ORIGINAL ARTICLE
Transcutaneous Electrical Nerve Stimulation in Patients With Knee Osteoarthritis Evidence From Randomized-controlled Trials Ling-Xiao Chen, MD,* Zhi-Rui Zhou, MD,wzz Yu-Lin Li, MD,* Guang-Zhi Ning, MD,* Yan Li, MD,* Xiao-Bo Wang, MD,* and Shi-Qing Feng, PhD*
Objectives: Transcutaneous electrical nerve stimulation (TENS) has been reported to relieve pain and improve function in patients with knee osteoarthritis. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of TENS for the management of knee osteoarthritis. Methods: We searched Embase, PubMed, CENTRAL, SIGLE, PEDro, and clinicaltrials.gov, up to June 2014 for literature related to TENS used for the treatment of knee osteoarthritis. Two authors independently screened the searched records based on the title and abstract. Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted by the 2 authors. Results: Eighteen trials were included in the qualitative systematic review, and 14 were included in the meta-analysis. TENS significantly decreased pain (standard mean difference, 0.79; 95% confidence interval [CI], 1.31 to 0.27; P < 0.00001) compared with control groups. There was no significant difference in the Western Ontario and McMaster Universities Osteoarthritis Index (standard mean differences, 0.13; 95% CI, 0.35 to 0.1; P = 0.09) or the rate of all-cause discontinuation (risk ratio, 0.77; 95% CI, 0.48 to 1.22; P = 0.94) between the TENS and control groups. Discussion: TENS might relieve pain due to knee osteoarthritis. Further randomized-controlled trials should focus on large-scale studies and a longer duration of follow-up. Key Words: transcutaneous electrical nerve stimulation, knee osteoarthritis, pain, meta-analysis, systematic review
(Clin J Pain 2016;32:146–154) Received for publication August 29, 2014; revised April 1, 2015; accepted March 1, 2015. From the *Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin; wDepartment of Radiation Oncology, Fudan University Shanghai Cancer Center; and zDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China. L.-X.C. and Z.-R.Z. contributed equally. L.-X.C.: data collection, data analysis, interpretation, and writing the paper; Z.-R.Z., Y.-L.L., and G.-Z.N.: data collection and data analysis; L.-X.C., Z.-R.Z., Y.-L.L., G.-Z.N., Y.L., Q.-L.W., X.B.W., and S.-Q.F.: study design, interpretation, and commenting on drafts of the paper; and L.-X.C., Z.-R.Z., Y.-L.L., G.-Z.N., Y.L., X.-B.W., S.-Q.F.: read and approved the final manuscript. The authors declare no conflict of interest. Reprints: Shi-Qing Feng, PhD, Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, People’s Republic of China (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.clinicalpain.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/AJP.0000000000000233
O
steoarthritis (OA) is an age-related disease and its prevalence increases 3%/y in women from 45 to 65 years old.1,2 It is the most common type of arthritis and may involve the whole joint. The disease destroys cartilage, damages tendons, changes the structures of joints, and causes inflammation of the synovium.3 When it occurs in the knees, the right knee is more susceptible than the left in men, whereas in women, there is no significant difference between the right and the left knees.4 Transcutaneous electrical nerve stimulation (TENS) is a neuromodulation therapy that is based on the “GateControl Theory” proposed by Melzack.5 TENS therapy initially used a stimulation frequency of 40 to 150 Hz and a pulse width of 50 to 100 ms to irritate sensory fibers.6 Today, many types of TENS are used. Acupuncture-like TENS stimulates both sensory and motor fibers, but it is associated with extra pain.7 Burst TENS was developed to decrease the pain while preserving the advantages of acupuncture-like TENS.8 In recent years, a new method called brief TENS was developed to simultaneously stimulate nociceptor, sensory, and motor fibers.6 Researchers are still working to improve TENS therapies by changing the stimulation frequency, pulse width, intensity, and treatment duration. At present, it is difficult to assess whether TENS is optimal with regards to the advantages and disadvantages of the procedure because the relevant studies have had small sample sizes and many studies have had conflicting results. A previous Cochrane Review published in 2009 discussed the treatment, but no definite conclusion was reached. We performed this systematic review and metaanalysis to conclusively determine whether TENS is an effective therapy for knee OA.
METHODS Criteria for Considering Studies Considering that randomized controlled trials (RCTs) are less biased than other types of studies, we only included RCTs about TENS used for the treatment of knee OA. Studies were considered acceptable for inclusion in the review and meta-analysis if they met the following criteria: (1) were about knee OA; (2) evaluated the outcomes of TENS; and (3) were RCTs. Trials were excluded if they: (1) were abstracts, letters, or meeting proceedings; (2) had repeated data or did not report outcomes of interest; (3) included only pulsed electrical stimulation or pulsed electrostimulation; and (4) included only interferential current stimulation (Supplemental Digital Content 1, http://links. lww.com/CJP/A168).
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Search Methods
Transcutaneous Electrical Nerve Stimulation
patients.9 The second was manual measurement using the graphs presented in the article.9
We searched Embase (from 1974 to June 2014), PubMed (from 1966 to June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), SIGLE (System for Information on Grey Literature in Europe), PEDro, and clinicaltrials.gov. Keywords and MeSH terms including “Transcutaneous Electrical Nerve Stimulation,” “TENS,” “osteoarthritis,” “knee,” “random,” and “controlled trials,” were used in the search strategy (appendices, Supplemental Digital Content 2, http://links.lww.com/CJP/A169). We also reviewed each reference list of all included articles for any papers that might have been overlooked.
w2 test and I2 test were used for testing the heterogeneity between studies. If heterogeneity was not present (P > 0.10, I2 < 50%), a fixed-effect model was adopted for the analysis, otherwise, a random-effect model was employed. Then, I2 was used to evaluate the heterogeneity (a value of I2 > 50% was considered to indicate high heterogeneity and a value of I2 < 25% was thought to indicate no heterogeneity9).
Selection of Studies
Assessment of Reporting Biases
Two authors independently made the initial selection based on the titles and abstracts of the papers. Any disagreement between the 2 authors was resolved by discussion. If there was still debate, a third reviewer (S.-Q.F.) was consulted and made a decision regarding its inclusion.
A funnel plot was used to identify possible publication bias if the number of studies was >10.9
Data Collection and Analysis Two authors screened the papers and removed references that were not eligible, and the corresponding authors were contacted if additional information was needed.
Data Extraction and Management Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted from each included study. One author entered the data into RevMan 5.3, after which another author would check all values.
