Osteoarthritis and Cartilage 22 (2014) 1090e1099
Effectiveness of continuous and pulsed ultrasound for the management of knee osteoarthritis: a systematic review and network meta-analysis C. Zeng, H. Li, T. Yang, Z.-h. Deng, Y. Yang, Y. Zhang, X. Ding, G.-h. Lei* Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
a r t i c l e i n f o
s u m m a r y
Article history: Received 12 March 2014 Accepted 28 June 2014
Background: To investigate the efficacy of continuous and pulsed ultrasound (US) in the management of knee osteoarthritis (OA). Design: This systematic review and network meta-analysis covered 12 trials in total. Electronic databases including MEDLINE, Embase and Cochrane Library were searched through to identify randomized controlled trials comparing the two modes of US with control interventions (sham or blank) or with each other. Bayesian network meta-analysis was used to integrate both the direct and indirect evidences on treatment effectiveness. Results: Pulsed US (PUS) is more effective in both pain relief and function improvement when compared with the control group; but for continuous US (CUS), there is only a significant difference in pain relief in comparison with the control group. In addition, no matter in terms of pain intensity or function at the last follow-up time point, PUS always exhibited a greater probability of being the preferred mode. However, the evidence of heterogeneity and the limitation in sample size of some studies could be a potential threat to the validity of results. Conclusions: Our findings indicated that PUS, with a greater probability of being the preferred mode, is more effective in both pain relief and function improvement when compared with the control group. However, CUS could only be considered as a pain relief treatment in the management of knee OA. The findings also confirmed that none of these modes is dangerous. Level of evidence: Level II, systematic review and network meta-analysis of randomized controlled trials. © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Ultrasound Pain Function Osteoarthritis Meta-analysis
Introduction Osteoarthritis (OA) is a progressive rheumatic disease, the incidence of which keeps rising with the growth of the ageing population in many societies. About 9 million people suffer from symptomatic, radiographically confirmed knee OA in the USA1. The main complaints of knee OA include: pain during body moving or weight bearing, stiffness, swelling, deformity and decreased walking time and distance. Therefore, the relevant therapies generally aim to relieve pain, improve functionality and mitigate
* Address correspondence and reprint requests to: G.-h. Lei, Department of Orthopaedics, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha, Hunan 410008, China. Tel: 86-0731-84327326. E-mail addresses: [email protected] (C. Zeng), [email protected], [email protected] (G.-h. Lei).
disability for enhancing the quality of life. As the prevalence of knee OA increases2, the increasing rates of knee arthroplasty, which is the only effective way of late phase, has made the identification of effective conservative treatments a high priority. Therapeutic ultrasound (US), based on the application of sound waves in tissues, is one of the most widely used physical agents in knee OA. There are two modes of US, continuous and pulsed. Continuous US (CUS) generates thermal effects by stimulating the process of tissue regeneration, changing cell membrane permeability and increasing intracellular calcium, while pulsed US (PUS) mainly produces non-thermal effects to increase tissue metabolism, enhance fibrous tissue extensibility and elevate pain threshold3e5. In the past few years, a rapidly growing interest in testing the effects of US has been observed, but no agreement was reached yet; especially, there is no exact conclusion on which modality of US (continuous or pulsed) is more effective in pain relief and functionality improvement of knee OA.
http://dx.doi.org/10.1016/j.joca.2014.06.028 1063-4584/© 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099
Recently, the Osteoarthritis Research Society International (OARSI) developed the guidelines (2014) for non-surgical management of knee OA6, which is the most up-to-date guideline till present. The recommendation level of US for knee-only OA was uncertain based on the results of two systematic reviews7,8 published in 2010 and one randomized controlled trial (RCT)9 published in 2012. Although these two previous systematic reviews covered several RCTs (one of them reported a statistically significant pain relief for knee OA7), evidence was limited because only six RCTs were available at that time. It is worth mentioning that whether the physical function was actually improved remains unclear. Furthermore, the authors admitted that the small sample size and low quality of trials included in their mode subgroup analyses (continuous or pulsed) inhibited further inferences7. Network meta-analysis has been recently developed to evaluate the relative effectiveness of several interventions and synthesize evidence across a network of randomized trials. The mainly strength of network meta-analysis is to combine the direct (studies compared PUS with CUS directly) and indirect estimates (studies compared PUS with CUS via control group) and calculated a mixed effect size as the weighted average of the direct evidence and the indirect evidence10. Comparing with traditional meta-analysis, network meta-analysis is able to offer information on comparisons for which no trails exist. In our case, the application of indirect evidence can improve the precision of the direct estimate by shortening the width of the confidence intervals in contrast to direct estimates alone11. Considering the accumulation of new trials, this paper intended to conduct an up-to-date systematic review and Bayesian network meta-analysis covering all the available direct and indirect evidences on US effects in order to generate a unified and coherent analysis for all RCTs12e15. The objective of this study was to assess the effects of US (continuous or pulsed) on pain relief and function improvement for knee OA. Materials and methods Literature search The electronic databases of Medline, Embase and Cochrane library were searched through using a series of logic combination of keywords and text words related to OA, interested interventions and randomized controlled trials (Appendix 1). The latest electronic search was conducted in February 2014 to identify the references of the retrieved papers and reviews. In addition, the following websites were searched through manually to identify unpublished and ongoing studies: Current Controlled Trials (http://www.controlledtrials.com/), ClinicalTrials.gov (http://www.clinicaltrials.gov/)and the World Health Organization International Clinical Trials Registry (http://apps.who.int/trialsearch/Default.aspx). Study selection Two researchers reviewed all the retrieved abstracts and full texts independently. Disagreements were resolved through discussions and consultations to another researcher. Those papers meeting the following criteria were included in the analysis: (1) randomized controlled trials; (2) patients with knee OA (3) studies containing at least two of the following eligible treatments: PUS, CUS and control group (blank or sham); (4) studies reporting the pain or function outcomes of patients; (5) English literature. On the other hand, the trials with unbalanced additional modality (e.g., education or exercise) between groups were excluded.
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Quality assessment Two researchers evaluated the methodological quality separately. The modified oxford score16,17, a scale ranged from 0 to 7 according to the descriptions of randomization, concealment allocation, blinding method and reporting of participant withdrawals, was used to measure the methodological quality of included studies. Outcome measures The primary goal of this study was to identify the effectiveness of pain management and function improvement by applying the PUS or CUS therapy respectively. The degree of pain intensity after treatment was used as the measure of pain management effect. If a study reported multiple pain scales, the highest one on the hierarchy of pain scale related outcomes was selected, as described by Jüni and colleagues18. The WOMAC function was the preferred measure for function. If a study did not measure or report the WOMAC function, WOMAC total, Lequesne Index or other functional measurement scales were used in the analysis instead. If a study reported outcomes at multiple time points after treatment, only the data from the final follow-up time point was extracted for analysis. The effect of pain management and function improvement was expressed as the standard mean differences (SMD) between different treatment arms. A negative value of SMD indicates lower pain intensity and better status of function after treatment. Statistical analysis The random effect Bayesian network meta-analysis was performed to compare the pain management and function improvement effect between different modes of US therapy for knee OA. The advantage of network meta-analysis is that it allows indirect comparisons of interventions among primary trials. In this study, the random effect Bayesian network meta-analysis was performed using WinBUGS software (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK), R version 3.0.2 (The R Foundation for Statistical Computing) and STATA software (version 11.0, StataCorp, College Station, TX). The codes of random effect models for multi-arm trials were available at http://www.mtm.uoi.gr/ (Appendix 2). Three Markov chains ran simultaneously with different initial values chosen arbitrarily. A total of 50,000 simulations were generated for each of the three sets of initial values, and the first 10,000 simulations were discarded due to the burn-in period. The pooled effect sizes were reported from the median of the posterior distribution. The corresponding 95% credible intervals with the 2.5th and 97.5th percentiles of the posterior distribution were used in this study, which could be interpreted in a way similar to the conventional 95% confidence intervals. In order to estimate the network inconsistency between indirect and direct estimates in each closed loop, the absolute difference between the direct and indirect treatment effect estimates was calculated. Loops with the lower CI limit did not reach the zero line were considered to represent statistically significant inconsistency19. The fit of the model to data can be measured by calculating the posterior mean residual deviance. If the mean of the residual deviance is similar to the number of data points of the model, it indicates that the model fits the data adequately20. All treatments were then ranked based on the level of effectiveness according to their posterior probabilities (first best, second best, third best, etc.). The probability values were summarized and reported as the surface under the cumulative ranking (SUCRA)21. SUCRA is equal to 1 for the best treatment, and 0 for the worst treatment.
