Antihypertensive effect of low-frequency transcutaneous electrical nerve stimulation (TENS) in comparison with drug treatment

Abstract

Hypertension is a major risk factor for vascular disease, yet blood pressure (BP) control is unsatisfactory low, partly due to side-effects. Transcutaneous electrical nerve stimulation (TENS) is well tolerated and studies have demonstrated BP reduction. In this study, we compared the BP lowering effect of 2.5 mg felodipin once daily with 30 min of bidaily low-frequency TENS in 32 adult hypertensive subjects (mean office BP 152.7/90.0 mmHg) in a randomized, crossover design. Office BP and 24-h ambulatory BP monitoring (ABPM) were performed at baseline and at the end of each 4-week treatment and washout period. Felodipin reduced office BP by 10/6 mmHg (p <0.001 respectively) and after washout BP rose to a level still significantly lower than at baseline. TENS reduced office BP by 5/1.5 mmHg (p <0.01, ns). After TENS washout, BP was further reduced and significantly lower than at baseline, but at levels similar to BP after felodipin washout and therefore reasonably caused by factors other than the treatment per se. ABPM revealed a significant systolic reduction of 3 mmHg by felodipin, but no significant changes were noted after TENS. We conclude that our study does not present any solid evidence of BP reduction of TENS.

Key Words::

• blood pressure
• felodipin
• hypertension
• transcutaneous electrical nerve stimulation
• TENS
• treatment

Introduction

The cause of essential hypertension is multifactorial and several lines of intervention are needed to attain sufficient blood pressure (BP) control. First line treatment is lifestyle intervention but drug treatment is often necessary to achieve adequate and prompt BP reduction. Despite the well known elevated risk of cardiovascular complications due to hypertension, BP control in studied countries is unsatisfactorily low. Rarely more than 30% of the patients reach their BP target in spite of pharmacological treatment (1). Several reasons to explain failure in treatment include insufficient lifestyle interventions, socio-economic factors and gender of the physician (2,3). Furthermore, intolerable side-effects may prevent successful treatment irrespective of the number of drugs, and with an increasing number of drugs the risk of interactions and side-effects grows. In elderly patients, who are at higher risk of cardiovascular events, other co-existing afflictions often contribute to polypharmacy and at the same time, these patients are generally more sensitive to side-effects and pharmacological interactions (4). Thus, there is a need for non-pharmacological treatment options.

Transcutaneous electrical nerve stimulation (TENS) constitutes no risk of interaction with pharmacological agents. The field of electrical stimulation including the mechanisms of TENS and electroacupuncture (EA) is being explored in several areas but the mechanisms are not fully understood. High-frequency TENS (70–100 Hz), considered to stimulate A beta fibres to activate the “gate control” mechanism (5) at spinal level, is widely used for the treatment of pain. Studies have shown vasodilating properties of both high-frequency (6,7) and low-frequency (1–15 Hz) (8–11) TENS and direct peripheral nerve stimulation (12,13). The results though are sometimes contradictory (9–11,14), as are the results from studies of the response during opioid antagonist administration (9,13,15–17). According to reports from clinical studies, high- frequency TENS have improved tissue healing (18,19). Apart from prompt BP reduction, antihypertensive effect of low-frequency TENS has been reported after longer periods of treatment (20,21) but these results have not been sufficiently confirmed.

The primary objective of this randomized crossover design study of subjects with grade I–II hypertension was to evaluate the antihypertensive effect of low-frequency TENS in comparison to the calcium-channel blocker felodipin, with the secondary objective to evaluate the tolerability of the stimulation therapy.

Materials and methods

Subjects and recruitment

Most subjects were recruited by advertisement in a daily newspaper and four by the research team after having shown interest in participation in other studies.

Eligible for inclusion were men and women of more than 18 years of age with a history of hypertension. Individuals with systolic BP (SBP) of 140–170 mmHg and/or diastolic BP (DBP) of 90–105 mmHg or established hypertension with current medication with a maximum of one BP lowering agent were included. Patients with second- or third-degree atrioventricular block and current use of opiates or other intoxicants as well as neurological disorders (such as Parkinson's disease, multiple sclerosis or peripheral neuropathy) were not included. Subjects in need of treatment with TENS, regardless of the reason, were excluded.

Study design

This prospective, randomized, crossover study was conducted at Sahlgrenska University Hospital/Östra, Gothenburg, Sweden, in accordance with the Declaration of Helsinki and with approval by the Regional Ethical Review Board, University of Gothenburg (2008-01–07, Dnr: 647-07). Written informed consent was obtained from all subjects. All subjects tried TENS prior to the decision of participation. The medical history was taken and a physical examination including ECG was performed. In case of current treatment, this was terminated and an office BP was measured after 2 and 4 weeks before decision of inclusion. If the inclusion criteria were met, an office BP was measured and ambulatory BP monitoring (ABPM) was performed. In randomized order, the subjects were allocated to treatment with TENS or felodipin followed by a washout period, a second treatment period with the alternative treatment and a final follow-up period. All periods of treatment, washout and follow-up were 28±4 days. Office BP and ABP were recorded prior to randomization and after each treatment and washout period.

