Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis. Intermittent claudication (IC) is the most common manifestation and is reported to affect between 10% and 30% of the population older than 60 years.1 Peripheral arterial disease can be asymptomatic in the early stages; however, as the disease progresses, the increasing atherosclerosis manifests as IC,2 which is the cardinal symptom of PAD. Intermittent claudication is defined as pain in the lower limb(s) that is experienced during walking and is relieved by rest.3,4 Patients experiencing IC are characterized by reduced levels of daily physical activity, which is associated with diminished performance of personal, social, and occupational activities of daily life. Many individuals become housebound and dependent on others.5,6 Study results show that patients with severe IC have a quality of life that equates to those with terminal cancer.7
The management of PAD and IC is primarily through the modification of risk factors, with endovascular intervention in severe cases and most medical therapies having only a modest benefit.8,9 Exercise therapy, particularly supervised, is a mainstay of PAD and IC management that has been shown to have a significant effect on increasing walking distance, self-reported physical activity, measured cardiorespiratory fitness, exercise time, and functional ability.3,10–16 Despite the clear benefits of exercise therapy, more than 45% of patients are noncompliant with healthcare professional advice to take regular exercise and to walk “through” IC pain.11 The pain associated with IC has been identified as a key barrier to walking.17 Although acknowledged as a problem, there is limited published literature in which analgesic interventions for IC pain are examined.
Transcutaneous electrical nerve stimulation (TENS) is a safe, inexpensive, and noninvasive method of providing mild electrical stimulation for the relief of pain.18,19 Transcutaneous electrical nerve stimulation has been reported to provide greater analgesic effects than does placebo TENS (P-TENS) for musculoskeletal,20 postoperative,21 and neuropathic pain.22 Packaged in a compact, portable unit that is easy to apply via small electrodes placed on the skin, a TENS unit can be kept unobtrusively in a pocket or clipped to a trouser belt while being used to reduce pain and improve daily functioning.23 However, thus far, TENS has not been tested as a method of reducing pain and improving walking-related function in patients with IC pain.
There are 2 main stimulation patterns, or dosages, of TENS used in clinical practice: high-frequency TENS (HF-TENS) and low-frequency TENS (LF-TENS). It has been suggested in studies conducted to date that the fast-acting, reflexive mechanism of HF-TENS may act most effectively at the mild (pain threshold) level of the pain experience. Low-frequency TENS, however, may act most effectively at the stronger (pain tolerance) level of the pain experience because of extrasegmental but longer-lasting analgesic effects.23
In addition, although TENS has not been widely tested as a method of pain relief of IC, in a previous investigation, reductions in pain (hypoalgesia) were observed with HF-TENS in healthy volunteers experiencing experimentally induced ischemic pain in the lower limb.24 This may be due to the focus on exercise and endovascular intervention as treatments of the condition and limited investigation into the nature of IC pain. In addition, the potential for high-frequency versus low-frequency patterns of TENS to affect different portions of the IC pain experience has not been examined.
We hypothesized that the 2 types of TENS might favorably, but differentially, affect discrete portions of the IC pain experience, for instance, when pain is mild (which normally occurs in PAD patients after walking a short distance) or when it becomes more severe (during continued walking). We therefore aimed to investigate the effects of HF-TENS and LF-TENS on measures of pain and walking performance in patients with PAD and IC.
Materials and Methods
Ethical approval for the study was obtained from the National Health Service East of Scotland Research Ethics Service (reference number: 09/S1402/15). Forty participants with stable PAD and IC were recruited from the vascular outpatient clinic at Ninewells Hospital, Dundee, Scotland, and block randomized into 2 experimental groups (HF-TENS and LF-TENS). The participants provided written informed consent and were included if they had a clinical diagnosis of PAD and stable IC of more than 3 months’ duration; had Fontaine stage II claudication; had a resting ankle brachial index (ABI) of less than 0.90 in at least 1 leg; had walking limited only by claudication; had independent and safe mobility (no walking aids); were cognitively stable and able to follow instructions; and were able to read and complete the questionnaires. Participants were excluded if they were younger than 40 years; had planned surgical or endovascular intervention for PAD; had comorbidities causing pain in the lower limb; had ataxic gait or history of increased falls (unsafe for treadmill walking); had myocardial infarction within the previous 6 months, cardiac dysrhythmia, or a cardiac pacemaker; had current or previous sensation abnormalities in the lower limbs; had epilepsy; had a medical diagnosis of or self-reported psychiatric illness; or had previous experience of using TENS.