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The classic pairwise meta-analysis was also performed by using STATA software (version 11.0, StataCorp, College Station, TX). The heterogeneity was tested by Q statistics (P 0.05 was considered heterogeneous) and I2 statistics, which measures the percentage of the total variation across various studies (I2 50% was considered heterogeneous). To evaluate the publication bias, Begg's tests22 were performed, where a P value less than 0.5 was considered to reflect publication bias.
Results Study selection and characteristics Figure 1 showed the selection process of the included trials in this study. A total of 1769 records were identified from the preliminary database and website search and 993 records were selected after removing duplicates. Then 927 records excluded with reasons and 66 full-text trials were evaluated for eligibility. Eventually, 12 studies were included in this research9,23e33. The characteristics of the included studies were listed in Table I. The methodological quality assessment (Table II) showed that three studies belonged to low quality (score 3), four belonged to medium quality (scored 4 or 5), and the rest belonged to high quality (scored 6 or 7). Data from eight studies involving a total of 525 patients with knee OA was available for network meta-analysis9,23e29. Figure 2 showed the network structure of the comparisons for the primary outcomes.
Pain intensity The results of network meta-analysis and pairwise metaanalysis were reported in Table III. PUS achieved a significantly lower pain intensity compared to the control group (SMD: 0.59, 95%CI: 0.89 to 0.26), and CUS achieved a significantly better effect of pain management compared to the control group (SMD: 0.41, 95%CI: 0.67 to 0.07). However, there was no significant difference between the PUS and CUS group in terms of pain intensity after treatment (SMD: 0.18, 95%CI: 0.94 to 0.37). No evidence of inconsistency between direct and indirect estimates was found in this network meta-analysis. Evaluation of the goodness of fit indicated adequate fit with a posterior mean residual deviance of 20.07 (19 data points). The distribution of probability of each treatment for this outcome was shown in Fig. 3. PUS is most likely to be the best treatment (93%) compared to CUS (56%) and the control group (0%). Pairwise meta-analysis showed nearly the same results (Table III). Significant evidence of heterogeneity was only observed in the comparison between PUS and the control group (P ¼ 0.07, I2 ¼ 54%). There was no publication bias among various studies. The original pain outcomes of the studies which were not included in meta-analysis were reported in Appendix 3. Function Table III also showed the outcomes of network meta-analysis for function. It indicated that only the PUS therapy was significantly more effective in terms of function improvement compared to the
Fig. 1. Flowchart for the selection of included trials.
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Table I Characteristics of the included studies Study
Groups
Balance*
N
Age (years)
Gender (M/F)
Mean BMI
Parameters of intervention
Interested outcome (pain/function)
Test timez
Loyola-S anchez 2012
G1: PUS G2: sham
None
14 13
62.6 61.2
3/11 3/10
34 30.4
VAS/WOMAC function
8 weeks
Ulus 2012
G1: CUS G2: sham
20 20
60.7 60.3
3/17 3/17
31.6 31.1
VAS/WOMAC function and LI
0 week
Tascioglu 2010
G1: G2: G3: G1: G2: G1: G2: G1: G2: G3: G1: G2: G1: G2: G3: G1: G2: G1: G2:
CUS PUS sham CUS sham PUS blank CUS PUS blank CUS blank CUS PUS sham PUS sham CUS sham
Hot pack, interferential current, exercise None
9.5 min 3 times 8 weeks, 20% duty cycle, 1 MHz, average temporal intensity: 0.2 W/cm2, therapeutic dose: 112.5 J/cm2 10 min 5 times 3 weeks, 1 MHz, 1 W/cm2
27 28 27 34x 33 32 31 48 56 42 20x 20 20 20 20 50 50 34x 35x
59.7 61.4 60 53.6 56.2 65y
10/17 7/21 9/18 6/28 7/26 27/113y
30 30.8 28.7 None
5 min 5 times 2 weeks, 1 MHz, 2 W/cm2
VAS/WOMAC total
2 days
VAS/WOMAC function
2 days
None
VAS/LI
0, 1 year
62y
23/97y
None
VAS/LI
0, 1 year
57.6 61.1 56.9 58.2 57.1 58.3y
Only Females 6/14 4/16 3/17 72/15y
29.8 27.7 27.9 30.9 29.5 None
5 min 5 times 2 weeks, 1 MHz, 1 W/cm2 5 min 3 times 8 weeks, 1 MHz, 2.5 W/cm2 5 min 3 times 8 weeks, 1 MHz, continuous: 1.5 W/cm2; pulsed: 2.5 W/cm2 10 min 3 times 8 weeks, 1 MHz, 1.5 W/cm2 12 min 5 times 2 weeks, CUS: 1 MHz, 1 W/cm2; PUS: 1 MHz, 1 W/cm2 30 min 5 treatments
VAS/LI
0 week
VAS/WOMAC function
0, 6 months
VAS/LI
0,4 weeks
69.4x 65.7x
8/26 11/35
BMI
VAS/gait velocity
0, 12 weeks
G1: G2: G1: G2:
CUS blank CUS sham
63.1 62 60y
2/13 3/12 e
e
VAS WOMAC Likert's scale/WOMAC function and LI
0 week
€ o € nenel 2009 Ozg Huang 2005a Huang 2005b
Cetin 2008 Cakir 2013
Yang PF 2011 Falconer J 1992
Külcü 2009 Kapidzic 2011
None Exercise Exercise, hot pack Exercise, hot pack Exercise
None None
None Thermotherapy and exercises
15 15 40 50
e
30 min 12 treatments (2e3 times per week over 4e6 weeks); increments of 0.1 W/cm2 to maximum 2.5 W/cm2 10 min 5 sessions 3 weeks; 1 MHz, 1.5 W/cm2 5 min, 3 weeks, 0.8 W/cm2
0 week
W, watt; ms, microsecond; N, number of subjects; M, male; F, female; BMI, Body Mass Index; VAS, visual analogue scale (0e10); WOMAC function, function subscale of Western Ontario and McMaster University Osteoarthritis Index (0e68); WOMAC total, Western Ontario and McMaster University Osteoarthritis Index consists three subscales (pain, stiffness and functional status, 0e96); LI, Lequesne index (0e26). * Usual cares which were balance between groups. y Only data for the whole trial is available. z 0 means at the end of the treatment. x Only data from the baseline is available.