Assessment of the Risk of Bias in Included Studies Two authors used the Cochrane risk of bias tool for RCTs (the RoB tool) to assess the quality of the included trials. The RoB tool included 7 domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The judgment for each domain was a low risk of bias, a high risk of bias, or an unclear risk of bias and 2 authors independently evaluated the risk of studies.
Measurements of the Treatment Effect Dichotomous Data Dichotomous data were used for reporting on allcause discontinuation. These data were reported as risk ratios (RRs) with 95% confidence intervals (CIs).
Continuous Data For continuous data (eg, pain which was measured by a Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities [WOMAC] Osteoarthritis Index), the standard mean differences (SMDs) with 95% CIs were used.
Assessment of Heterogeneity
Data Synthesis Meta-analyses were only performed when studies were considered to be sufficiently homogeneous, and a randomeffect model was first used for the pooled analysis. If we found that the heterogeneity was 0.05).
The WOMAC Index The pooled estimate of 6 studies indicated there that was no significant difference in the WOMAC indices between the TENS and the control groups (SMD, 0.13; 95% CI, 0.35 to 0.1; P = 0.09, I2 = 48%) (Fig. 3).
All-Cause Discontinuation A meta-analysis results of 5 studies indicated that there was no significant difference in the rates of all-cause discontinuation between the TENS and the control groups (RR, 0.77; 95% CI, 0.48 to 1.22; P = 0.94, I2 = 0%) (Fig. 4).
Secondary Outcomes Range of Movement (ROM)
Three studies mentioned ROM.31,32,34 Law indicated that there was no significant difference between the TENS and
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TABLE 1. Study Characteristics of Included Studies
References
Comparators
Sample Mean Age Size (SD)
Adedoyin et al22 Atamaz et al23
exe vs. IFC + exe vs. TENS + exe TENS S vs. TENS vs. IFCs S vs. IFCs vs. SWD S vs. SWD
203
Cetin et al24
100
Cheing et al26
SWD + HP + iso vs. TENS + HP + iso vs. US + HP + iso vs. HP + iso vs. iso TENS 20 vs. TENS 40 vs. TENS 60 vs. placebo TENS vs. placebo vs. exe vs. TENS + exe
Chen et al27
TENS vs. HA
Cheing et al25
TENS vs. sham FargasBabjak 28 et al Itoh et al29 ACP vs. TENS vs. ACP + TENS vs. CT Kolen et al30 LTENS vs. ITENS vs. RTENS
46
55.41 (9.21)
50 51 32 74
65.5 65.3 (8.3) 64.1 (6.1) 60.9 (7.3) 64.3 (9.2) 66.52 (7.2) 67.96 (9.94) —
80
6
1, 2
80
2
5, 7, 11
60-100
Hong Kong Hong Kong
0.5
1
100
1
1
80
Taiwan
3
3/20
Canada
1.5
1, 2, 3, 5, 6, 7, 8, 9 1, 7
122 — 2/100
0.5
Hong Kong Brazil
0.5
1, 3, 4
100
3
1, 2, 3, 7
100
1
1, 3, 4
61
Hong Kong UK
6
36
—
USA
—
1, 2, 12, 13, 14, 15 16
150
30
65 70 57 (11.8) 55 (14.4) 57 (10.9) 58.1
UK
3
1
50
Multicenter
—
1, 4, 6
—
Turkey
—
6, 7
Law et al32
TENS vs. placebo
39
Mascarin et al33
TENS vs. KIN vs. US
40
Ng et al34
TENS vs. EA vs. CT
24
82.7 (6.1) 84.3 (6.9) 80.00 (5.8) 83.2 (5.4) 74.1 (13.1) 74.9 (11.2) 64.8 (7.0) 59.6 (7.2) 62.8 (7.6) 85
224
Pietrosimone TENS vs. comparsion vs. placebo et al36 Smith et al37 TENS vs. placebo Vance et al38 H TENS vs. L TENS vs. placebo
75 100
2.5 —
4
Hong Kong
36
TENS vs. EA vs. ice vs. placebo
1, 2
1, 2 1, 2, 3, 7, 10 1, 3, 4
TENS2 vs. TENS100 vs. TENS2/100 vs. placebo
Yurtkuran and Kocagil39
1
62-83 Japan 61.9 (11.6) Netherland
Law and Cheing31
Palmer et al35 TENS vs. TENS S vs. placebo
Nigeria
60.7 (6.5) Multicenter 61.9 (6.9) 61.3 (7.8) 62.0 (7.9) 61.4 (8.2) 61.6 (7.4) 59.82 (9.05) Turkey
38 62
Country
Stimulation FollowFrequency TENS up (mo) Outcomes (Hz)
2 110
4
1:pain; 2: Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; 3: range of movement; 4: “Timed Up-And-Go” test; 5: Lequesne index; 6: pain threshold; 7: walking time; 8: patient global assessment; 9: disability in ADL; 10: maximum voluntary contraction; 11: peak torque levels; 12: extensor muscle torque; 13: global assessment of change; 14: exercise adherence; 15: exercise self-efficacy; 16: peak external knee flexion moment and angle. ACP indicates acupuncture; CT, control treatment; EA, electroacupuncture; Exe, exercise; H TENS, high-frequency TENS; HA, intra-articular hyaluronic acid injections; HP, hot packs; Ice, ice massage; IFC, interferential current; IFCs S, IFC sham; Iso, isokinetic exercise; ITENS, irradiation TENS; KIN, kinesiotherapy; L TENS, low-frequency TENS; LTENS, lowest-resistance TENS; RTENS, random site TENS; SWD S, SWD sham; SWD, shortwave diathermy; TENS 20, 20 minutes TENS 5 days a week for 2 weeks; TENS 40, 40 minutes TENS 5 days a week for 2 weeks; TENS 60, 60 minutes TENS 5 days a week for 2 weeks; TENS S, TENS sham; TENS, transcutaneous electrical nerve stimulation; TENS100, 100 Hz TENS; TENS2, 2 Hz TENS; TENS2/100, an alternating frequency of 2 Hz and 100 Hz TENS; US, ultrasound.
placebo group in terms of the pain-related range of knee motion.34 Another study by Law and colleagues also showed that there were no significant differences between the TENS and placebo groups with regard to pain-limited knee ROM. However, for the maximum range of motion of the knee, the TENS group had a significant improvement on day 10 and during the follow-up.32 The study by Ng et al34 indicated that Copyright
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there was no significant difference between the TENS group and the control group in the total passive knee ROM.
