While the basic science underlying the mechanism of action of TENS has been well researched,13,21 the optimal stimulation parameters for pain management remain elusive.14 TENS has been administered at a variety of intensities in clinical practice and research investigations;10,11,16 929
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Hypoalgesic Effects of TENS Intensity
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intensities include below sensory detection threshold (ie, not perceptible), just above sensory detection threshold (ie, barely perceptible), between sensory detection and pain threshold (ie, strong but comfortable or strong nonpainful) and above pain threshold (ie, maximal tolerable). For postoperative pain, a key meta-analysis found larger reductions in postoperative analgesic consumption when TENS was applied using adequate intensities, ie, strong, nonpainful intensity.2 Similarly, adequate intensities have been confirmed as essential for reductions in postoperative pain in a clinical trial on postoperative pain.19 In experimental pain studies, increases in pressure pain thresholds (PPTs) were observed with the highest intensities of TENS.20 However, no previous study has systematically investigated the dose response for intensity of TENS. Adequate blinding is an inherent difficulty in TENS research,12,22 as it is impossible to fully blind individuals to sensations generated by TENS. We recently reported successful blinding of participants using a sham TENS device that delivers current at a perceptible intensity for less than 1 minute.9,20 The aim of the current study was to establish the dose response for TENS intensity using pressure algometry in healthy participants. In addition, the effectiveness of blinding across different intensities was assessed.
Methods Participants Ethical approval was obtained from the University of Ulster’s Research Ethics Committee. One hundred and thirty TENS na€ıve healthy volunteers (65 males, 65 females, age range 18 to 64 years old, mean age 23 years, 113 right handed) were recruited from the staff and student population of the University by poster, e-mail and classroom advertisement. Participants were screened for relevant contraindications including injury or nerve damage to the upper limbs, current pain, pregnancy, chronic illness, cardiac pacemaker, epilepsy, allergies to the TENS electrodes, currently taking pain medication, skin conditions, or deficient skin sensation in the area of electrode placement. After giving informed written consent, participants were randomly allocated to one of 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and, Transient Placebo TENS. No participants withdrew from the study and all participants were included in the analysis. Randomization to groups was performed using a computer generated random number list compiled by a statistician (EMcC-G) not involved in data collection; randomization was stratified for gender thus ensuring equal numbers of males and females in each group. Group allocation was concealed by writing the group allocation onto cards and sealing them in consecutively numbered opaque envelopes. PPT readings from the 2 recording sites were also taken in a random order; this randomization was also performed using a computer-generated random number list compiled by a team member (DW) not
involved in data collection. This random order for PPT readings was also written onto cards and sealed in the same opaque envelopes as described above. The envelopes were locked in a secure cabinet with restricted access and opened after the participant gave consent.
Sample Size Sample size was calculated using a mean difference of 11.97 N (between 2 active TENS groups) and standard deviation of 12.63 N obtained from a recent study on PPT and TENS by 1 of the research team.5 At a significance level of .05, power of 80%, and 5 groups, it was calculated that 26 participants were required in each group (Minitab, v.15, State College, PA), giving a total number of 130 participants for the study.