control group (SMD: 0.57, 95%CI: 1.12 to 0.01). There was no significant difference between CUS and the control group (SMD: 0.26, 95%CI: 0.79 to 0.28), and between PUS and CUS (SMD: 0.31, 95%CI: 0.94 to 0.37) in terms of function improvement. There was no evidence of inconsistency between the direct and indirect evidences. The model had an adequate fit to data, with a posterior mean residual deviance of 19.64 (19 data points). Figure 4 displayed the distribution of probability of each treatment ranked at each of the three possible positions. According to the result of the posterior probability values of rank, it was found that PUS is most likely (98%) to be the best treatment for function improvement, followed by CUS (51%) and the control group (9%). The pairwise meta-analysis also ended up with similar results as the network meta-analysis in terms of function. However, there was significant heterogeneity between the two direct comparisons (PUS vs control: P ¼ 0.00, I2 ¼ 83%; PUS vs CUS: P ¼ 0.005, I2 ¼ 81%). Based on the P values of Beggs' test, publication bias did not exist among various studies. The functional results of the studies excluded from this network meta-analysis were reported in Appendix 3. Adverse effects There were only three trials that reported adverse effects. Two of them claimed that no adverse effect related to the CUS
treatment was observed, and one study reported the adverse effect of electric shock/stinging sensation related to the PUS treatment. However, there was no significant difference between the intervention and the control group in terms of the incidence of adverse effect. Discussion This network meta-analysis reviewed two kinds of therapeutic US (continuous or pulsed) in terms of pain relief and function improvement for patients with knee OA. It was found that PUS is more effective in terms of both pain relief and function improvement when compared with the control group (blank and sham), but for CUS, the significant difference only exists in pain relief in comparison with the control group. In addition, no matter in terms of pain intensity or function at the last follow-up time point, PUS is most likely to be the preferred mode. Recently, a provincial survey conducted in Canada indicated that a majority of physical therapists (85%) expressed interest in the effectiveness of US in pain relief and physical function34. However, the recommendations mentioned in the current clinical practice guidelines have not arrived at any agreement which against helping policy makers, service commissioners, and providers to judge the efficacy of US therapy. One guideline recommended US for OA management35; three guidelines were
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Table II Methodological evaluation of included studies Study
Randomized Concealment Blinding Follow-up Total method allocation method score
nchez 2012 Loyola-Sa Ulus 2012 Tascioglu 2010 € o € nenel 2009 Ozg Huang 2005a Huang 2005b Cetin 2008 Cakir 2013 Yang 2011 Falconer 1992 Külcü 2009 Kapidzic 2011
2 2 1 1 1 1 1 2 1 1 2 1
2 2 2 0 2 2 0 0 0 0 0 0
2 2 2 2 2 2 2 2 0 2 0 0
1 1 1 1 1 1 1 1 1 1 1 1
7 7 6 4 6 6 4 5 2 4 3 2
against the use of US36e38; three guidelines, including the latest one, regarded US as an uncertain appropriate modality6,39,40; other four guidelines did not even mention about US as a treatment option41e44. Two reviews published in 2010 involving five and six randomized controlled trials respectively reached a similar conclusion that therapeutic US might be beneficial (pain
PUS
3(147) 3(199)
5(224)
5(328)
CUS
6(331) 6(286) control
Fig. 2. Structure of network formed by interventions and their direct comparisons. The lines between treatment nodes indicate the direct comparisons made within randomized trials. The width of the lines is proportional to the number of trials comparing each pair of treatments. Numbers represent numbers of trials (number of analyzed patients) per comparison. Inside numbers are for pain outcome and outside numbers are for function outcome.
relief and function improvement) for patients with knee OA7,8. With the accumulation of evidences, especially for the mode (continuous or pulsed) subgroup, this network meta-analysis further supported that PUS could be the preferred mode in terms of both pain relief and function improvement without significant adverse effects. In vitro studies have supported the effects of PUS in inducing chondrocyte proliferation and matrix production in human articular cartilage45e49. Meanwhile, based on a number of researches establishing animal models of cartilage injury, in vivo experiments also showed that low intensity PUS was beneficial to cartilage health50e55. There was also a study suggesting that PUS with topical lidocaine gel could induce greater anaesthetic effects compared to CUS with topical lidocaine gel and lidocaine application alone56. The findings of these studies were consistent with the results obtained here. On the other hand, unlike the athermal mechanical effects generated by the application of PUS, CUS aims to generate thermal effects which could increase capillary permeability and tissue metabolism, enhance fibrous tissue extensibility, and especially elevate the pain threshold5,57. Likewise, CUS was proved to be an effective way only in pain relief for patients with knee OA in this study. As far as we know, this is the first network meta-analysis of US for knee OA, which compiled evidences from both direct and indirect comparisons for evaluating the relative effectiveness in pain relief and function improvement. In addition, this study overcame two limitations which were admitted in the previous classical meta-analysis7. One is the effects of co-interventions (including education or exercise) which could be effective in pain relief and function improvement. The control group of this study was limited to sham or blank control, and the additional modality was required to be balanced between groups in order to eliminate the potential impact of standard care. Under such circumstance, it is meaningful to conclude that US was effective as long as the results were significant. Otherwise, it is uncomfortable to draw a definite conclusion whether US is beneficial or not when the results were non-significant. The other limitation resolved is the powerful mode subgroup analysis which was conducted in this network meta-analysis. Furthermore, Beggs' test suggested that publication bias was not observed among the included studies. Nevertheless, the limitations of this study should not be ignored. Firstly, variations of US sessions, doses and differences in final follow-up time point might contribute to the significant evidence of heterogeneity, particularly for the possible doseeresponse patterns which could greatly affect the performance of US. However, because of the limited number of included trials and insufficient descriptions of treatment parameters, this study could not explore it in depth. Fortunately, no obvious evidence of inconsistency was observed in this network meta-analysis. Secondly, several included
Table III Results of network meta-analysis and pairwise meta-analysis Comparison PUS vs control Pain Function CUS vs control Pain Function PUS vs CUS Pain Function
Network meta-analysis, SMD (95%CI)
Pairwise meta-analysis, SMD (95%CI)
Heterogeneity (P/I2)
Publication bias (P value of Beggs' test)
0.59 (0.89, 0.26) 0.57 (1.12, 0.01)
0.55 (0.90, 0.21) 0.63 (1.31, 0.06)
0.07/54% 0.00/83%
0.086 0.462
0.41 (0.67, 0.07) 0.26 (0.79, 0.28)
0.40 (0.67, 0.14) 0.24 (0.47, 0.00)
0.21/30% 0.29/18%
1.000 1.000
0.18 (0.49, 0.17) 0.31 (0.94, 0.37)
0.13 (0.41, 0.15) 0.33 (1.10, 0.45)
0.71/0% 0.005/81%
1.000 0.296
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PUS
.4 .2 0
.2 0 1
2
3
1
2
3
.6
.8
1
control
0
.2
.4
Cumulative Probabilities
.4
.6
.6
.8
.8
1
1
CUS
1095
1
2
3
Rank
Graphs by Treatment
Fig. 3. Rankings for pain intensity. Graph displays distribution of probabilities for each treatment. X-axis represents the possible rank of each treatment (from the best rank to worse according to the outcomes), Y-axis represents the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.
function improvement when compared with the control group. However, CUS could only be considered as a pain relief treatment in the management of knee OA. The findings also confirmed that none of these modes is dangerous.
studies measured the pain or function parameters too shortly after all treatment courses. It is uncertain whether these effects may diminish after a long time. Thirdly, the low level of methodological quality and the limitation in sample size of some studies could be a potential threat to the validity of results. Fourthly, this study only focused on the effectiveness of pain relief and function improvement, it is difficult to measure other indices in this Bayesian network meta-analysis.
Contribution of authors All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CZ and GL contributed to the study concept and design and drafted the manuscript. HL, TY and ZD contributed to data collection. YY, YZ and XD contributed to preparation and data analysis. GL contributed to revision of the manuscript. All
Conclusion Our findings indicated that PUS, with a greater probability of being the preferred mode, is more effective in both pain relief and
.4
.4
0
.2
.2 0 1
2
3
1
2
3
.6
.8
1
control
0
.2
.4
Cumulative Probabilities
.6
.6
.8
.8
1
PUS
1
CUS
1 Graphs by Treatment
2
3
Rank
Fig. 4. Rankings for function. Graph displays distribution of probabilities for each treatment. X-axis represents the possible rank of each treatment (from the best rank to worse according to the outcome), Y-axis represents the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.
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the authors contributed to the interpretation of the data and critically reviewed the manuscript for publication.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgements This work was supported by Hunan Provincial Innovation Foundation for Postgraduate, the Fundamental Research Funds for the Central Universities of Central South University, the National Natural Science Foundation of China (Nos. 81201420, 81272034), the Provincial Science Foundation of Hunan (No. 14JJ3032), the Scientific Research Project of the Development and Reform Commission of Hunan Province (No. [2013]1199), the Scientific Research Project of Science and Technology Office of Hunan Province (No. 2013SK2018), the Doctoral Scientific Fund Project of the Ministry of Education of China (No. 20120162110036).
