Effect of Phonophoresis On Patients With Knee Osteoarthritis: A Systematic Review And Meta-Analysis of Randomized Controlled Trials

Phonophoresis is an alternative treatment for knee osteoarthritis. However, evidence supporting the advantages of phonophoresis remains inconsistent. This systematic review and meta-analysis was conducted to illustrate the effect of phonophoresis. The PubMed, Cochrane Library, and Embase databases were searched for relevant studies from the date of their inception to 28 June, 2021. The eligibility criteria were: (1) randomized controlled trials (RCTs); (2) patients diagnosed as having knee osteoarthritis; (3) treatment with either phonophoresis or therapeutic ultrasound with placebo gels; and (4) reporting clinical and functional outcomes. Continuous variables are expressed as standardized mean differences (SMDs) with 95% condence intervals (CIs). Analysis was performed using RevMan 5.3 software. The analysis included nine RCTs covering a total of 423 patients. The intervention group signicantly outperformed the control group in visual analog scale score [SMD = −0.65, 95% CI (−1.04, −0.25), P = 0.001], Western Ontario and McMaster Universities Arthritis Index (WOMAC) score [SMD = −0.71, 95% CI (−1.26, −0.16), P = 0.01], and walk test score [SMD = −0.67, 95% CI (−1.21, −0.13), P = 0.02]. As a result, phonophoresis might alleviate pain and improve function in the short term. Further high-quality, large-scale RCTs are required to conrm the benets.


Introduction
Knee osteoarthritis is characterized by the breakdown of articular cartilage over time. 1,2 Although cartilage breakdown is the major disease characteristic, osteoarthritis affects all joint tissues, including the synovial membrane, which is usually associated with increased pain and joint dysfunction. 2,3 Common clinical symptoms include knee pain with gradual onset and that worsens with activity, knee stiffness and swelling, pain after prolonged sitting or resting, and pain that worsens over time. 4 Some studies have reported that approximately 13% of women and 10% of men aged 60 years and older have symptomatic knee osteoarthritis. 5,6 Treatment initially involves nonsurgical modalities and progresses to surgical treatment once nonsurgical methods are no longer effective. 4 These interventions do not alter the disease process, but they may substantially diminish pain and disability. 7,8 According to several studies, self-management programs, muscle strengthening, low-impact aerobic exercises, neuromuscular education, and physical activity are recommended for patients with knee osteoarthritis. [9][10][11][12] Oral pharmacological agents such as nonsteroidal antiin ammatory drugs (NSAIDs) and corticosteroids are also effective treatment for knee osteoarthritis. [13][14][15] However, oral antiin ammatory drugs may increase the risks of gastrointestinal, renal, and other systemic toxicities. Topical gels are an alternative treatment with fewer complications compared with oral anti-in ammatory drugs. [16][17][18] As a treatment modality, ultrasound has been studied for many decades. 19 Its therapeutic effect is mainly derived from the absorption of mechanical energy and the production of heat in tissues. 20 Phonophoresis involves the use of ultrasound to deliver therapeutic drugs by absorption and permeation through the skin. 21 Phonophoresis with anti-in ammatory gels has been reported to treat pain and in ammation in many musculoskeletal conditions. [22][23][24][25] Despite the wide use of phonophoresis, scienti c evidence to support its use is insu cient, especially with regard to symptomatic knee osteoarthritis. Wu et al. conducted a systematic review and meta-analysis comparing the effects of therapeutic ultrasound for knee osteoarthritis. 26 A subgroup analysis indicated that a phonophoresis ultrasound group exhibited lower visual analog scale (VAS) scores than a conventional nondrug ultrasound group. 26 No signi cant differences were observed in Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. 26 However, only three randomized controlled trials (RCTs) were included in that study. Moreover, according to our electronic database search, more RCTs have been published recently. Thus, we conducted this study to assess the effect of phonophoresis on knee osteoarthritis symptoms.

Method
This systematic review was registered prospectively on the International Prospective Register of Systematic Reviews (PROSPERO) database under the number CRD42021266126 on August 6, 2021.

Eligibility criteria
The eligibility criteria were as follows: (1) RCTs; (2) patients diagnosed as having knee osteoarthritis; (3) treatment with either phonophoresis or therapeutic ultrasound with placebo gel; and (4) reporting clinical outcomes including VAS score, WOMAC score, range of motion, and walk test scores. We excluded articles with only protocols and non-peer-reviewed articles, such as conference papers and letters to the editor. No language restriction was applied in our search strategy.

Search strategy
The authors independently reviewed the literature, extracted data, and performed crosschecks in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 27 We searched electronic databases, namely PubMed, EMBASE, and Cochrane. We established group A based on phonophoresis and its synonyms; group B was formed using knee osteoarthritis and its synonyms. We intersected groups A and B to prepare our keywords for searching the aforementioned electronic databases (keywords are listed in the appendix). If available, RCTs were identi ed using the re ned search functions of the databases. Additional articles were identi ed through a manual search of the reference lists of the relevant articles. The databases were searched from their inception to 28 June, 2021. Two reviewers independently reviewed the full texts of all potentially relevant articles to identify articles that met the eligibility criteria. Their decisions were then compared, and disagreements were resolved through discussion with a third reviewer.

Data items
The following data were obtained from each RCT: the characteristics of therapeutic ultrasound; the number and mean age of the participants in the intervention and control groups; the content of the gel; and outcome measurements.