TENS

The electrodes were placed on the hand over musculus abductor pollicis between the first and second metacarpal bone and over musculus extensor carpi radialis two finger breadths distal to the radial part of the bend of the arm. The electrode placement was chosen in accordance with a previous study by our group (21) and corresponds to acupuncture points LI 4 and LI 10, respectively. The stimulation was bilateral and performed 30 min in the morning and 30 min in the evening. We used 2-Hz Primo Pro stimulators from CefarCompex (Sweden) that produces two bursts of eight pulses each second. The current is alternating with a biphasic asymmetrical waveform and because of the polarity with greater activity under one of the adhesive electrodes (cathode, black), these were placed on the arm. The amplitude of the current was set by the subjects with the recommendation to increase the amplitude gradually to trigger contractions of the underlying muscles without reaching painful levels. The subjects were asked to keep a treatment diary and the stimulator registered the total time of stimulation. To evaluate the tolerability of the stimulation, all subjects were asked if they would consider stimulation as a prolonged treatment, and if not, whether discomfort or practical difficulty was the main reason.

Drug treatment

Calcium-channel blocker felodipin (2.5 mg) was taken orally each morning during the treatment period. Felodipin is one of several well studied first-line drugs for the treatment of hypertension. The antihypertensive effects are achieved early, it is well tolerated and requires no specific measures of follow-up. The BP reducing effect of the chosen dosage is documented (22) and according to a meta-analysis by Law et al. (23), a BP reduction of approximately 6/4 mmHg can be expected by treatment with half a so-called standard dose of calcium-channel blockers. 2.5 mg of felodipin equals a half standard dose and the low-dose regimen was chosen to minimize drop-out secondary to side-effects and hypotension in this group of subjects with grade II hypertension at most.

Outcome measures

Office BP measurements were performed after 5 min of rest in the supine position, with a manual sphygmomanometer and the arm at heart level. The BP was measured in both arms and the recorded value was the mean of at least two measurements in the arm with the highest pressure.

During ABPM, the BP was measured three times per hour during the daytime (06:00 to 23:00 h) and two to three times per hour during the night, using ABP monitors from Spacelabs Medical (Issaquah, WA, USA), models 90207 and 90217. The mean values for each hour were used for statistical analysis.

Statistical analysis

The sample size needed was based on the following calculation. To explore a difference between treatment regimens of 8/4±20/11 mmHg we would with 80% power need to examine 31 individuals (t-test (ANOVA) for difference of means in 2 × 2 crossover design). A pilot study by Jacobsson et al. (21) showed a TENS mediated BP reduction of 6/4mmHg. Our choice of a BP difference of 8/4 mmHg was partially based on this study and partially to compensate for statistical regression towards the mean. All tests we considered significant at the alpha level p <0.05.

One-sample t-test was used for testing significant change between two measurements and the subjects were used as their own control. A two-sample t-test was used for testing significant difference in mean between two groups.

SPSS (version 17) and analysis programs developed at the department of Community Medicine and Public Health at University of Gothenburg were used for analysis.

Results

Baseline characteristics

32 participants (mean age 55 years, mean Body Mass Index (BMI) 27.9 kg/m²) of which 24 were Caucasian men (mean age 54 (26–67) years, mean BMI 27.3 (20.4–32.3) kg/m²) and 8 Caucasian women (mean age 57 (46–67) years, mean BMI 29.6 (21–47.3) kg/m²) were investigated.

Initially 41 individuals were included, but nine subjects were excluded for the following reasons: one because of late received information of both day- and night-time employment and two because of resumed anti-hypertensive medication on their own initiative. Two chose to discontinue the participation as they moved from the region and one because of TENS discomfort. Three subjects showed a total stimulation time of less than 60% of the lower intended stimulation time and were removed from the analysis, whereas the remaining subjects all had stimulation percentages above 70%.

Office BP measurements

At baseline, there was no significant difference between the groups. Compared with TENS, treatment with felodipin reduced BP by 5.3/4.8 mmHg (p <0.05 and p <0.001).

Compared with baseline (SBP 152.7±8.9 mmHg and DBP 90.0±7.1 mmHg), TENS reduced SBP to 148.0±12.1 mmHg (p <0.01), while the slight reduction of DBP to 88.5±6.3 mmHg was non- significant. After the TENS washout period, SBP was reduced to 145.6±10.4 mmHg and DBP to 87.2±9.3 mmHg (p <0.001 and p <0.05, respectively). Felodipin treatment reduced SBP to 142.7±11.7 mmHg and DBP to 83.7±8.7 mmHg (p <0.001 for both). After felodipin washout, SBP rose to 145.8±12.5 mmHg and DBP rose to 86.9±9.2 mmHg, but both remained significantly lower than baseline (p <0.01 and p <0.05) (Figure 1).