Intervention Groups An investigator (TL), who was aware of group allocation, applied the TENS intervention. Active or Placebo TENS were applied to the dominant forearm using Select TENS units (Empi, USA) with a balanced asymmetrical waveform at 80 Hz frequency for 30 minutes (see details below). In all groups, 2 self-adhesive electrodes (50 50 mm; TensCare, UK) were positioned on the lateral aspect of the forearm: the distal electrode was placed 1 cm proximal to the proximal border of the anatomical snuffbox and the proximal electrode was placed at a distance of 3 cm from the distal electrode. Participants in all TENS groups (active and placebo) were told they may or may not feel a sensation during the intervention. The pulse duration increased (to a maximum of 400 ms) as the current amplitude increased and ranged between 60 and100 ms. The TENS units were calibrated using an oscilloscope (Model 1602, Gould Electronics, UK) prior to the study commencing. The interventions were as follows: 1) Strong Non Painful TENS. Current amplitude was slowly increased until a level was reached that participants reported was the maximum level they could tolerate below pain threshold. Participants were asked every 3 minutes if the intensity of TENS they were feeling had decreased, and if so, the investigator increased current amplitude until participants reported the same intensity level again; 2) Sensory Threshold TENS. Current amplitude was slowly increased until sensory threshold was reached (ie, barely perceptible). Participants were asked every 3 minutes if the intensity of TENS they were feeling had decreased, and if so, the investigator increased the current amplitude until participants reported that sensory threshold was reached again; and 3) Below Sensory Threshold TENS. Current amplitude was slowly increased until sensory threshold was reached and then decreased to just below this level (ie, not perceptible). The current amplitude remained at this initial setting. Participants in this group were asked every 3 minutes if they were comfortable. Two placebo TENS were delivered: 1) No Current Placebo TENS. A sham device delivered no current (ie, not perceptible). An Empi Select device was used but no current was delivered. Participants in this group were asked every 3 minutes if they were comfortable. Any questions
Moran et al about the lack of TENS sensation in either placebo group were dealt with by the investigator saying that some types of TENS treatments are ‘‘barely perceptible’’; and 2) Transient Placebo TENS. A sham device delivered current for less than 1 minute at a barely perceptible intensity (Select device, Empi, USA) as previously described and validated.9,20 Stimulation was delivered at sensory threshold for 42 seconds (burst stimulus, 80 Hz frequency, 5 seconds cycle time) after which the TENS amplitude reset to 0 mA. These parameters were chosen as they produced a comfortable sensation which lasted long enough for the participant to be aware of it but was too brief to have any definite physiological effect. Participants in this group were asked every 3 minutes if they were comfortable.
Outcome Measure Pressure pain threshold (PPT) was assessed as the primary outcome measure using a pressure algometer (Type II; Somedic Inc, Sweden) which has been shown to be a valid, reliable, and sensitive analgesic assay in the evaluation of hypoalgesic effects of electrophysical agents.1,7 The algometer was applied at a rate of 50 kPas1 with a 1-cm2 probe tip. The outcome assessor (SH) was blinded to treatment group. PPT measurements were assessed at 2 different sites on the dominant upper limb: 1) 3 cm distal to the distal end of the anatomical snuff box in the midline of the belly of the first dorsal interosseous muscle; and 2) on the anterior aspect of the forearm, 7.5 cm proximal to the distal wrist crease. These sites were chosen to examine the effects of TENS within the area of stimulation and in a distal area that was supplied by the stimulated nerve (superficial radial). Participants were asked to say ‘‘stop’’ when the sensation they were feeling turned to pain (distinct from pressure or discomfort); the algometer was then immediately removed and the measurement recorded. Two PPT measurements, taken 10 seconds apart, were recorded at each time point. In a preliminary reliability study (Hawthorne et al, 2009, unpublished data), the outcome assessor (SH) demonstrated excellent intrarater reliability for PPT measurements (Intraclass Correlation Coefficient values: hand, .956; forearm, .974). During the study, PPT was recorded before TENS (Pre-TENS, from hand and forearm), at 15 minutes (during TENS from forearm only), at 30 minutes (immediately after TENS was switched off, from hand and forearm), and at 60 minutes (30 minutes after TENS was switched off, from hand and forearm). It was not possible to record PPT at 15 minutes from the hand as this area was concealed to maintain blinding while the outcome assessor recorded PPT.
Blinding Attempts were made to blind group allocation for participants in the placebo and active TENS groups as follows: the sham TENS device looked similar to the active TENS device; all participants were told verbally that they may or may not feel a sensation; all participants were asked not to discuss any sensations experienced with the outcome assessor; and all participants were
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TENS na€ıve. Further, the outcome assessor (SH) was unaware of the TENS group and a separate investigator applied TENS (TL). At the end of data collection, the effectiveness of blinding was assessed by TL asking the participant which TENS intervention did they think was delivered with 3 options for the answer: ‘‘real’’, ‘‘placebo’’, or ‘‘don’t know’’. After the participant had left the room, the outcome assessor was asked the same question.
