Perspective. What Makes Transcutaneous Electrical Nerve Stimulation Work? Making Sense of the Mixed Results in the Clinical Literature

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1 Perspective What Makes Transcutaneous Electrical Nerve Stimulation Work? Making Sense of the Mixed Results in the Clinical Literature Kathleen A. Sluka, Jan M. Bjordal, Serge Marchand, Barbara A. Rakel Transcutaneous (TENS) is a nonpharmacological treatment for control of pain. It has come under much scrutiny lately with the Center for Medicare Services rendering a recent decision stating that TENS is not reasonable and necessary for the treatment of CLBP [chronic low back pain]. When reading and analyzing the existing literature for which systematic reviews show that TENS is inconclusive or ineffective, it is clear that a number of variables related to TENS application have not been considered. Although many of the trials were designed with the highest of standards, recent evidence suggests that factors related to TENS application need to be considered in an assessment of efficacy. These factors include dosing of TENS, negative interactions with long-term opioid use, the population and outcome assessed, timing of outcome measurement, and comparison groups. The purpose of this perspective is to highlight and interpret recent evidence to help improve the design of clinical trials and the efficacy of TENS in the clinical setting. K.A. Sluka, PT, PhD, FAPTA, Department of Physical Therapy and Rehabilitation Science, College of Medicine, College of Nursing, Pain Research Program, University of Iowa, 100 Medical Education Bldg, #1-252, Iowa City, IA (USA). Address all correspondence to Dr Sluka at: kathleen-sluka@uiowa.edu. J.M. Bjordal, PT, PhD, Physical Therapy Research Group, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; and Centre for Evidence-Based Practice, Bergen University College, Bergen, Norway. S. Marchand, PhD, Département de Chirurgie, Centre de Recherche clinique Étienne-Le Bel du CHUS, Université de Sherbrooke, Québec, Canada. B.A. Rakel, RN, PhD, Department of Physical Therapy and Rehabilitation Science, College of Medicine, College of Nursing, Pain Research Program, University of Iowa. [Sluka KA, Bjordal JM, Marchand S, Rakel BA. What makes transcutaneous work? Making sense of the mixed results in the clinical literature. Phys Ther. 2013;93: ] 2013 American Physical Therapy Association Published Ahead of Print: May 2, 2013 Accepted: April 24, 2013 Submitted: July 30, 2012 Post a Rapid Response to this article at: ptjournal.apta.org October 2013 Volume 93 Number 10 Physical Therapy f 1397

2 stimulation (TENS) is an electrotherapeutic procedure used for pain control that has been examined in the medical literature since its introduction by Wall and Sweet in It has come under much scrutiny lately with the Center for Medicare Services rendering a recent decision stating that TENS is not reasonable and necessary for the treatment of CLBP [chronic low back pain]. 2 Several systematic reviews similarly show TENS is ineffective or inconclusive for a variety of painful conditions. 3 9 In light of these recent reports, we believe it is critical to take a closer look at TENS effectiveness in clinical trials. We suggest that several factors, not commonly taken into account when designing clinical trials for TENS, could contribute to the confusion in the literature on TENS effectiveness. These factors include: (1) those that affect TENS efficacy dosing (intensity) of TENS, negative interactions with long-term opioid use, tolerance, and the population assessed; (2) appropriate outcome measurement timing of assessment and type of outcome; and (3) appropriate comparison groups. These factors need to be considered in the design of randomized controlled clinical trials and systematic reviews to effectively evaluate TENS. This perspective article will elaborate on the above factors, giving examples from the primary literature on TENS to make recommendations for future clinical trials and systematic reviews. Factors Affecting TENS Efficacy Dosing of TENS Intensity of stimulation (amplitude). It has become increasingly clear in the last decade that intensity of TENS is critically important to obtain a positive effect. Specifically, stimulation amplitude must be of sufficient strength to produce an analgesic response Three recent studies in individuals who were healthy support this finding. 10,13,14 Specifically, TENS delivered at a strong but comfortable intensity provided a significant analgesic effect, whereas TENS delivered at or below sensory threshold was ineffective. 10,13,14 Thus, amplitude must be increased to an adequate level to produce analgesia. Although typically high-frequency TENS is applied to produce a nonpainful paresthesia, we suggest that all patients should be encouraged to increase intensity to a strong but comfortable intensity, just below pain threshold, and continue to increase intensity as tolerated. Low-frequency TENS, on the other hand, is typically applied at higher intensities that produce motor contractions, and we also propose to increase intensity as tolerated. Analysis in systematic reviews that consider dosing show that high intensities are associated with significant reductions in both postoperative and osteoarthritis pain and lower intensities are not effective. 