The “Timed Up-And-Go” Test (TUGC) Four studies used the TUGC as an outcome measurement, but none provided adequate data to perform a
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FIGURE 2. Forest plot of pain. CI indicates confidence interval.
meta-analysis.31,32,34,38 There was no significant difference between the TENS and the control groups in these studies.
Other studies Vance 2012 The intervention methods used in the study by Vance and colleagues included high-frequency TENS (HF-TENS), placebo TENS, and low-frequency TENS (LF-TENS). A total of 25 patients were assigned to HF-TENS, 25 to LFTENS, and 25 to placebo. The outcomes included the cutaneous mechanical pain threshold, pressure pain threshold, heat pain threshold, heat temporal summation and pain intensity at rest and during the TUG. The HFTENS group had a significantly increased pressure pain threshold compared with the placebo TENS group. There was no significant different among the 3 groups in any other outcomes.
Mascarin 2012
The interventions used in the study by Mascarin et al33 were kinesiotherapy (KIN), ultrasound (US), and electrotherapy (TENS). A total of 16 patients were assigned to the KIN, 12 to the TENS, and 10 to the US group. The outcomes evaluated included the severity of pain determined by a VAS, ROM, the 6-minute walking test, and the WOMAC osteoarthritis index. TENS group did not show any advantages over the US or KIN groups in any of the outcomes.
Chen 2013
The interventions used in the study by Chen et al38 were intra-articular hyaluronic acid (HA) and TENS. A total of 27 patients were assigned to the HA group, and 23 were assigned to the TENS group. The outcomes included a VAS for pain, the Lequesne index, the ROM, walking time, patient global assessment, pain threshold, disability in
FIGURE 3. Forest plot of Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. CI indicates confidence interval.
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FIGURE 4. Forest plot of all-cause discontinuation. CI indicates confidence interval.
activities of daily living, and the minimal clinically important improvement. TENS significantly decreased the VAS scores at the 2-week follow-up, but there was no significant difference at 2- and 3-month follow-up examinations. The TENS group had a significant reduction in the Lequesne index at the 2-week and 3-month follow-up, whereas no significant difference was noted at the 2-month follow-up. Although the TENS group had advantages in the walking time at the 2-month follow-up and in the patient global assessment at the 2-week and 3-month follow-up examinations, there was no significant difference between the 2 groups in the ROM, walking time, or patient global assessment. With regard to the minimal clinically important improvement, the TENS group had a significant improvement compared with the HA group. The study did not mention any comparison between the 2 groups for the activities of daily living or pain threshold.
Kolen 2012
The interventions used in the study by Kolen et al30 were lowest-resistance TENS, irradiation TENS, and random site TENS. A total of 24 patients were assigned to lowest-resistance TENS, 26 to irradiation TENS, and 24 to random site TENS. The outcomes assessed included the pain intensity at rest determined by VAS, ROM, WOMAC, 6-minute walking test, maximum voluntary contraction, Hospital Anxiety and Depression Scale, Pain Anxiety Symptoms Scale (PASS20), and the Pain Catastrophizing Scale. Lowest-resistance TENS significantly decreased the pain intensity compared with random site TENS. There were no significant differences for the other outcomes among the 3 groups.
Sensitivity Analyses Overall, the outcomes regarding pain were stable. The meta-regression analysis for pain showed that neither the year nor country of publication was related to heterogeneity (Supplemental Fig. 3, Supplemental Digital Content 5, http://links.lww.com/CJP/A172). The sensitivity analyses excluding the studies one by one and changing the model did not change the results. Further, the trim-and-fill method showed no missing study. The details of the sensitivity analysis are shown in Supplemental Table 1 Copyright
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(Supplemental Digital Content 6, http://links.lww.com/ CJP/A173).
Assessment of Reporting Biases The funnel plot of pain showed no obvious asymmetry (Supplemental Fig. 4, Supplemental Digital Content 7, http://links.lww.com/CJP/A174). In addition, Egger’s test and the trim-and-fill method indicated that there was no obvious publication bias.
GRADE Profile Evidence The GRADE quality of evidence is shown in Table 2.
DISCUSSION Summary of the Main Results The meta-analyses indicated that: (1) patients who received TENS had significantly decreased pain compared with the control group; (2) there was no significant difference between the TENS and control groups in terms of the WOMAC index and all-cause discontinuation; (3) there was no significant difference between the TENS and control groups in the pain-limited ROM, total passive knee ROM, or TUG; and (4) TENS might significantly improve the maximum knee ROM on day 10 and during follow-up compared with the control group.
Agreements and Disagreements in the Current Literature A previous Cochrane review that included 13 studies about TENS indicated that: (1) TENS significantly decreased pain compared with the control group (SMD, 0.85; 95% CI, 1.36 to 0.34; P < 0.00001, I2 = 83%); (2) there was no significant difference between the TENS and control groups in the rates of withdrawal or drop-out because of adverse events (RR, 0.6; 95% CI, 0.03 to 14.15; P = 0.15, I2 = 51%); (3) there was no significant difference between the TENS and control groups with regard to knee function (SMD, 0.33; 95% CI, 0.69 to 0.03; P = 0.18, I2 = 36%); and (4) the funnel plot of data related to pain was asymmetrical (Egger’s test, P < 0.001). Our article excluded 2 studies with a high-risk bias in random sequence generation to decrease the potential bias and included 7 new research studies not included in the
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TABLE 2. Grade of Evidence
Transcutaneous Electrical Nerve Stimulation for Knee Osteoarthritis Patient or population: patients with knee osteoarthritis Settings: outpatient Intervention: transcutaneous electrical nerve stimulation Illustrative Comparative Risks* (95% CI) Assumed Risk Corresponding Risk
Outcomes
Control
Pain Follow-up: 2-24 wk
Range of movement “Timed Up-And-Go” test Follow-up: 2-4 wk
Relative Effect (95% CI)
Quality of the Evidence (GRADE) Comments ""~~ lowwz
310 (6 studies)
"""~ moderatew
RR 0.77 (0.48 to 1.22)
274 (5 studies)
"""~ moderatew
See comment
Not estimable
100 (3 studies)
See comment
Not estimable
200 (4 studies)
"""~ moderatey """~ moderatew
Study population 228 per 1000 Moderate 673 per 1000 See comment See comment
No. Participants (Studies) 607 (12 studies)
The mean pain in the intervention groups was 0.79 SDs lower (1.31 to 0.27 lower) The mean Western Ontario and McMaster Universities Osteoarthritis Index in the intervention groups was 0.13 SDs lower (0.35 lower to 0.1 higher)
Western Ontario and McMaster Universities Osteoarthritis Index Follow-up: 2-24 wk All-cause discontinuation Follow-up: 6-24 wk
Transcutaneous Electrical Nerve Stimulation
175 per 1000 (109 to 278) 518 per 1000 (323 to 821)
GRADE Working Group grades of evidence: High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate. *The basis for the assumed risk (eg, the median control group risk across studies) is provided below. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). wSome studies had high-risk biases. zI2 > 50%. yThe outcome measurements were different among studies. CI indicates confidence interval; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RR, risk ratio.