Data Analyses Data were analyzed independently by 2 members of the team (CH and FM) who were blind to group allocation using SPSS (v.15.0): an average of the 2 PPT scores recorded at each time point was used for analyses. Shapiro-Wilk tests showed that data were normally distributed; therefore, parametric tests were used to analyze the data. PPT difference scores (variation from baseline values) were analyzed using between-within groups ANOVA, 1-way ANOVA,and post hoc Scheffe tests. To test dose-response effects, the area under the curve was calculated for the 60-minute testing period and correlated with the maximum current amplitude using a Pearson’s correlation coefficient test. Current amplitudes between the groups were compared using 1-way ANOVA and post hoc Scheffe tests. Significance was set at P # .05. Data are presented as the mean 6 S.E.M.
Results The current amplitude (mA) for each amplitude unit on the Select device was calculated by measuring the peak-to-peak voltage of the waveform across a 1 kU resistor on an oscilloscope (Model 1602; Gould Electronics, UK). The mean maximum current amplitude used during the 30 minutes was recorded for each group as follows: Strong Non Painful TENS, 39.13 6 1.27 mA (n = 26); Sensory Threshold TENS, 22.46 6 .84 mA (n = 26); and Below Sensory Threshold TENS, 11.49 6 .74 mA (n = 26) (mean 6 SEM). The current amplitudes of each group were significantly different from each other (P = .0001), showing we were able to apply TENS at several different doses using intensity as dose.
Changes in PPT with TENS The average (mean 6 SEM) baseline PPT of the hand was 221.25 6 8.91 kPa and of the forearm was 264.96 6 11.01 kPa and was not significantly different between groups. Fig 1 illustrates the variation in PPT from baseline for all intervention groups (differences data) at the hand (A) and forearm (B). Statistical analyses of the PPT differences data showed significant differences: over time at the forearm recording points (P = .008); between groups at the hand (P = .005) and forearm (P = .002); and a significant interaction between time and group at the forearm (P = .001). In the hand, the Strong Non Painful TENS group showed a significant hypoalgesic effect compared to the Transient Placebo TENS and No Current Placebo TENS groups at 30 minutes (P = .001, Fig 1A). There was no significant difference between Sensory Threshold TENS and any of the other groups.
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Hypoalgesic Effects of TENS Intensity
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Time (minutes) Figure 1. (A). Hand PPT (kPa) Differences from Baseline (*Indicates Strong Non Painful TENS significantly different to Transient Placebo TENS and No Current Placebo TENS, P = .001). (B). Forearm PPT (kPa) Differences from Baseline (*Indicates Strong Non Painful TENS significantly different to Below Sensory Threshold TENS, No Current Placebo TENS, and Transient Placebo TENS, P < .0001; **Indicates Strong Non Painful TENS significantly different to Below Sensory Threshold TENS, P = .003). In the forearm, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to the Below Sensory Threshold TENS, No Current Placebo TENS, and Transient Placebo TENS groups at 30 minutes (P < .0001, Fig 1B). At 60 minutes, PPT continued to be elevated in the Strong Non Painful TENS group compared to the Below Sensory Threshold TENS group (P = .003). Similar to the hand data, there was no significant difference between Sensory Threshold TENS and any other group.
Relationship Between Current Amplitude and Hypoalgesia To examine the relationship between current amplitude and hypoalgesia, we assessed the effects of active
TENS at different intensities by comparing the area under the curve for changes in PPT at the forearm for the 60-minute period. Fig 2A is a scatter plot of the maximum pulse amplitude (mA) used for each participant and the area for the change in PPT (kPa) in the forearm for the 3 active TENS groups (r2 = .33, P = .003). The summary of the area for each individual group is represented in Fig 2B showing the greatest effect occurring with the highest intensity group.