Appendix 1. Search strategies for Pubmed, Ovid/MEDLINE, The Cochrane Library and Ovid/EMBASE database
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
coxarthro$.ti,ab,sh. arthros$.ti,ab. arthrot$.ti,ab. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab. ((knee$ or joint$) adj3 stiff$).ti,ab Or/1-11 randomized controlled trial.pt. controlled clinical trial.pt. randomi?ed.ab. placebo.ab,tw. controlled.ti,ab randomly.ti,ab. trial.ti,ab. groups.ti,ab ((randomized controlled trials) or (random$ allocation) or (double blind) or (single blind)).tw ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw Or/13-22 exp ultrasonography/ exp Ultrasonic Therapy/ (ultrasound$ or ultrasonic$).tw. short wave therapy.tw. ultrasonograph$.tw. Ultraso$.ti,ab,sh Or/24-29 12 and 23 and 30
Pubmed 1. osteoarthro*[tiab] or gonarthriti*[tiab] or gonarthro*[tiab] or coxarthriti*[tiab] or coxarthro*[tiab] or osteo?arthritis[tiab] 2. (knee*[tiab] or joint*[tiab]) and (pain*[tiab] or discomfort* [tiab]) 3. (knee*[tiab] or joint*[tiab]) and stiff*[tiab] 4. 1 or 2 or 3 5. randomized[tiab] 6. placebo[tiab] 7. controlled[tiab] 8. random*[tiab] 9. trial*[tiab] 10. groups[tiab] 11. ((singl*[tiab] or doubl*[tiab] or tripl*[tiab]) and (mask*[tiab] or blind*[tiab])) 12. Or/5-11 13. Ultrasonography[tiab] 14. Ultrasonic[tiab] 15. ultrasound*[tiab] or ultrasonic*[tiab] 16. short[tiab] and wave[tiab] 17. ultrasonograph*[tiab] 18. Ultraso*[tiab] 19. Or 13-18 20. 4 and 12 and 19
Ovid/MEDLINE 1. 2. 3. 4. 5. 6.
osteoarthriti$.ti,ab,sh. osteoarthro$.ti,ab,sh. osteo?arthritic.ti,ab,sh. gonarthriti$.ti,ab,sh. gonarthro$.ti,ab,sh. coxarthriti$.ti,ab,sh.
The Cochrane Library #1 (osteoarthritis* OR osteoarthro* OR gonarthriti* OR gonarthro* OR coxarthriti* OR coxarthro* OR arthros* OR arthrot* OR ((knee* OR joint*) near/3 (pain* OR ach* OR discomfort*)) OR ((knee*OR joint*) near/3 stiff*)) #2 MeSH descriptor Osteoarthritis explode all trees #3 #1 or #2 #4 short wave therapy in Clinical Trials #5 ultrasonograph in Clinical Trials #6 (ultrasound* or ultrasonic*) in Clinical Trials #7MeSH descriptor Ultrasonography explode all trees #8 MeSH descriptor Short-Wave Therapy explode all trees #9 #4 or #5 or #6 or #7 or #8 #10 #3 and #9
Ovid/EMBASE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
osteoarthriti$.ti,ab,sh. osteoarthro$.ti,ab,sh. osteo?arthritic.ti,ab,sh. gonarthriti$.ti,ab,sh. gonarthro$.ti,ab,sh. coxarthriti$.ti,ab,sh. coxarthro$.ti,ab,sh. arthros$.ti,ab. arthrot$.ti,ab. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab. ((knee$ or joint$) adj3 stiff$).ti,ab Or/1-11 randomized controlled trial.pt. controlled clinical trial.pt.
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15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
randomi?ed.ab. placebo.ab,tw. controlled.ti,ab randomly.ti,ab. trial.ti,ab. groups.ti,ab ((randomized controlled trials) or (random$ allocation) or (double blind) or (single blind)).tw ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw Or/13-22 exp ultrasonography/ exp Ultrasonic Therapy/ (ultrasound$ or ultrasonic$).tw. short wave therapy.tw. ultrasonograph$.tw. Ultraso$.ti,ab,sh Or/24-29 12 and 23 and 30
Appendix 2. WinBUGS codes of random effect models for multi-arm trials
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Appendix 3. Results of the studies not included in the network meta-analysis Study
Groups
Pain scale/function scale
Yang PF 2011
G1: PUS G2: placebo
VAS/LI
Falconer J 1992
G1: G2: G1: G2:
VAS/gait velocity
Külcü 2009
Kapidzic 2011
CUS placebo CUS blank
G1: CUS G2: placebo
VAS/WOMAC
Likert's scale/WOMAC function and LI
Outcome of pain
Outcome of function
Original data
Significance of difference
Original data
Significance of difference
Effect index G1: 0.36 ± 0.28 G2: 0.10 ± 0.19 NR
P ¼ 0.000
Effect index G1: 0.31 ± 0.42 G2: 0.03 ± 0.11 NR
P ¼ 0.000
Median (range) G1: 2 (0e6) G2: 5 (2e10) Difference of before and after treatment G1: 0.83 ± 0.51 G2: 0.53 ± 0.40
NS P < 0.0001
P < 0.05
Median (range) G1: 11.5 (0e26) G2: 24 (18e30) Difference of before and after treatment G1: 0.61 ± 0.55 G2: 0.38 ± 0.70
NS P < 0.0001
P < 0.05
NS: not significant, NR: not report.
References 1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al, National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Arthritis Rheum 2008;58:26e35. 2. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, et al. Osteoarthritis: new insights, part 1: the disease and its risk factors. Ann Intern Med 2000;133:635e46. 3. Johns LD. Nonthermal effects of therapeutic ultrasound: the frequency resonance hypothesis. J Athl Train 2002;37:293e9. 4. Rand SE, Goerlich C, Marchand K, Jablecki N. The physical therapy prescription. Am Fam Physician 2007;76:1661e6. 5. Baker KG, Robertson VJ, Duck FA. A review of therapeutic ultrasound: biophysical effects. Phys Ther 2001;81:1351e8. 6. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363e88. 7. Loyola-Sanchez A, Richardson J, MacIntyre NJ. Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis. Osteoarthritis Cartilage 2010;18(9):1117e26. 8. Rutjes AW, Nuesch E, Sterchi R, Juni P. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2010;(1):CD003132. 9. Ulus Y, Tander B, Akyol Y, Durmus D, Buyukakıncak O, Gul U, et al. Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study. Int J Rheum Dis 2012;15:197e206. 10. Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med 2013;159:130e7. 11. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997;50: 683e91. 12. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 2005;331:897e900. 13. Caldwell DM, Welton NJ, Ades AE. Mixed treatment comparison analysis provides internally coherent treatment effect estimates based on overviews of reviews and can reveal inconsistency. J Clin Epidemiol 2010;63:875e82.
14. Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med 2002;21:2313e24. 15. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004;23: 3105e24. 16. Elia N, Tramer MR. Ketamine and postoperative pain-a quantitative systematic review of randomized trials. Pain 2005;113: 61e70. 17. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1e12. 18. Jüni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approach to treating the individual. Best Pract Res Clin Rheumatol 2006;20:721e40. 19. Veroniki A, Salanti G. Graphical exploration of inconsistency in a network of randomized trials in R., http://www.mtm.uoi.gr/ index.php/how-to-do-an-mtm/10-how-to-do-an-mtm/18inconsistency; 2012. 20. Spiegelhalter DJ, Best NG. Bayesian approaches to multiple sources of evidence and uncertainty in complex costeffectiveness modelling. Stat Med 2003;22:3687e709. 21. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multipletreatment meta-analysis: an overview and tutorial. J Clin Epidemiol 2011;64:163e71. 22. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088e101. 23. Cakir S, Hepguler S, Ozturk C, Korkmaz M, Isleten B, Atamaz FC. Efficacy of therapeutic ultrasound for the management of knee osteoarthritis: a randomized, controlled, and double-blind study. Am J Phys Med Rehabil 2014;93:405e12. 24. Loyola-S anchez A, Richardson J, Beattie KA, Otero-Fuentes C, Adachi JD, MacIntyre NJ. Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo-controlled pilot study. Arch Phys Med Rehabil 2012;93:35e42. 25. Tascioglu F, Kuzgun S, Armagan O, Ogutler G. Short-term effectiveness of ultrasound therapy in knee osteoarthritis. J Int Med Res 2010;38:1233e42. € nenel L, Aytekin E, Durmus¸oglu G. A double-blind trial of 26. Ozgo clinical effects of therapeutic ultrasound in knee osteoarthritis. Ultrasound Med Biol 2009;35:44e9.