11,15 Thus, we suggest that amplitude should be increased to the highest tolerable level and, at a minimum, should reach a strong but comfortable sensation. Furthermore, as TENS is not always tolerated at higher intensities by all patients, TENS amplitude and usage should be carefully monitored. Analysis should examine effectiveness between adequate verses inadequate intensities. Another variable that could influence results is accounting for habituation when regulating TENS intensity (ie, perceptual-sensory adaptation to TENS). Clinically, patients and therapists typically increase intensity to maintain the strong, but comfortable intensity during a session, and a recent study showed that, in a single session, there was a greater analgesic effect when TENS intensity was titrated upward during therapy. 16 Repeated use. Several clinical studies show a cumulative effect of TENS with a variety of pain conditions For example, there was a cumulative reduction in pain with repeated application of TENS (2 / week) in people with chronic low back pain. 19 The literature does not provide definite answers to why this cumulative long-lasting TENS effect occurs. One possibility is that TENS reduces sensitization that normally occurs in chronic pain. Sensitization can occur in the peripheral or central nervous system and is associated with enhanced excitability of neurons along the pathways. Specifically, neurons show increased spontaneous firing, increased response to noxious stimuli, and increased responses to innocuous stimuli. In addition, chronic pain conditions are associated with a loss of descending pain inhibition. 21 Together, the enhanced excitability and loss of inhibition result in increased pain. There is experimental evidence that TENS reduces this central excitability and restores inhibition with repeated usage. Strong-intensity electrical stimulation reduces central sensitization in animal models of pain and activates descending inhibitory pathways We hypothesize that repeated TENS may cause a re-booting of one or more of the sensitization processes that results in a cumulative and longer-lasting TENS effect. Alternatively, it is possible that the cumulative effect could be secondary to reductions in pain, allowing increases in physical activity. These increases in physical activity would have the added benefit of decreasing pain and present as a cumulative effect of treatment. It should be noted that repeated application of the same dose (frequency, intensity, duration) of TENS daily over a week results in analgesic tolerance in animals with inflammation and individuals who are healthy. 27,28 This result may seem 1398 f Physical Therapy Volume 93 Number 10 October 2013

3 in direct contrast to that observed in the clinical trials mentioned above showing a cumulative effect of TENS. However, clinical trials in people with chronic pain conditions showing a cumulative effect generally increase intensity to a patient descriptor such as strong, but comfortable. Thus, patients likely become more comfortable with TENS over time and are able to tolerate higher intensities. In support, preclinical studies show that increasing intensity 10% daily delays the onset of analgesic tolerance. 29 Furthermore, people with a pain condition have altered neuronal processing that could directly modify the mechanisms related to the development of tolerance. The effects of repeated stimulation of TENS at the same dosage in people with chronic pain conditions are largely unknown, and this is a gap in the literature that needs further evaluation. Stimulation frequency. Different frequencies of stimulation, as stated above, activate different mechanisms. Furthermore, patients typically find higher frequencies more comfortable, and thus higher frequencies are usually tried before lower frequencies. However, because repeated TENS can produce analgesic tolerance, 27,28 mixedfrequency TENS may be a better choice. Modulating between low and high frequencies significantly delays opioid tolerance. 30 On the other hand, if patients are taking opioid analgesics, high-frequency TENS will likely be more effective than low-frequency TENS and should be used alone. 31,32 Long-term usage. Lastly, payers are concerned about long-term effectiveness of repeated TENS. By itself, TENS is not considered curative, and thus one would not expect its effects to be observed for weeks, months, or years after stopping stimulation. However, long-term usage of TENS (over months or years) is common with people buying and using TENS units for months or years, particularly for chronic pain conditions. The majority of controlled clinical trials examine TENS efficacy with a single treatment or up to a few weeks of treatment. Two studies, however, examined long-term usage of TENS in patients with chronic pain through a retrospective interview. 33,34 These studies showed that those who use TENS longterm ( 6 months) have significant decreases in pain with activities, increased activity levels, and decreased use of pain medications and health services. Prospective studies are needed that examine long-term TENS efficacy when compared with a placebo. Long-term efficacy should not be confused with long-term follow-up where patients have not used the TENS unit for months prior to evaluation. Interactions With Pharmacological Agents stimulation produces its effects through activation of opioid receptors in the central nervous system. Low-frequency TENS (1 10 Hz) activates mu-opioid receptors, and high-frequency TENS ( Hz) activates delta-opioid receptors. 