Blinding Data The outcome assessor responded that she did not know group allocation for all 130 participants, thus showing adequate blinding. The number of participants who correctly guessed their allocated intervention was
Moran et al
Figure 2. (A). Scatter plot of the maximum pulse amplitude (mA) used and the area for the change in PPT (kPa) in the forearm for the 60-minute period for each participant in the Strong Non Painful TENS (Δ), Sensory Threshold TENS (-), and Below Sensory Threshold TENS (Ο) groups (n = 78). (B). Mean area for the change in PPT (kPa) in the forearm for the 60-minute period for Strong Non Painful TENS (C), Sensory Threshold TENS (B), and Below Sensory Threshold (A) TENS groups (n = 78). For comparison, areas for the 2 placebos (Pl) are shown in open symbols (V = Transient Placebo; Δ = No Current Placebo). *Indicates significantly different from Below Sensory Threshold and both Placebo TENS groups.
as follows: Strong Non Painful TENS, 17/26 (65%); Sensory Threshold TENS, 18/26 (69%); Below Sensory Threshold TENS, 14/26 (54%); No Current Placebo TENS, 7/26 (27%); and Transient Placebo TENS, 4/26 (15%). Analysis of these responses showed a significant difference between groups with the Transient Placebo TENS group showing the least number of correct responses (chi-square test, P < .0001). Overall, these data show adequate blinding of the placebo groups as well as the active TENS groups.
Discussion The current study showed, for the first time, a doseresponse effect for TENS. Specifically, using intensity as dose, we have shown that the highest intensities of TENS (Strong Non Painful, Sensory Threshold) produce greater hypoalgesia than lower intensities (Below
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Sensory Threshold) or placebo. Further, the degree of hypoalgesia produced by TENS was significantly correlated with the amplitude of TENS currents and therefore shows that TENS should be delivered at the highest tolerable intensity. These data agree with prior studies that show intensity of stimulation correlates with hypoalgesia in healthy controls,20 and that intensity is a critical factor for postoperative pain reduction.2,19 Our study showed no hypoalgesia with TENS delivered just below sensory threshold, further supporting the notion that TENS should be delivered at a strong intensity. Surprisingly, however, there was no statistically significant difference between the Strong Non Painful (highest intensity) and Sensory Threshold (middle intensity) TENS groups. Further, the Sensory Threshold TENS group was not significantly different from Placebo or Below Sensory Threshold TENS groups. This is a similar pattern seen in typical pharmacological studies with multiple doses. This pattern could be because we continuously increased the current amplitude throughout the application to maintain the target intensity level and could therefore have achieved an adequate intensity towards the end of the stimulation to produce hypoalgesia in some subjects. In a recent study, we showed that increasing current amplitude to maintain the same level of intensity throughout TENS application produced a greater hypoalgesia than keeping the intensity at the initial level.18 Our data agrees with this study and suggests that even starting at sensory threshold intensity and continuously increasing current amplitude to maintain this intensity is enough to produce hypoalgesia. Previous TENS laboratory studies have been conducted to investigate frequency,4 electrode site,3 segmental versus extra segmental stimulation,6 type of electrode,9 and stimulation intensity hypoalgesic effects of TENS.8,15 It is difficult to interpret effects of stimulation intensity in such studies since several variables were varied at the same time. For example, Chesterton et al6 showed that 30 minutes of low frequency (4Hz) extrasegmental stimulation TENS (applied to the leg), at ‘‘maximum tolerable’’ intensity, produced a rapid onset hypoalgesic effect (significant compared to control and sham groups) in the hand. In contrast, high frequency (110 Hz) segmental TENS (applied to the forearm) at ‘‘strong but comfortable’’ intensity produced comparable hypoalgesic levels. Direct comparisons of intensity have been done in several studies using 2 levels. PPT significantly increased