previous Cochrane review. Our results basically agreed with the previous findings. However, we performed several sensitivity analyses for pain, which the previous study could not include, but none of these changed the results. On the basis of the present results, we believe that TENS can relieve pain in patients with knee OA. With regard to publication bias, Egger’s test showed that there was asymmetry (P < 0.05), but Begg’s test revealed symmetry (P > 0.05); therefore, a trim-and-fill method was used, and the results indicated there were no missing studies. These results indicated that there was no obvious publication bias. In this article, we included some studies that described new methods of TENS that the previous Cochrane Review did not mention. We also compared TENS with active treatments (ie, KIN, US, and HA). In addition, some new outcomes such as the ROM and the “TUGC test were
included in the current article, which were not evaluated in the previous Cochrane review. Currently, 2 groups are applying randomized-controlled methods to assess the efficacy (pain and function) of TENS in people with knee OA. Their results might supply evidence with high quality that may allow for more definitive conclusions to be drawn regarding the outcomes of TENS.
Strengths and Weaknesses The current paper had several strengths, including the following: (1) we used a comprehensive search strategy to minimize the possibilities of publication bias; (2) sensitivity analyses were performed to test the robustness of the outcomes with high heterogeneity, (3) only RCTs were included in this article, and (4) the GRADE was used to evaluate the quality of evidence.
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However, the results of the article should be interpreted with caution due to the existence of some limitations. First, only papers written in English were included in this article, although we searched for studies in all languages, which means that there may have been a selection bias. Second, the sample size of the RCTs was small; therefore, we could not completely exclude type-II errors or draw definitive conclusions. Third, there was substantial heterogeneity due to the different methodologies used, outcomes measured, and the presentation of data. These issues made it difficult to reach any strong conclusions. Fourth, the duration of follow-up was too short; therefore, we could not further evaluate the influence of TENS on knee OA. Fifth, the quality of the included studies was low, so any recommendation based on these studies should be interpreted with caution. Sixth, although the pooled estimate of the effects of TENS on pain relief was significant (0.79), it was below the 3-point reduction considered to indicate a clinically meaningful change; therefore, we considered that this was a modest effect, and we could not draw a strong conclusion regarding the impact of TENS on pain relief.
CONCLUSIONS Considering the results of the sensitivity analyses, TENS might be an effective therapy to relieve pain in patients with knee OA. Larger-scale and longer-term RCTs are needed. In addition, more studies are needed to ascertain the economic feasibility of TENS. ACKNOWLEDGMENT The authors thank Dr Yong Zhou, MD, Tianjin Medical University General Hospital, Heping District, Tianjin, People’s Republic of China; for data extracting. REFERENCES 1. Scott D, Kowalczyk A. Osteoarthritis of the knee. Am Fam Physician. 2008;77:1149–1150. 2. Alshami M. Knee osteoarthritis related pain: a narrative review of diagnosis and treatment. Int J Health Sci. 2014;8:85–104. 3. Budden L. Osteoarthritis: more than a stiff joint. Aust Nurs Midwif J. 2014;21:45. 4. Michael JW, Schlu¨ter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch Arztebl Int. 2010;107:152–162. 5. Melzack R, Wall P. Pain mechanisms: a new theory. Science. 1965;150:971–977. 6. Rutjes AW, Nuesch E, Sterchi R, et al. Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database Syst Rev. 2009;4:Cd002823. 7. Francis RP MP, Johnson MI. Comparison of post-treatment effects of conventional and acupuncture-like transcutaneous electrical nerve stimulation (TENS): a randomised placebocontrolled study using cold-induced pain and healthy human participants. Physiother Theory Pract. 2011;27:578–585. 8. Rodrı´ guez-Ferna´ndez AL G-SV, Gu¨eita-Rodrı´ guez J, Ferna´ndez-de-Las-Pen˜as C. Effects of burst-type transcutaneous electrical nerve stimulation on cervical range of motion and latent myofascial trigger point pain sensitivity. Arch Phys Med Rehabil. 2011;92:1353–1358. 9. Higgins JGS. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2011. The Cochrane Collaborationk. Available at: http://www.cochrane-handbook.org. Accessed March, 2011. 10. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–406.
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11. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–394. 12. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64:395–400. 13. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol. 2011;64:407–415. 14. Shirazi ZR, Shafaee R, Abbasi L. The effects of transcutaneous electrical nerve stimulation on joint position sense in patients with knee joint osteoarthritis. Physiother Theory Pract. 2014;7:495–499. 15. Defrin R, Ariel E, Peretz C. Segmental noxious versus innocuous electrical stimulation for chronic pain relief and the effect of fading sensation during treatment. Pain. 2005;115:152–160. 16. Fary RE, Carroll GJ, Briffa TG, et al. The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial. Arthritis Rheum. 2011;63:1333–1342. 17. Garland D, Holt P, Harrington JT, et al. A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2007;15:630–637. 18. Quirk AS NR, Newman KJ. An evaluation of interferential therapy, shortwave diathermy and exercise in the treatment of osteoarthrosis of the knee. Physiotherapy. 1985;71:55–57. 19. Zizic TM, Hoffman KC, Holt PA, et al. The treatment of osteoarthritis of the knee with pulsed electrical stimulation. J Rheumatol. 1995;22:1757–1761. 20. Adedoyin RA OM, Fagbeja OO. Effect of interferential current stimulation in management of osteo-arthritic knee pain. Physiotherapy. 2002;88:493–499. 21. Bal STY, Grgan A. The effectiveness of transcutaneous electrical nerve stimulation in patients with knee osteoarthritis. J Rheumatol Med Rehabil. 2007;18:1–5. 22. Adedoyin RA, Olaogun MOB, Oyeyemi AL. Transcutaneous electrical nerve stimulation and interferential current combined with exercise for the treatment of knee osteoarthritis: a randomised controlled trial. Hong Kong Physiother J. 2005;23:13–19. 23. Atamaz FC, Durmaz B, Baydar M, et al. Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy in knee osteoarthritis: a double-blind, randomized, controlled, multicenter study. Arch Phys Med Rehabil. 2012;93:748–756. 24. Cetin N, Aytar A, Atalay A, et al. Comparing hot pack, shortwave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2008;87:443–451. 25. Cheing GL, Tsui AY, Lo SK, et al. Optimal stimulation duration of TENS in the management of osteoarthritic knee pain. J Rehabil Med. 2003;35:62–68. 26. Cheing GL, Hui-Chan CW, Chan KM. Does four weeks of TENS and/or isometric exercise produce cumulative reduction of osteoarthritic knee pain? Clin Rehabil. 2002;16:749–760. 27. Chen WL, Hsu WC, Lin YJ, et al. Comparison of intraarticular hyaluronic acid injections with transcutaneous electric nerve stimulation for the management of knee osteoarthritis: a randomized controlled trial. Archives of Physical Medicine and Rehabilitation. 2013;94:1482–1489. 28. Fargas-Babjak A, Rooney P, Gerecz E. Randomized trial of Codetron for pain control in osteoarthritis of the hip/knee. Clin J Pain. 1989;5:137–141. 29. Itoh K, Hirota S, Katsumi Y, et al. A pilot study on using acupuncture and transcutaneous electrical nerve stimulation (TENS) to treat knee osteoarthritis (OA). Chin Med. 2008;3:2.