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27. Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis Rheum 2005;15:812e20. 28. Huang MH, Lin YS, Lee CL, Yang RC. Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis. Arch Phys Med Rehabil 2005;86:1545e51. 29. Cetin N, Aytar A, Atalay A, Akman MN. Comparing hot pack, short-wave 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;87:443e51. 30. Kapidzic S. Measurement of therapeutic effect of ultrasound on knee osteoarthritis; double blind study. Ann Phys Rehabil Med 2011;54S:e180e3. 31. Yang PF, Li D, Zhang SM, Wu Q, Tang J, Huang LK, et al. Efficacy of ultrasound in the treatment of osteoarthritis of the knee. Orthop Surg 2011;3:181e7. 32. Falconer J, Hayes KW, Chang RW. Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res 1992;5:29e35. 33. Külcü DG, Güls¸en G, Altunok EÇ. Short-term efficacy of pulsed electromagnetic field therapy on pain and functional level in knee osteoarthritis: a randomized controlled study. Turk J Rheumatol 2009;24:144e8. 34. MacIntyre NJ, Busse JW, Bhandari M. Physical therapists in primary care are interested in high quality evidence regarding efficacy of therapeutic ultrasound for knee osteoarthritis: a provincial survey. ScientificWorldJournal 2013;2013:348014. 35. Conaghan P, Birrell F, Burke M, Cumming J, Dickson J, Dieppe P, et al. Osteoarthritis: National Clinical Guideline for Care and Management in Adults. London, UK: Royal College of Physicians; 2008. 36. The Royal Australian College of General Practitioners. Guideline for the Non-surgical Management of Hip and Knee Osteoarthritis, http://www.racgp.org.au/guidelines/osteoarthritis; 2009. 37. Vogels E, Hendricks H, Van Baar M, Dekker J, Hopman-Rock M, Oostendorp R, et al. Clinical Practice Guidelines for Physical Therapy Inpatients with Osteoarthritis of the Hip or Knee, http://www.cebp.nl/media/m1; 2003. 38. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137e62. 39. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al, Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003;62:1145e55. 40. Philadelphia Panel. Philadelphia panel evidence-based clinical practice guidelines on selected rehabilitation interventions for knee pain. Phys Ther 2001;81:1675e700. 41. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al, American College of Rheumatology. American College of Rheumatology 2012 recommendations for the
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Effectiveness of continuous and pulsed ultrasound for the management of knee osteoarthritis: a systematic review and network meta-analysis C. Zeng, H. Li, T. Yang, Z.-h. Deng, Y. Yang, Y. Zhang, X. Ding, G.-h. Lei* Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
a r t i c l e i n f o
s u m m a r y
Article history: Received 12 March 2014 Accepted 28 June 2014
Background: To investigate the efficacy of continuous and pulsed ultrasound (US) in the management of knee osteoarthritis (OA). Design: This systematic review and network meta-analysis covered 12 trials in total. Electronic databases including MEDLINE, Embase and Cochrane Library were searched through to identify randomized controlled trials comparing the two modes of US with control interventions (sham or blank) or with each other. Bayesian network meta-analysis was used to integrate both the direct and indirect evidences on treatment effectiveness. Results: Pulsed US (PUS) is more effective in both pain relief and function improvement when compared with the control group; but for continuous US (CUS), there is only a significant difference in pain relief in comparison with the control group. In addition, no matter in terms of pain intensity or function at the last follow-up time point, PUS always exhibited a greater probability of being the preferred mode. However, the evidence of heterogeneity and the limitation in sample size of some studies could be a potential threat to the validity of results. Conclusions: Our findings indicated that PUS, with a greater probability of being the preferred mode, is more effective in both pain relief and function improvement when compared with the control group. However, CUS could only be considered as a pain relief treatment in the management of knee OA. The findings also confirmed that none of these modes is dangerous. Level of evidence: Level II, systematic review and network meta-analysis of randomized controlled trials. © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Ultrasound Pain Function Osteoarthritis Meta-analysis
Introduction Osteoarthritis (OA) is a progressive rheumatic disease, the incidence of which keeps rising with the growth of the ageing population in many societies. About 9 million people suffer from symptomatic, radiographically confirmed knee OA in the USA1. The main complaints of knee OA include: pain during body moving or weight bearing, stiffness, swelling, deformity and decreased walking time and distance. Therefore, the relevant therapies generally aim to relieve pain, improve functionality and mitigate
* Address correspondence and reprint requests to: G.-h. Lei, Department of Orthopaedics, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha, Hunan 410008, China. Tel: 86-0731-84327326. E-mail addresses: [email protected] (C. Zeng), [email protected], [email protected] (G.-h. Lei).
disability for enhancing the quality of life. As the prevalence of knee OA increases2, the increasing rates of knee arthroplasty, which is the only effective way of late phase, has made the identification of effective conservative treatments a high priority. Therapeutic ultrasound (US), based on the application of sound waves in tissues, is one of the most widely used physical agents in knee OA. There are two modes of US, continuous and pulsed. Continuous US (CUS) generates thermal effects by stimulating the process of tissue regeneration, changing cell membrane permeability and increasing intracellular calcium, while pulsed US (PUS) mainly produces non-thermal effects to increase tissue metabolism, enhance fibrous tissue extensibility and elevate pain threshold3e5. In the past few years, a rapidly growing interest in testing the effects of US has been observed, but no agreement was reached yet; especially, there is no exact conclusion on which modality of US (continuous or pulsed) is more effective in pain relief and functionality improvement of knee OA.
http://dx.doi.org/10.1016/j.joca.2014.06.028 1063-4584/© 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099
Recently, the Osteoarthritis Research Society International (OARSI) developed the guidelines (2014) for non-surgical management of knee OA6, which is the most up-to-date guideline till present. The recommendation level of US for knee-only OA was uncertain based on the results of two systematic reviews7,8 published in 2010 and one randomized controlled trial (RCT)9 published in 2012. Although these two previous systematic reviews covered several RCTs (one of them reported a statistically significant pain relief for knee OA7), evidence was limited because only six RCTs were available at that time. It is worth mentioning that whether the physical function was actually improved remains unclear. Furthermore, the authors admitted that the small sample size and low quality of trials included in their mode subgroup analyses (continuous or pulsed) inhibited further inferences7. Network meta-analysis has been recently developed to evaluate the relative effectiveness of several interventions and synthesize evidence across a network of randomized trials. The mainly strength of network meta-analysis is to combine the direct (studies compared PUS with CUS directly) and indirect estimates (studies compared PUS with CUS via control group) and calculated a mixed effect size as the weighted average of the direct evidence and the indirect evidence10. Comparing with traditional meta-analysis, network meta-analysis is able to offer information on comparisons for which no trails exist. In our case, the application of indirect evidence can improve the precision of the direct estimate by shortening the width of the confidence intervals in contrast to direct estimates alone11. Considering the accumulation of new trials, this paper intended to conduct an up-to-date systematic review and Bayesian network meta-analysis covering all the available direct and indirect evidences on US effects in order to generate a unified and coherent analysis for all RCTs12e15. The objective of this study was to assess the effects of US (continuous or pulsed) on pain relief and function improvement for knee OA. Materials and methods Literature search The electronic databases of Medline, Embase and Cochrane library were searched through using a series of logic combination of keywords and text words related to OA, interested interventions and randomized controlled trials (Appendix 1). The latest electronic search was conducted in February 2014 to identify the references of the retrieved papers and reviews. In addition, the following websites were searched through manually to identify unpublished and ongoing studies: Current Controlled Trials (http://www.controlledtrials.com/), ClinicalTrials.gov (http://www.clinicaltrials.gov/)and the World Health Organization International Clinical Trials Registry (http://apps.who.int/trialsearch/Default.aspx). Study selection Two researchers reviewed all the retrieved abstracts and full texts independently. Disagreements were resolved through discussions and consultations to another researcher. Those papers meeting the following criteria were included in the analysis: (1) randomized controlled trials; (2) patients with knee OA (3) studies containing at least two of the following eligible treatments: PUS, CUS and control group (blank or sham); (4) studies reporting the pain or function outcomes of patients; (5) English literature. On the other hand, the trials with unbalanced additional modality (e.g., education or exercise) between groups were excluded.