with intensities of ‘‘strong but comfortable nonpainful’’ but not ‘‘sensory threshold’’ with high frequency TENS (100 Hz) for 20 minutes.1 Similarly, an intensity described as ‘‘to tolerance without pain’’ showed greater hypoalgesia when compared to ‘‘strong but comfortable’’ intensity with low frequency (2 Hz).15 By definition, these 2 levels of intensity should be very similar, if not identical; this highlights the importance of semantics when describing intensity of TENS. In the future, it would be wise to describe TENS intensity by referring to perceptual thresholds (ie, above or below sensory detection or pain threshold). The second objective of our study was to compare 2 types of placebo TENS: a no-current placebo and a novel
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transient placebo. An adequate placebo is an essential component of trial design in pain research and has proven challenging for TENS due to the perceived sensations of active TENS. While TENS-na€ıve participants are usually recruited for laboratory and clinical studies, the problem remains of how to produce a realistic placebo that mimics the perceived sensations of the active device but produces no analgesia. Typically, clinical trials utilize inactive TENS units that deliver no current, or more recently, subsensory levels of stimulation.17,22 The current study used a new placebo unit, termed Transient Placebo TENS, that delivers a short duration of stimulation. Our group has previously validated this transient placebo20 when delivered at maximal tolerable intensity showing both a lack of hypoalgesia and adequate blinding of both the investigator and the participant. In the current study, the transient placebo TENS was delivered at a sensory threshold intensity level in an effort to further improve blinding. Our prior study20 assessed blinding by asking participants ‘‘Do you think you received an active or placebo treatment?‘‘ and showed that 60% of participants in the transient placebo group correctly identified the intervention as placebo. In the current study, the degree of blinding was higher in
References 1. Aarskog R, Johnson MI, Demmink JH, Lofthus A, Iversen V, Lopes-Martins R, Joensen J, Bjordal JM: Is mechanical pain threshold after transcutaneous electrical nerve stimulation (TENS) increased locally and unilaterally? A randomized placebo-controlled trial in healthy subjects. Physiother Res Int 12:251-263, 2007 2. Bjordal JM, Johnson MI, Ljunggreen AE: Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic consumption. A meta-analysis with assessment of optimal treatment parameters for postoperative pain. Eur J Pain 7:181-188, 2003 3. Brown L, Tabasam G, Bjordal JM, Johnson MI: An investigation into the effect of electrode placement of transcutaneous electrical nerve stimulation (TENS) on experimentally induced ischemic pain in healthy human participants. Clin J Pain 23: 735-743, 2007 4. Chen CC, Johnson MI: An investigation into the effects of frequency-modulated transcutaneous electrical nerve stimulation (TENS) on experimentally-induced pressure pain in healthy human participants. J Pain 10:1029-1037, 2009
Hypoalgesic Effects of TENS Intensity the Transient Placebo TENS group with only 15% of participants correctly identifying that they received placebo. These data support this transient placebo as a useful model since no hypoalgesic effects were observed, and if used at a sensory threshold intensity level, it produces a very high level of participant blinding. In conclusion, this experimental pain study demonstrated a dose response for the intensity of TENS with higher intensities producing a superior hypoalgesic effect than the lower intensities or placebo groups. It is accepted that this study has limitations as it was conducted on healthy participants and future studies will need to be performed on clinical pain conditions to support this observation. The clinical implication of this study is that, ideally, TENS should be delivered at a strong nonpainful intensity level in order to produce maximum pain relief. Finally, this study also provided further data to support the use of a transient placebo TENS as opposed to a no-current placebo TENS in clinical trials.
Acknowledgments Tracey Leonard and Stephanie Hawthorne are equal contributors to this paper.