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30. Kolen AF, de Nijs RN, Wagemakers FM, et al. Effects of spatially targeted transcutaneous electrical nerve stimulation using an electrode array that measures skin resistance on pain and mobility in patients with osteoarthritis in the knee: a randomized controlled trial. Pain. 2012;153:373–381. 31. Law PP, Cheing GL. Optimal stimulation frequency of transcutaneous electrical nerve stimulation on people with knee osteoarthritis. J Rehabil Med. 2004;36:220–225. 32. Law PP, Cheing GL, Tsui AY. Does transcutaneous electrical nerve stimulation improve the physical performance of people with knee osteoarthritis? J Clin Rheumatol. 2004;10:295–299. 33. Mascarin NC, Vancini RL, Andrade ML, et al. Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial. BMC Musculoskeletal Disorders. 2012;13:182. 34. Ng MM, Leung MC, Poon DM. The effects of electroacupuncture and transcutaneous electrical nerve stimulation on patients with painful osteoarthritic knees: a randomized controlled trial with follow-up evaluation. J Altern Complement Med. 2003;9:641–649. 35. Palmer S, Domaille M, Cramp F, et al. Transcutaneous electrical nerve stimulation as an adjunct to education and
36.
37.
38.
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exercise for knee osteoarthritis: a randomized controlled trial. Arthritis Care Res. 2014;66:387–394. Pietrosimone BG, Saliba SA, Hart JM, et al. Effects of disinhibitory transcutaneous electrical nerve stimulation and therapeutic exercise on sagittal plane peak knee kinematics and kinetics in people with knee osteoarthritis during gait: a randomized controlled trial. Clinical Rehabilitation. 2010;24:1091–1101. Smith CR, Lewith GT, Machin D. TNS and osteo-arthritic pain. Preliminary study to establish a controlled method of assessing transcutaneous nerve stimulation as a treatment for the pain caused by osteo-arthritis of the knee. Physiotherapy. 1983;69:266–268. Vance CG, Rakel BA, Blodgett NP, et al. Effects of transcutaneous electrical nerve stimulation on pain, pain sensitivity, and function in people with knee osteoarthritis: a randomized controlled trial. Phys Ther. 2012;92:898–910. Yurtkuran M, Kocagil T. TENS, electroacupuncture and ice massage: comparison of treatment for osteoarthritis of the knee. Am J Acupunct. 1999;27:133–140.
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Transcutaneous Electrical Nerve Stimulation in Patients With Knee Osteoarthritis Evidence From Randomized-controlled Trials Ling-Xiao Chen, MD,* Zhi-Rui Zhou, MD,wzz Yu-Lin Li, MD,* Guang-Zhi Ning, MD,* Yan Li, MD,* Xiao-Bo Wang, MD,* and Shi-Qing Feng, PhD*
Objectives: Transcutaneous electrical nerve stimulation (TENS) has been reported to relieve pain and improve function in patients with knee osteoarthritis. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of TENS for the management of knee osteoarthritis. Methods: We searched Embase, PubMed, CENTRAL, SIGLE, PEDro, and clinicaltrials.gov, up to June 2014 for literature related to TENS used for the treatment of knee osteoarthritis. Two authors independently screened the searched records based on the title and abstract. Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted by the 2 authors. Results: Eighteen trials were included in the qualitative systematic review, and 14 were included in the meta-analysis. TENS significantly decreased pain (standard mean difference, 0.79; 95% confidence interval [CI], 1.31 to 0.27; P < 0.00001) compared with control groups. There was no significant difference in the Western Ontario and McMaster Universities Osteoarthritis Index (standard mean differences, 0.13; 95% CI, 0.35 to 0.1; P = 0.09) or the rate of all-cause discontinuation (risk ratio, 0.77; 95% CI, 0.48 to 1.22; P = 0.94) between the TENS and control groups. Discussion: TENS might relieve pain due to knee osteoarthritis. Further randomized-controlled trials should focus on large-scale studies and a longer duration of follow-up. Key Words: transcutaneous electrical nerve stimulation, knee osteoarthritis, pain, meta-analysis, systematic review
(Clin J Pain 2016;32:146–154) Received for publication August 29, 2014; revised April 1, 2015; accepted March 1, 2015. From the *Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin; wDepartment of Radiation Oncology, Fudan University Shanghai Cancer Center; and zDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China. L.-X.C. and Z.-R.Z. contributed equally. L.-X.C.: data collection, data analysis, interpretation, and writing the paper; Z.-R.Z., Y.-L.L., and G.-Z.N.: data collection and data analysis; L.-X.C., Z.-R.Z., Y.-L.L., G.-Z.N., Y.L., Q.-L.W., X.B.W., and S.-Q.F.: study design, interpretation, and commenting on drafts of the paper; and L.-X.C., Z.-R.Z., Y.-L.L., G.-Z.N., Y.L., X.-B.W., S.-Q.F.: read and approved the final manuscript. The authors declare no conflict of interest. Reprints: Shi-Qing Feng, PhD, Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, People’s Republic of China (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.clinicalpain.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/AJP.0000000000000233
O
steoarthritis (OA) is an age-related disease and its prevalence increases 3%/y in women from 45 to 65 years old.1,2 It is the most common type of arthritis and may involve the whole joint. The disease destroys cartilage, damages tendons, changes the structures of joints, and causes inflammation of the synovium.3 When it occurs in the knees, the right knee is more susceptible than the left in men, whereas in women, there is no significant difference between the right and the left knees.4 Transcutaneous electrical nerve stimulation (TENS) is a neuromodulation therapy that is based on the “GateControl Theory” proposed by Melzack.5 TENS therapy initially used a stimulation frequency of 40 to 150 Hz and a pulse width of 50 to 100 ms to irritate sensory fibers.6 Today, many types of TENS are used. Acupuncture-like TENS stimulates both sensory and motor fibers, but it is associated with extra pain.7 Burst TENS was developed to decrease the pain while preserving the advantages of acupuncture-like TENS.8 In recent years, a new method called brief TENS was developed to simultaneously stimulate nociceptor, sensory, and motor fibers.6 Researchers are still working to improve TENS therapies by changing the stimulation frequency, pulse width, intensity, and treatment duration. At present, it is difficult to assess whether TENS is optimal with regards to the advantages and disadvantages of the procedure because the relevant studies have had small sample sizes and many studies have had conflicting results. A previous Cochrane Review published in 2009 discussed the treatment, but no definite conclusion was reached. We performed this systematic review and metaanalysis to conclusively determine whether TENS is an effective therapy for knee OA.