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Quality assessment Two researchers evaluated the methodological quality separately. The modified oxford score16,17, a scale ranged from 0 to 7 according to the descriptions of randomization, concealment allocation, blinding method and reporting of participant withdrawals, was used to measure the methodological quality of included studies. Outcome measures The primary goal of this study was to identify the effectiveness of pain management and function improvement by applying the PUS or CUS therapy respectively. The degree of pain intensity after treatment was used as the measure of pain management effect. If a study reported multiple pain scales, the highest one on the hierarchy of pain scale related outcomes was selected, as described by Jüni and colleagues18. The WOMAC function was the preferred measure for function. If a study did not measure or report the WOMAC function, WOMAC total, Lequesne Index or other functional measurement scales were used in the analysis instead. If a study reported outcomes at multiple time points after treatment, only the data from the final follow-up time point was extracted for analysis. The effect of pain management and function improvement was expressed as the standard mean differences (SMD) between different treatment arms. A negative value of SMD indicates lower pain intensity and better status of function after treatment. Statistical analysis The random effect Bayesian network meta-analysis was performed to compare the pain management and function improvement effect between different modes of US therapy for knee OA. The advantage of network meta-analysis is that it allows indirect comparisons of interventions among primary trials. In this study, the random effect Bayesian network meta-analysis was performed using WinBUGS software (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK), R version 3.0.2 (The R Foundation for Statistical Computing) and STATA software (version 11.0, StataCorp, College Station, TX). The codes of random effect models for multi-arm trials were available at http://www.mtm.uoi.gr/ (Appendix 2). Three Markov chains ran simultaneously with different initial values chosen arbitrarily. A total of 50,000 simulations were generated for each of the three sets of initial values, and the first 10,000 simulations were discarded due to the burn-in period. The pooled effect sizes were reported from the median of the posterior distribution. The corresponding 95% credible intervals with the 2.5th and 97.5th percentiles of the posterior distribution were used in this study, which could be interpreted in a way similar to the conventional 95% confidence intervals. In order to estimate the network inconsistency between indirect and direct estimates in each closed loop, the absolute difference between the direct and indirect treatment effect estimates was calculated. Loops with the lower CI limit did not reach the zero line were considered to represent statistically significant inconsistency19. The fit of the model to data can be measured by calculating the posterior mean residual deviance. If the mean of the residual deviance is similar to the number of data points of the model, it indicates that the model fits the data adequately20. All treatments were then ranked based on the level of effectiveness according to their posterior probabilities (first best, second best, third best, etc.). The probability values were summarized and reported as the surface under the cumulative ranking (SUCRA)21. SUCRA is equal to 1 for the best treatment, and 0 for the worst treatment.
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The classic pairwise meta-analysis was also performed by using STATA software (version 11.0, StataCorp, College Station, TX). The heterogeneity was tested by Q statistics (P 0.05 was considered heterogeneous) and I2 statistics, which measures the percentage of the total variation across various studies (I2 50% was considered heterogeneous). To evaluate the publication bias, Begg's tests22 were performed, where a P value less than 0.5 was considered to reflect publication bias.
Results Study selection and characteristics Figure 1 showed the selection process of the included trials in this study. A total of 1769 records were identified from the preliminary database and website search and 993 records were selected after removing duplicates. Then 927 records excluded with reasons and 66 full-text trials were evaluated for eligibility. Eventually, 12 studies were included in this research9,23e33. The characteristics of the included studies were listed in Table I. The methodological quality assessment (Table II) showed that three studies belonged to low quality (score 3), four belonged to medium quality (scored 4 or 5), and the rest belonged to high quality (scored 6 or 7). Data from eight studies involving a total of 525 patients with knee OA was available for network meta-analysis9,23e29. Figure 2 showed the network structure of the comparisons for the primary outcomes.
Pain intensity The results of network meta-analysis and pairwise metaanalysis were reported in Table III. PUS achieved a significantly lower pain intensity compared to the control group (SMD: 0.59, 95%CI: 0.89 to 0.26), and CUS achieved a significantly better effect of pain management compared to the control group (SMD: 0.41, 95%CI: 0.67 to 0.07). However, there was no significant difference between the PUS and CUS group in terms of pain intensity after treatment (SMD: 0.18, 95%CI: 0.94 to 0.37). No evidence of inconsistency between direct and indirect estimates was found in this network meta-analysis. Evaluation of the goodness of fit indicated adequate fit with a posterior mean residual deviance of 20.07 (19 data points). The distribution of probability of each treatment for this outcome was shown in Fig. 3. PUS is most likely to be the best treatment (93%) compared to CUS (56%) and the control group (0%). Pairwise meta-analysis showed nearly the same results (Table III). Significant evidence of heterogeneity was only observed in the comparison between PUS and the control group (P ¼ 0.07, I2 ¼ 54%). There was no publication bias among various studies. The original pain outcomes of the studies which were not included in meta-analysis were reported in Appendix 3. Function Table III also showed the outcomes of network meta-analysis for function. It indicated that only the PUS therapy was significantly more effective in terms of function improvement compared to the
Fig. 1. Flowchart for the selection of included trials.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099
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Table I Characteristics of the included studies Study
Groups
Balance*
N
Age (years)
Gender (M/F)
Mean BMI
Parameters of intervention
Interested outcome (pain/function)
Test timez
Loyola-S anchez 2012
G1: PUS G2: sham
None
14 13
62.6 61.2
3/11 3/10
34 30.4
VAS/WOMAC function
8 weeks
Ulus 2012
G1: CUS G2: sham
20 20
60.7 60.3
3/17 3/17
31.6 31.1
VAS/WOMAC function and LI
0 week
Tascioglu 2010
G1: G2: G3: G1: G2: G1: G2: G1: G2: G3: G1: G2: G1: G2: G3: G1: G2: G1: G2:
CUS PUS sham CUS sham PUS blank CUS PUS blank CUS blank CUS PUS sham PUS sham CUS sham
Hot pack, interferential current, exercise None
9.5 min 3 times 8 weeks, 20% duty cycle, 1 MHz, average temporal intensity: 0.2 W/cm2, therapeutic dose: 112.5 J/cm2 10 min 5 times 3 weeks, 1 MHz, 1 W/cm2
27 28 27 34x 33 32 31 48 56 42 20x 20 20 20 20 50 50 34x 35x
59.7 61.4 60 53.6 56.2 65y
10/17 7/21 9/18 6/28 7/26 27/113y
30 30.8 28.7 None
5 min 5 times 2 weeks, 1 MHz, 2 W/cm2
VAS/WOMAC total
2 days
VAS/WOMAC function
2 days
None
VAS/LI
0, 1 year
62y
23/97y
None
VAS/LI
0, 1 year
57.6 61.1 56.9 58.2 57.1 58.3y
Only Females 6/14 4/16 3/17 72/15y
29.8 27.7 27.9 30.9 29.5 None
5 min 5 times 2 weeks, 1 MHz, 1 W/cm2 5 min 3 times 8 weeks, 1 MHz, 2.5 W/cm2 5 min 3 times 8 weeks, 1 MHz, continuous: 1.5 W/cm2; pulsed: 2.5 W/cm2 10 min 3 times 8 weeks, 1 MHz, 1.5 W/cm2 12 min 5 times 2 weeks, CUS: 1 MHz, 1 W/cm2; PUS: 1 MHz, 1 W/cm2 30 min 5 treatments
VAS/LI
0 week
VAS/WOMAC function
0, 6 months
VAS/LI
0,4 weeks
69.4x 65.7x
8/26 11/35
BMI
VAS/gait velocity
0, 12 weeks
G1: G2: G1: G2:
CUS blank CUS sham
63.1 62 60y
2/13 3/12 e
e
VAS WOMAC Likert's scale/WOMAC function and LI
0 week
€ o € nenel 2009 Ozg Huang 2005a Huang 2005b
Cetin 2008 Cakir 2013
Yang PF 2011 Falconer J 1992
Külcü 2009 Kapidzic 2011
None Exercise Exercise, hot pack Exercise, hot pack Exercise
None None
None Thermotherapy and exercises
15 15 40 50
e
30 min 12 treatments (2e3 times per week over 4e6 weeks); increments of 0.1 W/cm2 to maximum 2.5 W/cm2 10 min 5 sessions 3 weeks; 1 MHz, 1.5 W/cm2 5 min, 3 weeks, 0.8 W/cm2
0 week
W, watt; ms, microsecond; N, number of subjects; M, male; F, female; BMI, Body Mass Index; VAS, visual analogue scale (0e10); WOMAC function, function subscale of Western Ontario and McMaster University Osteoarthritis Index (0e68); WOMAC total, Western Ontario and McMaster University Osteoarthritis Index consists three subscales (pain, stiffness and functional status, 0e96); LI, Lequesne index (0e26). * Usual cares which were balance between groups. y Only data for the whole trial is available. z 0 means at the end of the treatment. x Only data from the baseline is available.