26,35 Clinically available opioid analgesics use mu-opioid receptors to produce their effects. If opioid tolerance is present, it would follow that lowfrequency TENS would be ineffective and high-frequency TENS would still work. Initial studies in an animal model showed that low-frequency TENS was ineffective if animals were tolerant to morphine, a muopioid agonist; high-frequency TENS was still effective. 32 These findings were recently confirmed in patients with chronic pain, again showing that low-frequency TENS was ineffective if opioid tolerance was present, but high-frequency TENS was still effective. 31 These results underline the importance of understanding the potential interactions of drugs with TENS, and future research should explore other pharmacologic interactions. Patient Population stimulation may not be effective for all pain conditions. Understanding pain biology and the underlying mechanisms of the pain condition treated with TENS will help in defining the appropriate patient populations. Transcutaneous electrical nerve stimulation works by increasing endogenous inhibition and reducing central excitability. 23,24,26,35 37 Both loss of inhibition and increased central excitability are key components in most chronic pain conditions. 21,38,39 Using this knowledge of pain biology, Johnson and Martinson 40 performed a rigorous meta-analysis that included data from 27 randomized trials on patients with chronic ( 3 months) musculoskeletal pain. They reported that TENS had a favorable pooled effect that was greater than placebo. Using these same principles, TENS has been shown to be effective for osteoarthritis, fibromyalgia, and neuropathic pain, all conditions with enhanced excitability and reduced inhibition. 17,41 44 Factors Related to Outcome Assessment Timing of Outcome Measurement As with any intervention, measurement of outcomes should occur during peak effect. Several studies in people with chronic pain showed peak effects of TENS when the unit was on or immediately after stopping TENS. 19,44 46 Transcutaneous is an adjunct treatment for pain control that produces its effects through activation of the endogenous inhibition system using neurotransmitters October 2013 Volume 93 Number 10 Physical Therapy f 1399

4 with defined duration of action. Thus, measurement of TENS efficacy should be done when TENS has the greatest effect. Some studies have measured TENS effect 1 week to 6 months after stopping TENS (for example, see Deyo et al 47 ). This approach is unlikely to demonstrate an effect. For comparison, one would test efficacy of morphine during peak effect and not several days after being given the drug. We suggest that the effects of TENS should be examined while the TENS unit is activated and after a designated period of use (eg, before and during TENS after a single treatment and after 1 month or 3 months of treatment). Effects of long-term usage of TENS should be examined (ie, a clinical trial should include a minimum of 1 month of treatment but should consider several months in the design). Measurement of pain intensity prior to TENS at each follow-up visit (eg, 1 month, 2 months, 3 months, and so on) examines for cumulative effects, and measurement of pain during TENS on each visit examines effects of longterm usage. If pain intensity prior to TENS is lowered at follow-up, it would be useful to investigate the duration of the TENS effect and whether similar results can be achieved with a subsequent TENS treatment. 19 This design will answer questions of long-term effectiveness as well as questions of effectiveness over a long duration of continued use. Outcomes Measured stimulation may differentially affect a variety of outcomes related to pain. Understanding the most important outcome measures used to examine TENS efficacy will improve its use and clinical effectiveness. Experts in clinical pain research proposed guidelines for the measurement of pain treatments outcomes under the name of IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) that focus on core outcome domains: pain, physical function, emotional function, global improvement, symptoms, and adverse events. 48,49 Although TENS may have an effect on resting pain in some populations, 18,19 it appears to be more effective for reducing pain during movement and hyperalgesia. 12,20,42,44,50 For example, in postoperative patients, there was a smaller effect of TENS on resting pain than in pain during walking and deep breathing, 12 and in patients with fibromyalgia, TENS was ineffective for resting pain but produced a significant reduction in walking pain. 41 These results suggest that application of TENS may be most effective during physical activity and exercise programs. Although it is not clear whether all conditions show this differential effect between resting and movement pain, we suggest future studies measure both to assess the efficacy of TENS. Movement pain is an evoked pain response. Similarly, measurement of hyperalgesia (ie, increased response to noxious stimuli) and allodynia (ie, painful response to previously nonpainful stimuli) are evoked pain responses. Prior work in patients who were healthy showed that pain thresholds were routinely increased by TENS. 10,13,16,27,51 In a clinical trial in patients with neuropathic pain, TENS reduced allodynia when compared with a placebo intervention. 17 Similarly, in patients with fibromyalgia and osteoarthritis, deep tissue hyperalgesia (pressure pain threshold measures) was reduced. 