METHODS Criteria for Considering Studies Considering that randomized controlled trials (RCTs) are less biased than other types of studies, we only included RCTs about TENS used for the treatment of knee OA. Studies were considered acceptable for inclusion in the review and meta-analysis if they met the following criteria: (1) were about knee OA; (2) evaluated the outcomes of TENS; and (3) were RCTs. Trials were excluded if they: (1) were abstracts, letters, or meeting proceedings; (2) had repeated data or did not report outcomes of interest; (3) included only pulsed electrical stimulation or pulsed electrostimulation; and (4) included only interferential current stimulation (Supplemental Digital Content 1, http://links. lww.com/CJP/A168).
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Search Methods
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patients.9 The second was manual measurement using the graphs presented in the article.9
We searched Embase (from 1974 to June 2014), PubMed (from 1966 to June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), SIGLE (System for Information on Grey Literature in Europe), PEDro, and clinicaltrials.gov. Keywords and MeSH terms including “Transcutaneous Electrical Nerve Stimulation,” “TENS,” “osteoarthritis,” “knee,” “random,” and “controlled trials,” were used in the search strategy (appendices, Supplemental Digital Content 2, http://links.lww.com/CJP/A169). We also reviewed each reference list of all included articles for any papers that might have been overlooked.
w2 test and I2 test were used for testing the heterogeneity between studies. If heterogeneity was not present (P > 0.10, I2 < 50%), a fixed-effect model was adopted for the analysis, otherwise, a random-effect model was employed. Then, I2 was used to evaluate the heterogeneity (a value of I2 > 50% was considered to indicate high heterogeneity and a value of I2 < 25% was thought to indicate no heterogeneity9).
Selection of Studies
Assessment of Reporting Biases
Two authors independently made the initial selection based on the titles and abstracts of the papers. Any disagreement between the 2 authors was resolved by discussion. If there was still debate, a third reviewer (S.-Q.F.) was consulted and made a decision regarding its inclusion.
A funnel plot was used to identify possible publication bias if the number of studies was >10.9
Data Collection and Analysis Two authors screened the papers and removed references that were not eligible, and the corresponding authors were contacted if additional information was needed.
Data Extraction and Management Information including the authors, study design, mean age, sex, study population, stimulation frequency (of TENS), outcome measures, and follow-up periods were extracted from each included study. One author entered the data into RevMan 5.3, after which another author would check all values.
Assessment of the Risk of Bias in Included Studies Two authors used the Cochrane risk of bias tool for RCTs (the RoB tool) to assess the quality of the included trials. The RoB tool included 7 domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The judgment for each domain was a low risk of bias, a high risk of bias, or an unclear risk of bias and 2 authors independently evaluated the risk of studies.
Measurements of the Treatment Effect Dichotomous Data Dichotomous data were used for reporting on allcause discontinuation. These data were reported as risk ratios (RRs) with 95% confidence intervals (CIs).
Continuous Data For continuous data (eg, pain which was measured by a Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities [WOMAC] Osteoarthritis Index), the standard mean differences (SMDs) with 95% CIs were used.
Assessment of Heterogeneity
Data Synthesis Meta-analyses were only performed when studies were considered to be sufficiently homogeneous, and a randomeffect model was first used for the pooled analysis. If we found that the heterogeneity was 0.05).
The WOMAC Index The pooled estimate of 6 studies indicated there that was no significant difference in the WOMAC indices between the TENS and the control groups (SMD, 0.13; 95% CI, 0.35 to 0.1; P = 0.09, I2 = 48%) (Fig. 3).
All-Cause Discontinuation A meta-analysis results of 5 studies indicated that there was no significant difference in the rates of all-cause discontinuation between the TENS and the control groups (RR, 0.77; 95% CI, 0.48 to 1.22; P = 0.94, I2 = 0%) (Fig. 4).