control group (SMD: 0.57, 95%CI: 1.12 to 0.01). There was no significant difference between CUS and the control group (SMD: 0.26, 95%CI: 0.79 to 0.28), and between PUS and CUS (SMD: 0.31, 95%CI: 0.94 to 0.37) in terms of function improvement. There was no evidence of inconsistency between the direct and indirect evidences. The model had an adequate fit to data, with a posterior mean residual deviance of 19.64 (19 data points). Figure 4 displayed the distribution of probability of each treatment ranked at each of the three possible positions. According to the result of the posterior probability values of rank, it was found that PUS is most likely (98%) to be the best treatment for function improvement, followed by CUS (51%) and the control group (9%). The pairwise meta-analysis also ended up with similar results as the network meta-analysis in terms of function. However, there was significant heterogeneity between the two direct comparisons (PUS vs control: P ¼ 0.00, I2 ¼ 83%; PUS vs CUS: P ¼ 0.005, I2 ¼ 81%). Based on the P values of Beggs' test, publication bias did not exist among various studies. The functional results of the studies excluded from this network meta-analysis were reported in Appendix 3. Adverse effects There were only three trials that reported adverse effects. Two of them claimed that no adverse effect related to the CUS
treatment was observed, and one study reported the adverse effect of electric shock/stinging sensation related to the PUS treatment. However, there was no significant difference between the intervention and the control group in terms of the incidence of adverse effect. Discussion This network meta-analysis reviewed two kinds of therapeutic US (continuous or pulsed) in terms of pain relief and function improvement for patients with knee OA. It was found that PUS is more effective in terms of both pain relief and function improvement when compared with the control group (blank and sham), but for CUS, the significant difference only exists in pain relief in comparison with the control group. In addition, no matter in terms of pain intensity or function at the last follow-up time point, PUS is most likely to be the preferred mode. Recently, a provincial survey conducted in Canada indicated that a majority of physical therapists (85%) expressed interest in the effectiveness of US in pain relief and physical function34. However, the recommendations mentioned in the current clinical practice guidelines have not arrived at any agreement which against helping policy makers, service commissioners, and providers to judge the efficacy of US therapy. One guideline recommended US for OA management35; three guidelines were
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Table II Methodological evaluation of included studies Study
Randomized Concealment Blinding Follow-up Total method allocation method score
nchez 2012 Loyola-Sa Ulus 2012 Tascioglu 2010 € o € nenel 2009 Ozg Huang 2005a Huang 2005b Cetin 2008 Cakir 2013 Yang 2011 Falconer 1992 Külcü 2009 Kapidzic 2011
2 2 1 1 1 1 1 2 1 1 2 1
2 2 2 0 2 2 0 0 0 0 0 0
2 2 2 2 2 2 2 2 0 2 0 0
1 1 1 1 1 1 1 1 1 1 1 1
7 7 6 4 6 6 4 5 2 4 3 2
against the use of US36e38; three guidelines, including the latest one, regarded US as an uncertain appropriate modality6,39,40; other four guidelines did not even mention about US as a treatment option41e44. Two reviews published in 2010 involving five and six randomized controlled trials respectively reached a similar conclusion that therapeutic US might be beneficial (pain
PUS
3(147) 3(199)
5(224)
5(328)
CUS
6(331) 6(286) control
Fig. 2. Structure of network formed by interventions and their direct comparisons. The lines between treatment nodes indicate the direct comparisons made within randomized trials. The width of the lines is proportional to the number of trials comparing each pair of treatments. Numbers represent numbers of trials (number of analyzed patients) per comparison. Inside numbers are for pain outcome and outside numbers are for function outcome.
relief and function improvement) for patients with knee OA7,8. With the accumulation of evidences, especially for the mode (continuous or pulsed) subgroup, this network meta-analysis further supported that PUS could be the preferred mode in terms of both pain relief and function improvement without significant adverse effects. In vitro studies have supported the effects of PUS in inducing chondrocyte proliferation and matrix production in human articular cartilage45e49. Meanwhile, based on a number of researches establishing animal models of cartilage injury, in vivo experiments also showed that low intensity PUS was beneficial to cartilage health50e55. There was also a study suggesting that PUS with topical lidocaine gel could induce greater anaesthetic effects compared to CUS with topical lidocaine gel and lidocaine application alone56. The findings of these studies were consistent with the results obtained here. On the other hand, unlike the athermal mechanical effects generated by the application of PUS, CUS aims to generate thermal effects which could increase capillary permeability and tissue metabolism, enhance fibrous tissue extensibility, and especially elevate the pain threshold5,57. Likewise, CUS was proved to be an effective way only in pain relief for patients with knee OA in this study. As far as we know, this is the first network meta-analysis of US for knee OA, which compiled evidences from both direct and indirect comparisons for evaluating the relative effectiveness in pain relief and function improvement. In addition, this study overcame two limitations which were admitted in the previous classical meta-analysis7. One is the effects of co-interventions (including education or exercise) which could be effective in pain relief and function improvement. The control group of this study was limited to sham or blank control, and the additional modality was required to be balanced between groups in order to eliminate the potential impact of standard care. Under such circumstance, it is meaningful to conclude that US was effective as long as the results were significant. Otherwise, it is uncomfortable to draw a definite conclusion whether US is beneficial or not when the results were non-significant. The other limitation resolved is the powerful mode subgroup analysis which was conducted in this network meta-analysis. Furthermore, Beggs' test suggested that publication bias was not observed among the included studies. Nevertheless, the limitations of this study should not be ignored. Firstly, variations of US sessions, doses and differences in final follow-up time point might contribute to the significant evidence of heterogeneity, particularly for the possible doseeresponse patterns which could greatly affect the performance of US. However, because of the limited number of included trials and insufficient descriptions of treatment parameters, this study could not explore it in depth. Fortunately, no obvious evidence of inconsistency was observed in this network meta-analysis. Secondly, several included
Table III Results of network meta-analysis and pairwise meta-analysis Comparison PUS vs control Pain Function CUS vs control Pain Function PUS vs CUS Pain Function
Network meta-analysis, SMD (95%CI)
Pairwise meta-analysis, SMD (95%CI)
Heterogeneity (P/I2)
Publication bias (P value of Beggs' test)
0.59 (0.89, 0.26) 0.57 (1.12, 0.01)
0.55 (0.90, 0.21) 0.63 (1.31, 0.06)
0.07/54% 0.00/83%
0.086 0.462
0.41 (0.67, 0.07) 0.26 (0.79, 0.28)
0.40 (0.67, 0.14) 0.24 (0.47, 0.00)
0.21/30% 0.29/18%
1.000 1.000
0.18 (0.49, 0.17) 0.31 (0.94, 0.37)
0.13 (0.41, 0.15) 0.33 (1.10, 0.45)
0.71/0% 0.005/81%
1.000 0.296
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099
PUS
.4 .2 0
.2 0 1
2
3
1
2
3
.6
.8
1
control
0
.2
.4
Cumulative Probabilities
.4
.6
.6
.8
.8
1
1
CUS
1095
1
2
3
Rank
Graphs by Treatment
Fig. 3. Rankings for pain intensity. Graph displays distribution of probabilities for each treatment. X-axis represents the possible rank of each treatment (from the best rank to worse according to the outcomes), Y-axis represents the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.