The experimental study design was a single-blind, placebo-controlled, phase 2a, proof-of-concept trial. Each participant attended 2 sessions, 6 to 9 days apart, with the majority of participants (n = 30) completing both tests within 7 days. A graded treadmill protocol25 was completed by the participant at each session. Active TENS was applied on the first occasion; and P-TENS, on the second. For the purpose of blinding, the participants were told that “different ‘dosages’ of TENS were being tested, some of which may not be perceptible.” To enhance blinding and reduce the risk for bias, 1 researcher applied the TENS and a different researcher, who was blinded to the study protocol and the order of intervention, conducted the treadmill test and recorded the primary outcome measures.
The treadmill procedure followed, described by Gardner et al,25 in which a GE Marquette treadmill was used. The participants were connected to a 12-lead echocardiograph (GE CASE Premium Stress System), which recorded continuously throughout the procedure. A familiarization session was completed first, in which the participants practiced walking at different speeds (1, 1.5, and 2 mph), and the self-report method of rating claudication symptoms was explained. Further safety instructions were also issued: the participants were reminded to report any feelings of pain distinct from claudication and any feelings of dizziness/light-headedness immediately so that the test could be stopped. This series of events took less than 10 minutes to complete, and the participant walked for a maximum of 30 seconds at each treadmill speed. Once this familiarization procedure was completed, the participants rested supine on a bed for 15 minutes in preparation for the full treadmill test.
Transcutaneous Electrical Nerve Stimulation Procedure
A NeuroTrac 3 TENS machine (Verity Medical Ltd, Surrey, United Kingdom) was fitted to the participant 5 minutes before each treadmill test and continued throughout the procedure. A segmental electrode application was used using self-adhesive carbon rubber electrodes measuring 5 × 5 cm (PhysioMed PALS electrodes, Glossop, United Kingdom). The 2 electrodes were attached to the TENS unit via the manufacturer leads. The area of pain reported by the participant during the familiarization session determined the electrode placement sites. The placement sites were at least 2 cm apart. Electrodes were commonly placed with 1 proximal and 1 distal to the gastrocnemius muscle belly.
The TENS machine was calibrated before use with a digital oscilloscope and tested manually by the investigator before every testing session. The HF-TENS stimulation parameters were calibrated to 120 Hz, pulse width of 200 microseconds, and patient-determined intensity of “strong but comfortable.” The LF-TENS stimulation was set at 2 Hz, pulse width of 200 microseconds, and patient-determined intensity of “strong but comfortable and slight muscle twitch.”
The same TENS model and programmed settings were used in the P-TENS condition but with an inconspicuous break in the wires. This allowed the unit to be switched on with the appearance of a working unit but without any current reaching the participant. This was checked and confirmed with the use of an oscilloscope as described above.
The participants were instructed to report the following:
- When they first experienced claudication symptoms (initial claudication distance [ICD])25
- When they reached the point at which they would usually stop walking (functional claudication distance [FCD])26,27
- When they could not walk any further because of claudication symptoms (absolute claudication distance [ACD])25
Pain quality and intensity were recorded using the McGill Pain Questionnaire (MPQ),28 administered 5 minutes after the participant completed the treadmill protocol. The MPQ consists of a vocabulary of adjectives from which the participant chooses appropriate words to describe the particular qualities of IC pain and accompanying feelings of distress and intrusion.29
The mean scores for ICD, FCD, and ACD were positively skewed, and heteroscedascity was detected. The variance within the data was not addressed with a log (10) transformation applied to normalize the data; thus, nonparametric statistics were used to analyze the data.
Wilcoxon signed rank tests were used to examine within-group differences in treadmill measures and MPQ–Pain Rating Index (MPQ-PRI) scores. To reduce the effect of interparticipant variability, individual change in ICD, FCD, and ACD between P-TENS and active TENS was calculated for each participant. Distance walked with P-TENS was subtracted from the distance walked with active TENS.30 Individual percentage change was also calculated for ICD, FCD, and ACD. The difference between the 2 sessions was calculated as a percentage of the distance walked with P-TENS. These values were then analyzed using Mann-Whitney U tests for between-group comparisons. Statistical significance was set at P = .05 (2 tailed), and analysis was performed using SPSS version 19.0.
Four participants were excluded from analysis because of noncompletion of the experimental procedure. Three had previously unknown exercise-limiting comorbidities, and one was unable to walk safely on the treadmill. The remaining 36 participants (18 in each group) were included in the analysis (29 men; mean age [range], 70 [54–87] years). This information and the flow of participants through the study are summarized and displayed, respectively, in Figure 1. The groups were similar in terms of demographic and disease data. The LF-TENS group had a significantly lower mean ABI (0.57 vs 0.63, t = 2.442) (Table 1).
Within-Group Profiles (High-Frequency and Low-Frequency Versus Placebo Transcutaneous Electrical Nerve Stimulation)
Results of ICD, FCD, and ACD are detailed in Table 2. Compared with P-TENS, median walking distance increased with TENS intervention in both groups. This was true with the exception of FCD in the HF-TENS group (median, 187–175 m) and ICD in the LF-TENS group (median, 81–76 m). All walking-related outcome measures changed with HF-TENS intervention. Only ACD changed with LF-TENS intervention (median, 179–288 m; Ws = 39; z = 2.025; P = .043; r = 0.48). There was no change in MPQ-PRI scores for either group (Table 2).