Secondary Outcomes Range of Movement (ROM)
Three studies mentioned ROM.31,32,34 Law indicated that there was no significant difference between the TENS and
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TABLE 1. Study Characteristics of Included Studies
References
Comparators
Sample Mean Age Size (SD)
Adedoyin et al22 Atamaz et al23
exe vs. IFC + exe vs. TENS + exe TENS S vs. TENS vs. IFCs S vs. IFCs vs. SWD S vs. SWD
203
Cetin et al24
100
Cheing et al26
SWD + HP + iso vs. TENS + HP + iso vs. US + HP + iso vs. HP + iso vs. iso TENS 20 vs. TENS 40 vs. TENS 60 vs. placebo TENS vs. placebo vs. exe vs. TENS + exe
Chen et al27
TENS vs. HA
Cheing et al25
TENS vs. sham FargasBabjak 28 et al Itoh et al29 ACP vs. TENS vs. ACP + TENS vs. CT Kolen et al30 LTENS vs. ITENS vs. RTENS
46
55.41 (9.21)
50 51 32 74
65.5 65.3 (8.3) 64.1 (6.1) 60.9 (7.3) 64.3 (9.2) 66.52 (7.2) 67.96 (9.94) —
80
6
1, 2
80
2
5, 7, 11
60-100
Hong Kong Hong Kong
0.5
1
100
1
1
80
Taiwan
3
3/20
Canada
1.5
1, 2, 3, 5, 6, 7, 8, 9 1, 7
122 — 2/100
0.5
Hong Kong Brazil
0.5
1, 3, 4
100
3
1, 2, 3, 7
100
1
1, 3, 4
61
Hong Kong UK
6
36
—
USA
—
1, 2, 12, 13, 14, 15 16
150
30
65 70 57 (11.8) 55 (14.4) 57 (10.9) 58.1
UK
3
1
50
Multicenter
—
1, 4, 6
—
Turkey
—
6, 7
Law et al32
TENS vs. placebo
39
Mascarin et al33
TENS vs. KIN vs. US
40
Ng et al34
TENS vs. EA vs. CT
24
82.7 (6.1) 84.3 (6.9) 80.00 (5.8) 83.2 (5.4) 74.1 (13.1) 74.9 (11.2) 64.8 (7.0) 59.6 (7.2) 62.8 (7.6) 85
224
Pietrosimone TENS vs. comparsion vs. placebo et al36 Smith et al37 TENS vs. placebo Vance et al38 H TENS vs. L TENS vs. placebo
75 100
2.5 —
4
Hong Kong
36
TENS vs. EA vs. ice vs. placebo
1, 2
1, 2 1, 2, 3, 7, 10 1, 3, 4
TENS2 vs. TENS100 vs. TENS2/100 vs. placebo
Yurtkuran and Kocagil39
1
62-83 Japan 61.9 (11.6) Netherland
Law and Cheing31
Palmer et al35 TENS vs. TENS S vs. placebo
Nigeria
60.7 (6.5) Multicenter 61.9 (6.9) 61.3 (7.8) 62.0 (7.9) 61.4 (8.2) 61.6 (7.4) 59.82 (9.05) Turkey
38 62
Country
Stimulation FollowFrequency TENS up (mo) Outcomes (Hz)
2 110
4
1:pain; 2: Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index; 3: range of movement; 4: “Timed Up-And-Go” test; 5: Lequesne index; 6: pain threshold; 7: walking time; 8: patient global assessment; 9: disability in ADL; 10: maximum voluntary contraction; 11: peak torque levels; 12: extensor muscle torque; 13: global assessment of change; 14: exercise adherence; 15: exercise self-efficacy; 16: peak external knee flexion moment and angle. ACP indicates acupuncture; CT, control treatment; EA, electroacupuncture; Exe, exercise; H TENS, high-frequency TENS; HA, intra-articular hyaluronic acid injections; HP, hot packs; Ice, ice massage; IFC, interferential current; IFCs S, IFC sham; Iso, isokinetic exercise; ITENS, irradiation TENS; KIN, kinesiotherapy; L TENS, low-frequency TENS; LTENS, lowest-resistance TENS; RTENS, random site TENS; SWD S, SWD sham; SWD, shortwave diathermy; TENS 20, 20 minutes TENS 5 days a week for 2 weeks; TENS 40, 40 minutes TENS 5 days a week for 2 weeks; TENS 60, 60 minutes TENS 5 days a week for 2 weeks; TENS S, TENS sham; TENS, transcutaneous electrical nerve stimulation; TENS100, 100 Hz TENS; TENS2, 2 Hz TENS; TENS2/100, an alternating frequency of 2 Hz and 100 Hz TENS; US, ultrasound.
placebo group in terms of the pain-related range of knee motion.34 Another study by Law and colleagues also showed that there were no significant differences between the TENS and placebo groups with regard to pain-limited knee ROM. However, for the maximum range of motion of the knee, the TENS group had a significant improvement on day 10 and during the follow-up.32 The study by Ng et al34 indicated that Copyright
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there was no significant difference between the TENS group and the control group in the total passive knee ROM.
The “Timed Up-And-Go” Test (TUGC) Four studies used the TUGC as an outcome measurement, but none provided adequate data to perform a
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FIGURE 2. Forest plot of pain. CI indicates confidence interval.
meta-analysis.31,32,34,38 There was no significant difference between the TENS and the control groups in these studies.
Other studies Vance 2012 The intervention methods used in the study by Vance and colleagues included high-frequency TENS (HF-TENS), placebo TENS, and low-frequency TENS (LF-TENS). A total of 25 patients were assigned to HF-TENS, 25 to LFTENS, and 25 to placebo. The outcomes included the cutaneous mechanical pain threshold, pressure pain threshold, heat pain threshold, heat temporal summation and pain intensity at rest and during the TUG. The HFTENS group had a significantly increased pressure pain threshold compared with the placebo TENS group. There was no significant different among the 3 groups in any other outcomes.
Mascarin 2012
The interventions used in the study by Mascarin et al33 were kinesiotherapy (KIN), ultrasound (US), and electrotherapy (TENS). A total of 16 patients were assigned to the KIN, 12 to the TENS, and 10 to the US group. The outcomes evaluated included the severity of pain determined by a VAS, ROM, the 6-minute walking test, and the WOMAC osteoarthritis index. TENS group did not show any advantages over the US or KIN groups in any of the outcomes.
Chen 2013
The interventions used in the study by Chen et al38 were intra-articular hyaluronic acid (HA) and TENS. A total of 27 patients were assigned to the HA group, and 23 were assigned to the TENS group. The outcomes included a VAS for pain, the Lequesne index, the ROM, walking time, patient global assessment, pain threshold, disability in
FIGURE 3. Forest plot of Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. CI indicates confidence interval.
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FIGURE 4. Forest plot of all-cause discontinuation. CI indicates confidence interval.
activities of daily living, and the minimal clinically important improvement. TENS significantly decreased the VAS scores at the 2-week follow-up, but there was no significant difference at 2- and 3-month follow-up examinations. The TENS group had a significant reduction in the Lequesne index at the 2-week and 3-month follow-up, whereas no significant difference was noted at the 2-month follow-up. Although the TENS group had advantages in the walking time at the 2-month follow-up and in the patient global assessment at the 2-week and 3-month follow-up examinations, there was no significant difference between the 2 groups in the ROM, walking time, or patient global assessment. With regard to the minimal clinically important improvement, the TENS group had a significant improvement compared with the HA group. The study did not mention any comparison between the 2 groups for the activities of daily living or pain threshold.