17,41,44 Thus, evoked pain responses may be more responsive to TENS than spontaneous (ie, resting) pain. In addition, multiple outcome measures related to patient improvement should be assessed. People with chronic pain may be willing to accept a certain level of pain and thus may increase activity levels despite reporting a similar level of pain with effective treatments. Hence, simple reduction in pain may not be observed with all treatments. Thus, additional measures, including effects on medication usage, health care usage, function, and quality of life, may be helpful to include. The effects on function can be assessed by a survey but also may include functional tests generally used in the clinic, such as the Six-Minute Walk Test. For example, Cheing and colleagues 43,50 showed TENS improved performance on the Timed Up & Go Test and reduced pain during walking in people with osteoarthritis. Alternatively, TENS may not have an impact on disability or function, as TENS is not an intervention for improving functional outcomes per se. For example, one study concluded that TENS for low back pain was ineffective based on a primary outcome measure of disability, while overlooking a significant effect on pain outcomes. 52 To facilitate future systematic reviews, it would be helpful if standardized outcomes were adopted so that meta-analysis could be performed. For example, using the 36-Item Short-Form Health Survey for quality of life or the Brief Pain Inventory for chronic pain allows comparison not only within a treatment but also with other treatments. Using the IMMPACT guidelines as outcome measures in clinical trials on pain (see will further assist in comparison between TENS and other treatments. 48,49 Factors Related to Trial Design General Design Clinically, TENS often is utilized daily for long periods in which the patient is sent home with the unit and 1400 f Physical Therapy Volume 93 Number 10 October 2013

5 allowed to use it as needed for pain relief. We suggest, therefore, that TENS be given to patients to use in their home environment and that they be instructed to use the device when they are physically active. This utilization of TENS would entail measurement of adherence to usage, ideally monitored electronically within the unit. Clinically, TENS is usually given to patients as an adjunct treatment designed to reduce pain it is not given as a sole treatment. Patients, therefore, are being managed with other treatments that could include pharmacological treatment aimed at reducing pain, psychological therapies aimed at cognitive and behavioral change, or exercise and physical activity aimed at improving physical function. We suggest, therefore, that TENS not be given as a stand-alone treatment but rather be evaluated as an adjunct to an ongoing stable treatment plan to more accurately assess its effectiveness for clinical use. Comparison Groups Use of an adequate placebo is critical to all pharmacological and nonpharmacological clinical trials on pain. Therefore, all TENS clinical trials should be done using a placebo TENS unit. A new placebo TENS unit, termed transient placebo TENS, has recently been developed, which turns on for a short duration ( 1 minute). This unit results in complete blinding of both the investigator applying the TENS and the patient and is significantly better than the traditional placebo applied in clinical trials, which is a unit that was modified to deliver no current. 10,44 Thus, it is now possible to perform a double-blind trial on TENS. We also recommend comparison with a standard care group and that TENS be given in addition to standard care treatments and not as a stand-alone treatment. We would not expect that TENS be the only treatment a patient receives but rather an adjunct treatment to a more complex treatment plan. It is important, therefore, to determine whether the addition of TENS to standard care has an effect beyond standard care alone. Summary In summary, more careful scrutiny of the existing literature is needed. The existing clinical literature is conflicting with regard to the effectiveness of TENS. Indeed, current Cochrane reviews of TENS and painful conditions ( ) end with a determination of inconclusive, insufficient, or conflicting evidence. 3 9 The Cochrane reviews suggest future research should be aimed at higher-quality trials, large multicenter trials, and trials designed with adequate power. We suggest that future clinical trials be designed taking into account adequate dosing of TENS, medication usage, timing of outcome measurements, outcomes measured, and the clinical population to be studied. Using the physiologic principles and basic science evidence on TENS mechanisms and time-effect profiles, along with the clinical evidence on dosing and outcomes, is imperative for future clinical design to adequately examine efficacy of TENS. These principles also are critically important when analyzing the existing literature in systematic reviews. Thus, future clinical trials and systematic reviews should use the principles outlined in this review to determine the efficacy of this inexpensive, nonpharmacological treatment for pain. All authors provided concept/idea/project design and writing. Dr Sluka has consulted for DJO Inc, Regeneron Pharmaceuticals Inc, and Abbott Laboratories and holds research grants from Medtronic Inc and Grunenthal GmbH. Dr Rakel receives research support from DJO Inc. This work was supported, in part, by National Institutes of Health grants AR052316, AR061371, AR063381, and NR DOI: /ptj References 1 Wall PD, Sweet WH. Temporary abolition of pain in man. 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