8. Claydon LS, Chesterton LS, Barlas P, Sim J: Effects of simultaneous dual-site TENS stimulation on experimental pain. Eur J Pain 12:696-704, 2008 9. Cowan SJ, McKenna J, McCrum-Gardner E, Johnson MI, Sluka KA, Walsh DM: An investigation of the hypoalgesic effects of TENS delivered by a glove electrode. J Pain 10: 694-701, 2009 10. Coyne PJ, MacMurren M, Izzo T, Kramer T: Transcutaneous electrical nerve stimulator for procedural pain associated with intravenous needlesticks. J Intraven Nurs 18: 263-267, 1995 11. De Angelis C, Perrone G, Santoro G, Nofroni I, Zichella L: Suppression of pelvic pain during hysteroscopy with a transcutaneous electrical nerve stimulation device. Fertil Steril 79: 1422-1427, 2003 12. Deyo RA, Walsh NE, Schoenfeld LS, Ramamurthy S: Can trials of physical treatments be blinded? The example of transcutaneous electrical nerve stimulation for chronic pain. Am J Phys Med Rehabil 69:6-10, 1990 13. Kalra A, Urban MO, Sluka KA: Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther 298:257-263, 2001
5. Chen CC, Johnson MI: An investigation into the hypoalgesic effects of high- and low-frequency Transcutaneous Electrical Nerve Stimulation (TENS) on experimentally-induced blunt pressure pain in healthy human participants. J Pain 11:53-61, 2010
14. Khadilkar A, Odebiyi DO, Brosseau L, Wells GA: Transcutaneous electrical nerve stimulation (TENS) versus placebo for chronic low-back pain. Cochrane Database of Systematic Reviews, Issue 4, 2008
6. Chesterton LS, Barlas P, Foster NE, Lundeberg T, Wright CC, Baxter GD: Sensory stimulation (TENS): Effects of parameter manipulation on mechanical pain thresholds in healthy human subjects. Pain 99:253-262, 2002
15. Lazarou L, Kitsios A, Lazarou I, Sikaras E, Trampas A: Effects of intensity of Transcutaneous Electrical Nerve Stimulation (TENS) on pressure pain threshold and blood pressure in healthy humans: A randomized, double-blind, placebo-controlled trial. Clin J Pain 25:773-780, 2009
7. Chesterton LS, Sim J, Wright CC, Foster NE: Interrater reliability of algometry in measuring pressure pain thresholds in healthy humans, using multiple raters. Clin J Pain 23: 760-766, 2007
16. Lehmann TR, Russell DW, Spratt KF, Colby H, Liu YK, Fairchild ML, Christensen S: Efficacy of electroacupuncture and TENS in the rehabilitation of chronic low back pain patients. Pain 26:277-290, 1986
Moran et al 17. Nnoaham KE, Kumbang J: Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database of Systematic Reviews, Issue 3, 2008 ~o MA, Laurino MF, Gallego NLG, Cabral CMN, 18. Pantalea Walsh DM, Rakel B, Vance C, Sluka KA, Liebano RE: An investigation of the effect of adjusting pulse amplitude during TENS application. Proceedings of the International Association for the Study of Pain 13th World Congress on Pain, Montreal, 2010. 19. Rakel B, Frantz R: Effectiveness of transcutaneous electrical nerve stimulation on postoperative pain with movement. J Pain 4:455-464, 2003
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20. Rakel B, Cooper N, Adams HJ, Messer BR, Frey Law LA, Dannen DR, Miller CA, Polehna AC, Ruggle RC, Vance CGT, Walsh DM, Sluka KA: A new transient sham TENS device allows for investigator blinding while delivering a true placebo treatment. J Pain 1:230-238, 2010 21. Sluka KA, Walsh DM: Transcutaneous Electrical Nerve Stimulation and Interferential Therapy, in Sluka KA (ed): Mechanisms and Management of Pain for the Physical Therapist, 1st ed, Seattle, WA, IASP Press, 2009, pp 167-190 22. Walsh DM, Howe TE, Johnson MI, Sluka KA: Transcutaneous electrical nerve stimulation for acute pain. Cochrane Database of Systematic Reviews, Issue 2, 2009