Between-Group Profiles (High-Frequency Versus Low-Frequency Transcutaneous Electrical Nerve Stimulation)
There was an overall increase in all measures in both groups as shown by the positive change values in Figures 2 and 3. The only difference between the groups was in change and percentage change in ICD (median [interquartile range (IQR)], 26  with HF-TENS and 6  with LF-TENS, U = 268, z = 2.073, P = .038, r = 0.49, and median [IQR], 43  with HF-TENS and 9  with LF-TENS, U = 267, z = 2.088, P = .037, r = 0.49, respectively) (Figures 2, 3).
The results of this study indicate that, compared with placebo, the application of TENS while walking on a treadmill is associated with a modest but statistically significant improvement of walking performance in patients with IC. These results indicate that TENS offers potential as a clinically useful intervention through which patients with IC can walk further before onset of pain and while experiencing pain.
The 2 different stimulus patterns of TENS used in this study were found to affect distinctive aspects of the pain experience. Initial claudication distance and ACD increased with HF-TENS, whereas only ACD increased with LF-TENS. The different stimulus patterns of HF-TENS and LF-TENS seem to have activated different mechanisms of hypoalgesia and distinct neurophysiological effects.
Increases in ICD and ACD were observed in the HF-TENS group, suggesting an immediate and prolonged hypoalgesic effect. Median FCD decreased with HF-TENS intervention; however, this seemed to be due to the large variance within the sample, as illustrated by an increase in IQR (Table 2). In addition, when correcting for baseline ability (change scores, Figures 2), median FCD was found to be greater than zero, therefore indicating an overall increase in walking distance. The increases in median ICD and ACD with HF-TENS were found to be significant with effect sizes of 0.69 (P = .004) and 0.53 (P = .025), respectively (Table 2 and Figures 2, 3). In the LF-TENS group, there was a decrease in median ICD but increases in FCD and ACD, suggesting a delayed but effective hypoalgesic effect at pain tolerance. The increase in ACD with LF-TENS was found to be significant with an effect size of 0.48 (P = .043) (Table 2). Owing to these findings, the investigators suggest that HF-TENS had an immediate and lasting effect: increasing walking distance at the mild (ICD) and more severe phases of the pain experience (ACD). The effects of LF-TENS however, were evident only when the pain was severe (ACD), indicating a delayed action. These results must be interpreted with caution because the significantly lower ABI in the LF-TENS group indicates more severe PAD, which could have contributed to the poor response. A further variable is the sequencing of the placebo after the TENS treatment, which could have unblinded the study for the participants and led to less of a response when no stimulation was perceived.
High-frequency TENS is proposed to act by activating large-diameter mechanoreceptors (Aβ-fibers) and δ-opioid receptors as well as increasing γ-aminobutyric acid in the spinal cord. It is associated with immediate, localized, segmental inhibition as conceived by the original gate control theory.31,32 Low-frequency TENS was originally theorized to act on smaller-diameter nociceptive afferents, brain stem structures, and supraspinal descending pathways, releasing endogenous opiates centrally and peripherally.32,33 In contrast to HF-TENS, it was thought that LF-TENS did not induce immediate hypoalgesia but had a latent effect of pain relief because of its more complex mechanisms.34 These differential mechanisms of action have recently been challenged.35 Nevertheless, the originally proposed mechanisms of action would explain the characteristics of hypoalgesia evident in the current study.
Our “proof-of-concept” results indicate that walking performance improved through HF-TENS during the period of treadmill walking that would normally correspond with the first appearance of IC pain and when it is growing in intensity. In contrast, LF-TENS did not seem to affect walking performance in those portions of the walking exercise. Instead, the effect of LF-TENS corresponds with that later period of treadmill walking when IC pain would normally be most severe and intolerable.
There is no consensus in the literature regarding modification of which aspect of the IC pain experience (ICD, FCD, or ACD) results in the greatest gains in walking performance and therefore the most effective management. From the results of the current study, it would seem that HF-TENS might be more effective because of the hypoalgesic effects evident throughout the pain experience. These conclusions, however, are tentative, and the relationships between the IC pain experience and different applications of TENS could be further explored in future investigations.