function improvement when compared with the control group. However, CUS could only be considered as a pain relief treatment in the management of knee OA. The findings also confirmed that none of these modes is dangerous.
studies measured the pain or function parameters too shortly after all treatment courses. It is uncertain whether these effects may diminish after a long time. Thirdly, the low level of methodological quality and the limitation in sample size of some studies could be a potential threat to the validity of results. Fourthly, this study only focused on the effectiveness of pain relief and function improvement, it is difficult to measure other indices in this Bayesian network meta-analysis.
Contribution of authors All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. CZ and GL contributed to the study concept and design and drafted the manuscript. HL, TY and ZD contributed to data collection. YY, YZ and XD contributed to preparation and data analysis. GL contributed to revision of the manuscript. All
Conclusion Our findings indicated that PUS, with a greater probability of being the preferred mode, is more effective in both pain relief and
.4
.4
0
.2
.2 0 1
2
3
1
2
3
.6
.8
1
control
0
.2
.4
Cumulative Probabilities
.6
.6
.8
.8
1
PUS
1
CUS
1 Graphs by Treatment
2
3
Rank
Fig. 4. Rankings for function. Graph displays distribution of probabilities for each treatment. X-axis represents the possible rank of each treatment (from the best rank to worse according to the outcome), Y-axis represents the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.
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the authors contributed to the interpretation of the data and critically reviewed the manuscript for publication.
Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgements This work was supported by Hunan Provincial Innovation Foundation for Postgraduate, the Fundamental Research Funds for the Central Universities of Central South University, the National Natural Science Foundation of China (Nos. 81201420, 81272034), the Provincial Science Foundation of Hunan (No. 14JJ3032), the Scientific Research Project of the Development and Reform Commission of Hunan Province (No. [2013]1199), the Scientific Research Project of Science and Technology Office of Hunan Province (No. 2013SK2018), the Doctoral Scientific Fund Project of the Ministry of Education of China (No. 20120162110036).
Appendix 1. Search strategies for Pubmed, Ovid/MEDLINE, The Cochrane Library and Ovid/EMBASE database
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
coxarthro$.ti,ab,sh. arthros$.ti,ab. arthrot$.ti,ab. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab. ((knee$ or joint$) adj3 stiff$).ti,ab Or/1-11 randomized controlled trial.pt. controlled clinical trial.pt. randomi?ed.ab. placebo.ab,tw. controlled.ti,ab randomly.ti,ab. trial.ti,ab. groups.ti,ab ((randomized controlled trials) or (random$ allocation) or (double blind) or (single blind)).tw ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw Or/13-22 exp ultrasonography/ exp Ultrasonic Therapy/ (ultrasound$ or ultrasonic$).tw. short wave therapy.tw. ultrasonograph$.tw. Ultraso$.ti,ab,sh Or/24-29 12 and 23 and 30
Pubmed 1. osteoarthro*[tiab] or gonarthriti*[tiab] or gonarthro*[tiab] or coxarthriti*[tiab] or coxarthro*[tiab] or osteo?arthritis[tiab] 2. (knee*[tiab] or joint*[tiab]) and (pain*[tiab] or discomfort* [tiab]) 3. (knee*[tiab] or joint*[tiab]) and stiff*[tiab] 4. 1 or 2 or 3 5. randomized[tiab] 6. placebo[tiab] 7. controlled[tiab] 8. random*[tiab] 9. trial*[tiab] 10. groups[tiab] 11. ((singl*[tiab] or doubl*[tiab] or tripl*[tiab]) and (mask*[tiab] or blind*[tiab])) 12. Or/5-11 13. Ultrasonography[tiab] 14. Ultrasonic[tiab] 15. ultrasound*[tiab] or ultrasonic*[tiab] 16. short[tiab] and wave[tiab] 17. ultrasonograph*[tiab] 18. Ultraso*[tiab] 19. Or 13-18 20. 4 and 12 and 19
Ovid/MEDLINE 1. 2. 3. 4. 5. 6.
osteoarthriti$.ti,ab,sh. osteoarthro$.ti,ab,sh. osteo?arthritic.ti,ab,sh. gonarthriti$.ti,ab,sh. gonarthro$.ti,ab,sh. coxarthriti$.ti,ab,sh.
The Cochrane Library #1 (osteoarthritis* OR osteoarthro* OR gonarthriti* OR gonarthro* OR coxarthriti* OR coxarthro* OR arthros* OR arthrot* OR ((knee* OR joint*) near/3 (pain* OR ach* OR discomfort*)) OR ((knee*OR joint*) near/3 stiff*)) #2 MeSH descriptor Osteoarthritis explode all trees #3 #1 or #2 #4 short wave therapy in Clinical Trials #5 ultrasonograph in Clinical Trials #6 (ultrasound* or ultrasonic*) in Clinical Trials #7MeSH descriptor Ultrasonography explode all trees #8 MeSH descriptor Short-Wave Therapy explode all trees #9 #4 or #5 or #6 or #7 or #8 #10 #3 and #9
Ovid/EMBASE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
osteoarthriti$.ti,ab,sh. osteoarthro$.ti,ab,sh. osteo?arthritic.ti,ab,sh. gonarthriti$.ti,ab,sh. gonarthro$.ti,ab,sh. coxarthriti$.ti,ab,sh. coxarthro$.ti,ab,sh. arthros$.ti,ab. arthrot$.ti,ab. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab. ((knee$ or joint$) adj3 stiff$).ti,ab Or/1-11 randomized controlled trial.pt. controlled clinical trial.pt.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
randomi?ed.ab. placebo.ab,tw. controlled.ti,ab randomly.ti,ab. trial.ti,ab. groups.ti,ab ((randomized controlled trials) or (random$ allocation) or (double blind) or (single blind)).tw ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw Or/13-22 exp ultrasonography/ exp Ultrasonic Therapy/ (ultrasound$ or ultrasonic$).tw. short wave therapy.tw. ultrasonograph$.tw. Ultraso$.ti,ab,sh Or/24-29 12 and 23 and 30
Appendix 2. WinBUGS codes of random effect models for multi-arm trials
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Appendix 3. Results of the studies not included in the network meta-analysis Study
Groups
Pain scale/function scale
Yang PF 2011
G1: PUS G2: placebo
VAS/LI
Falconer J 1992
G1: G2: G1: G2:
VAS/gait velocity
Külcü 2009
Kapidzic 2011
CUS placebo CUS blank
G1: CUS G2: placebo
VAS/WOMAC
Likert's scale/WOMAC function and LI
Outcome of pain
Outcome of function
Original data
Significance of difference
Original data
Significance of difference
Effect index G1: 0.36 ± 0.28 G2: 0.10 ± 0.19 NR
P ¼ 0.000
Effect index G1: 0.31 ± 0.42 G2: 0.03 ± 0.11 NR
P ¼ 0.000
Median (range) G1: 2 (0e6) G2: 5 (2e10) Difference of before and after treatment G1: 0.83 ± 0.51 G2: 0.53 ± 0.40
NS P < 0.0001
P < 0.05
Median (range) G1: 11.5 (0e26) G2: 24 (18e30) Difference of before and after treatment G1: 0.61 ± 0.55 G2: 0.38 ± 0.70
NS P < 0.0001
P < 0.05
NS: not significant, NR: not report.
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