Kolen 2012
The interventions used in the study by Kolen et al30 were lowest-resistance TENS, irradiation TENS, and random site TENS. A total of 24 patients were assigned to lowest-resistance TENS, 26 to irradiation TENS, and 24 to random site TENS. The outcomes assessed included the pain intensity at rest determined by VAS, ROM, WOMAC, 6-minute walking test, maximum voluntary contraction, Hospital Anxiety and Depression Scale, Pain Anxiety Symptoms Scale (PASS20), and the Pain Catastrophizing Scale. Lowest-resistance TENS significantly decreased the pain intensity compared with random site TENS. There were no significant differences for the other outcomes among the 3 groups.
Sensitivity Analyses Overall, the outcomes regarding pain were stable. The meta-regression analysis for pain showed that neither the year nor country of publication was related to heterogeneity (Supplemental Fig. 3, Supplemental Digital Content 5, http://links.lww.com/CJP/A172). The sensitivity analyses excluding the studies one by one and changing the model did not change the results. Further, the trim-and-fill method showed no missing study. The details of the sensitivity analysis are shown in Supplemental Table 1 Copyright
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(Supplemental Digital Content 6, http://links.lww.com/ CJP/A173).
Assessment of Reporting Biases The funnel plot of pain showed no obvious asymmetry (Supplemental Fig. 4, Supplemental Digital Content 7, http://links.lww.com/CJP/A174). In addition, Egger’s test and the trim-and-fill method indicated that there was no obvious publication bias.
GRADE Profile Evidence The GRADE quality of evidence is shown in Table 2.
DISCUSSION Summary of the Main Results The meta-analyses indicated that: (1) patients who received TENS had significantly decreased pain compared with the control group; (2) there was no significant difference between the TENS and control groups in terms of the WOMAC index and all-cause discontinuation; (3) there was no significant difference between the TENS and control groups in the pain-limited ROM, total passive knee ROM, or TUG; and (4) TENS might significantly improve the maximum knee ROM on day 10 and during follow-up compared with the control group.
Agreements and Disagreements in the Current Literature A previous Cochrane review that included 13 studies about TENS indicated that: (1) TENS significantly decreased pain compared with the control group (SMD, 0.85; 95% CI, 1.36 to 0.34; P < 0.00001, I2 = 83%); (2) there was no significant difference between the TENS and control groups in the rates of withdrawal or drop-out because of adverse events (RR, 0.6; 95% CI, 0.03 to 14.15; P = 0.15, I2 = 51%); (3) there was no significant difference between the TENS and control groups with regard to knee function (SMD, 0.33; 95% CI, 0.69 to 0.03; P = 0.18, I2 = 36%); and (4) the funnel plot of data related to pain was asymmetrical (Egger’s test, P < 0.001). Our article excluded 2 studies with a high-risk bias in random sequence generation to decrease the potential bias and included 7 new research studies not included in the
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TABLE 2. Grade of Evidence
Transcutaneous Electrical Nerve Stimulation for Knee Osteoarthritis Patient or population: patients with knee osteoarthritis Settings: outpatient Intervention: transcutaneous electrical nerve stimulation Illustrative Comparative Risks* (95% CI) Assumed Risk Corresponding Risk
Outcomes
Control
Pain Follow-up: 2-24 wk
Range of movement “Timed Up-And-Go” test Follow-up: 2-4 wk
Relative Effect (95% CI)
Quality of the Evidence (GRADE) Comments ""~~ lowwz
310 (6 studies)
"""~ moderatew
RR 0.77 (0.48 to 1.22)
274 (5 studies)
"""~ moderatew
See comment
Not estimable
100 (3 studies)
See comment
Not estimable
200 (4 studies)
"""~ moderatey """~ moderatew
Study population 228 per 1000 Moderate 673 per 1000 See comment See comment
No. Participants (Studies) 607 (12 studies)
The mean pain in the intervention groups was 0.79 SDs lower (1.31 to 0.27 lower) The mean Western Ontario and McMaster Universities Osteoarthritis Index in the intervention groups was 0.13 SDs lower (0.35 lower to 0.1 higher)
Western Ontario and McMaster Universities Osteoarthritis Index Follow-up: 2-24 wk All-cause discontinuation Follow-up: 6-24 wk
Transcutaneous Electrical Nerve Stimulation
175 per 1000 (109 to 278) 518 per 1000 (323 to 821)
GRADE Working Group grades of evidence: High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate. *The basis for the assumed risk (eg, the median control group risk across studies) is provided below. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). wSome studies had high-risk biases. zI2 > 50%. yThe outcome measurements were different among studies. CI indicates confidence interval; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; RR, risk ratio.
previous Cochrane review. Our results basically agreed with the previous findings. However, we performed several sensitivity analyses for pain, which the previous study could not include, but none of these changed the results. On the basis of the present results, we believe that TENS can relieve pain in patients with knee OA. With regard to publication bias, Egger’s test showed that there was asymmetry (P < 0.05), but Begg’s test revealed symmetry (P > 0.05); therefore, a trim-and-fill method was used, and the results indicated there were no missing studies. These results indicated that there was no obvious publication bias. In this article, we included some studies that described new methods of TENS that the previous Cochrane Review did not mention. We also compared TENS with active treatments (ie, KIN, US, and HA). In addition, some new outcomes such as the ROM and the “TUGC test were
included in the current article, which were not evaluated in the previous Cochrane review. Currently, 2 groups are applying randomized-controlled methods to assess the efficacy (pain and function) of TENS in people with knee OA. Their results might supply evidence with high quality that may allow for more definitive conclusions to be drawn regarding the outcomes of TENS.
Strengths and Weaknesses The current paper had several strengths, including the following: (1) we used a comprehensive search strategy to minimize the possibilities of publication bias; (2) sensitivity analyses were performed to test the robustness of the outcomes with high heterogeneity, (3) only RCTs were included in this article, and (4) the GRADE was used to evaluate the quality of evidence.
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However, the results of the article should be interpreted with caution due to the existence of some limitations. First, only papers written in English were included in this article, although we searched for studies in all languages, which means that there may have been a selection bias. Second, the sample size of the RCTs was small; therefore, we could not completely exclude type-II errors or draw definitive conclusions. Third, there was substantial heterogeneity due to the different methodologies used, outcomes measured, and the presentation of data. These issues made it difficult to reach any strong conclusions. Fourth, the duration of follow-up was too short; therefore, we could not further evaluate the influence of TENS on knee OA. Fifth, the quality of the included studies was low, so any recommendation based on these studies should be interpreted with caution. Sixth, although the pooled estimate of the effects of TENS on pain relief was significant (0.79), it was below the 3-point reduction considered to indicate a clinically meaningful change; therefore, we considered that this was a modest effect, and we could not draw a strong conclusion regarding the impact of TENS on pain relief.
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