Pain relief is thought to be the primary action of TENS; however, neither TENS group reported any change in MPQ-PRI scores. Whereas it is suggested in the results that pain intensity was not affected, an alternative explanation could be related to the experimental methodology. The MPQ was completed at the end of the treadmill test, and the participants were asked to describe their pain at ACD. The participants were therefore walking to the same level of pain intensity on both occasions. As discussed above, ACD increased with both types of TENS intervention, and thus, although there was no change in maximum pain intensity, the distance walked before ACD was reached was greater when using TENS compared with placebo. This result indicates that through TENS, rather than masking and reducing the experience of maximum pain in patients walking with IC pain, the time taken to reach pain tolerance is prolonged. This finding is in line with results of our experimental study of TENS for laboratory-induced lower limb ischemic pain in healthy volunteers.24,36
Compared with P-TENS, the median change in ACD with HF-TENS was 30 m; and with LF-TENS, 23 m. This relates to percentage increases of 13% for HF-TENS and 18% for LF-TENS (Figure 3). A 60% improvement in ACD has been suggested as a functionally significant improvement in walking distance for patients with IC.37 The observed effect of TENS on walking performance in the current study, conducted within the operational constraints imposed by a routine PAD clinic setting, was such that one might anticipate a degree of “dampening” of the potential effect of TENS. A familiarization or training effect has been shown with the Gardner treadmill test.38 Cognizant of this fact, the P-TENS condition was examined on the second testing session for every participant. By the nature of this design, any effect of TENS observed would be masked by the potential accommodation effect during the second treadmill test. The training/accommodation effect for the Gardner treadmill protocol has been found to be 15% for ACD.38 With this in mind, the significant increases of 13% and 18% with HF-TENS and LF-TENS may become closer to a clinically worthwhile improvement. Intermittent claudication medication is associated with an increase of approximately 30% compared with placebo.39 The change in ACD with TENS intervention, taking into account the possible treadmill walking accommodation effect (10%), is close to this level of improvement (increase of 23% and 28% compared with placebo). Investigators of future studies should include treadmill familiarization and use a randomized order of entry and a crossover design to more accurately explore the effect of TENS on walking performance in patients with IC.
The authors of this study make a novel contribution to the literature on the management of PAD and IC. There is no previously published report of the effect of TENS on walking performance and pain in this patient population. Our clinical results are also supported by our previous publication on HF-TENS for ischemic pain in healthy volunteers.24 However, this is a “proof-of-concept” study. The effectiveness of TENS as an adjunctive intervention for walking performance in patients with IC could be examined in more detail through further study. For example, further investigation is required in which the effects on pain, hemodynamic changes, and gait during treadmill walking are examined. There is also a need for investigations in which the effects of TENS on IC-limited walking in people with PAD are explored during more ecologically valid (over-ground) walking tasks.
One aspect of the current study that could be viewed as a limitation is the lack of a no-TENS control group. By neglecting to include a no-TENS control condition, it was not possible to accurately quantify the effect of the placebo effect of TENS. It has been proposed that part of the beneficial effect of TENS is the sense of “control” and the perception of receiving an “intervention” experienced by patients when applying the device. Without a no-TENS group, this effect cannot be quantified. The study was designed as a proof-of-concept, Medical Research Council phase 2a trial, and a pragmatic approach was assumed. When investigating the effects of TENS with the aim of evaluating physiologically quantifiable outcomes, TENS must demonstrate efficacy above placebo; therefore, the current study design is sufficient. Nevertheless, a no-TENS control should be included in future studies to allow investigation of the placebo response to TENS in PAD and IC.
Another possible limitation of this study was the ordering of intervention. Because the treadmill test with active TENS preceded the application of placebo for all participants, any effect of TENS observed could be temporal. This design was selected to account for participant familiarization with the treadmill test. Previous research has indicated that participants commonly walk approximately 15% further during subsequent graded treadmill tests.37 What this design achieves is that any signal detected (ie, an increase in walking distance with TENS) must have first exceeded the “noise” of familiarization. Overall, this design “handicapped” the study and ensured that any findings are more cautious.
Patients with IC experience a gradual buildup of pain to tolerance when exercising until the pain becomes intolerable. The authors of the current study aimed to investigate the effects of 2 types of TENS (high and low frequency) on the pain experienced and walking performance in patients with PAD and IC. The results indicate that the distance walked before tolerance increases through TENS. Both types of TENS were found to increase walking performance, but HF-TENS was more effective at prolonging the time to reach pain threshold.
- Transcutaneous electrical nerve stimulation may be a useful, cheap, safe, and noninvasive adjunct intervention used to facilitate walking and physical activity in patients with PAD and IC.
- Two different modes of TENS were applied over the site of IC pain during a standardized graded treadmill test.
- Initial claudication distance and ACD increased with HF-TENS, but only ACD increased with LF-TENS, compared with P-TENS.
- Transcutaneous electrical nerve stimulation intervention is associated with an increase in treadmill walking performance in patients with PAD and IC.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved
exercise therapy; intermittent claudication; ischemic pain; peripheral arterial disease; transcutaneous electrical nerve stimulation