Figure 1. Office blood pressure. Systolic (striped) and diastolic (white) blood pressure ±1 SD at baseline and after each study phase. Note the crossover design in which the treatment periods are non-consecutive. Significance of differences between groups indicated at brackets. Significance of changes versus baseline indicated at bars. ns, non significant, *p <0.05, **p <0.01, ***p <0.001.

ABPM

Felodipin lowered the 24-h ambulatory measurements of SBP by 3.4 mmHg and daytime ambulatory measurements of SBP by 3.8 mmHg (p <0.01 for both) without any effect on DBP. No significant alterations of either systolic or diastolic ABPM were found in response to TENS.

Heart rate

During the registration of heart rate, no significant changes were found in response to either treatment, neither during resting conditions nor during the ambulatory registrations.

TENS tolerability

90 per cent of the subjects reported their performed stimulation. The intended duration of stimulation was 28±4 days, attained by all but two subjects (19 days and 37 days). The average duration was 28.3 days. In 93%, the total stimulation time was recorded with an average of 30 h 4 min; 93% of the subjects responded to whether they would accept TENS as an option for further treatment. Of these, 62% responded affirmative, 19% were negative to further treatment due to the complicated and time consuming procedure, and 19% were negative partly because of discomfort.

Discussion

Treatment with felodipin significantly reduced BP compared with TENS with a difference of 5/5 mmHg. Compared with baseline, TENS reduced the office SBP by approximately 5 mmHg, whereas no significant DBP reduction was seen. However, both SBP and DBP after the TENS washout period were further reduced to significant levels compared with baseline. In response to felodipin we found a reduction of office BP by 10/6 mmHg, which remained significantly reduced after the washout period.

ABPM revealed significant SBP reduction after felodipin treatment, whereas no BP changes were seen after TENS.

As previously described, many studies have reported TENS-induced vasodilation but the BP reducing capability from a clinical point of view is not equally investigated. In a study of low-frequency TENS compared with placebo TENS in a blinded parallel group design, Kaada et al. (20) reported a significant BP difference of 7 mmHg between the groups at the end of two weeks of stimulation, but whether post-stimulatory BPs significantly differed from baseline BP was not reported. A study by Jacobsson et al. (21) that showed a prolonged BP reduction was small, open and non-randomized, which makes the results less firm and in need of confirmation. In an abstract by Wan et al. (24), the antihypertensive effects of EA (often described as being similar to transcutaneous electrical stimulation) was reported as significant with the effective rate similar to the compared calcium channel blocker nicarpidine. The extractable information is limited and the conclusion remains a matter of discussion.

We believe that our findings of reduced office BP after TENS, which remained after the washout, are not likely caused by the stimulation. The pharmacokinetics of felodipin cannot explain a BP reduction after the washout period of our study. The significantly reduced “prolonged” BP seen after the felodipin washout period must therefore be explained by other factors such as stress-induced rise in baseline BP or the statistical phenomenon of regression towards the mean. These factors would affect both groups in a similar manner and, since the BP levels after both felodipin washout and TENS washout did not differ, it is unlikely that the stimulation per se had any effect on BP reduction.

BP measured by ABPM is better correlated to clinical outcome than office measurements (25,26) partly by discerning white coat hypertension from true hypertension and partly because ABPM is a result of several measurements compared with office BP. Our study showed no significant effect by TENS on ambulatory BP. Measurements after TENS washout were slightly lower than after the period of stimulation, but again not lower than after felodipin washout.

Limitations

Our study has some limitations. The intensity of stimulation was chosen by the subjects based on the individual perception of pain. This and differences in electrode placement and dermal resistance might also lead to discomfort at varying degrees of afferent traffic. All subjects did, however, receive a distinct motor response, which in a study by Sherry et al. (10) was decisive for the vasodilating effect. The approximate mean office BP of 153/90 mmHg and the mean 24-h ambulatory BP of 139/86 mmHg at baseline corresponds to grade I hypertension only. The ABPM at baseline of one subject revealed normal BP (white coat hypertension) but no other distinction regarding the origin of the hypertensive states of our subjects were made. The rate of drop-out and exclusion was not inconsiderable but did not affect the statistical power of the study. Nine subjects of 41 were excluded but the majority for reasons not related to the treatments. Only one subject chose to discontinue the study because of TENS discomfort. The reasons for the low stimulation time of the three excluded subjects were not penetrated. No specific control of the percentage of taken felodipin tablets was made.

Summary and conclusion

We conclude that our study of bidaily TENS does not demonstrate any solid evidence of BP reduction, neither after 4 weeks of daily treatment nor after 4 weeks of follow-up. We aimed to investigate the tolerability of TENS and found that more than half the subjects could consider this treatment as an antihypertensive regimen but in light of the negligible BP reducing effect, however, this therapy cannot be recommended.

Acknowledgements

The authors sincerely wish to thank RN Anna-Pia Wentzel and RN Bodil Malmqvist for excellent technical assistance. This study was supported by grants to Professor C. Mannheimer and Associate Professor K. Manhem from the Swedish state under the LUA/ALF agreement.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.