Outcome measurements
The outcome measurements in this study were VAS score, WOMAC score, range of motion, and walk test scores. VAS is a measurement instrument of pain across a continuum of values; pain cannot be easily measured directly. 28 Higher VAS scores indicate worse pain.
WOMAC is a self-administered questionnaire widely applied for hip and knee osteoarthritis evaluations. 29 Higher WOMAC scores denotes worse pain, stiffness, and physical function. Range of motion is the range through which a joint can be moved. 30 The walk tests included in this study were the 6-minute walk test, timed up and go test, 15-m walk test, and 20-m walk test. 31,32 Risk-of-bias assessment The risk of bias was assessed using the RoB 2 tool, a revision of the Cochrane risk-of-bias tool for RCTs, which is widely applied for assessing the quality of RCTs. 33 The following domains were considered: (1) randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) outcome measurement, (5) selection of the reported result, and (6) overall bias. 33 Following the Cochrane Handbook for Systematic Reviews of Interventions, the risk of bias was assessed by two independent reviewers. 34 Disagreements between the reviewers were resolved through discussion and consultation with a third reviewer.

Statistical analysis
Statistical analyses were performed using RevMan 5.3 software, which was provided by the Cochrane Collaboration (https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download). Continuous data were extracted as changes from baseline measurements. For data with missing standard deviations, the data were estimated by calculating correlation coe cients according to the Cochrane Handbook for Systematic Reviews of Interventions. 34 . The results with P < 0.05 were considered statistically signi cant. We used the I 2 test to objectively measure statistical heterogeneity, with I 2 ≥ 75% indicating considerable heterogeneity. 35 A random effects model was used in this meta-analysis. Continuous variables are expressed as standardized mean differences (SMDs) with 95% con dence intervals (CIs). Because of the different contents of gels mentioned in the indicated studies, subgroup analysis was conducted based on different gel contents (corticosteroids, NSAIDs, and herbal gels).
A funnel plot was not used to test for publication bias because of the limited number of studies included in each analysis (< 10).

Walk tests
The results of walk tests were reported in ve studies, 38

Adverse Events
Of the nine selected RCTs, four reported whether adverse effects occurred. 38,39,42,45 No adverse events were observed in these studies, indicating that the interventions were well tolerated by the participants.

Discussion
Knee osteoarthritis is a degenerative joint cartilage condition. 1,2 Its common clinical symptoms include knee pain that is gradual in onset and that worsens with activity, knee stiffness and swelling, pain after prolonged sitting or resting, and pain that worsens over time. 4 Topical anti-in ammatory drugs are an alternative treatment choice, with fewer gastrointestinal complications relative to oral drugs. [16][17][18] In phonophoresis, ultrasound is used to deliver therapeutic drugs by absorption and permeation through the skin. 21 Despite its wide usage, supporting scienti c evidence is insu cient, especially with regard to symptomatic knee osteoarthritis. Thus, we conducted this study to assess the effect of phonophoresis on knee osteoarthritis symptoms. Our analysis revealed signi cant intergroup differences favoring phonophoresis according to VAS, WOMAC, and walk test scores. Subgroup analysis revealed signi cant differences favoring phonophoresis with NSAID gel according to VAS and walk test scores, whereas it revealed signi cant differences favoring corticosteroid gel according to WOMAC scores.
Therapeutic ultrasound is a deep-heating modality used in physical therapy. 41 According to Rao et al., therapeutic ultrasound is generated by a transducer that converts electrical energy to ultrasound by using the piezoelectric principle. 46 Although the exact mechanism of its effect is not well known, the effect may be composed of two components, namely thermal effect and nonthermal effect. 47 In terms of thermal effects, therapeutic ultrasound induces muscle relaxation, increases connective tissue extensibility, and increases local blood ow, all of which induce tissue regeneration and reduce in ammation. 41,47 Nonthermal ultrasound effects are related to acoustic cavitation with resultant increases in cell permeability, which is a potential pain relief mechanism. 47 Phonophoresis is the use of ultrasound to deliver therapeutic drugs by absorption and permeation through the skin. 21 The advantage of therapeutic ultrasound is that it may promote the transdermal penetration of therapeutic drugs. 42,45 Moreover, this method is noninvasive and has a minimal risk of adverse effects associated with systemic administration of anti-in ammatory drugs, and it combines the therapeutic effects of ultrasound and topical drugs. 42 Phonophoresis accounts for up to 30% of physiotherapy visits in some medical centers. 44 Recently, gels with different contents have been made available for phonophoresis. The common gels are corticosteroid and NSAID gels. In the selected RCTs, two focused on corticosteroid gels, 37,40 six focused on NSAID gels, 39,41−45 and one focused on herbal gels. 38 The two studies that used corticosteroid gels used dexamethasone gels. 37,40 In the six RCTs that focused on NSAID gels, three used diclofenac gels, 39,41,44 one used ibuprofen gel, 45 one used ketoprofen gel, 43 and one used piroxicam gel. 42 The herbal gel was Phyllanthus amarus gel. 38 Although each type of gel had anti-in ammatory effects; their chemical properties (e.g., their permeability to the tissue through ultrasound waves) differed, as reported by Akinbo et al. 44 In a literature review, Srbely et al. indicated that the depth of penetration of a drug depends on its mass (which is inversely proportional to its molecular weight). 48 . Molecular weight is different from the contents of gels discussed in the selected RCTs. Dexamethasone has a high molecular weight; thus, it has a low drug mass and high permeability through ultrasound waves. The aforementioned reasons may explain why patients in the corticosteroid gel subgroup exhibited greater improvements in some outcomes than those in the NSAID gel subgroup. 44 Thus, drug selection for phonophoresis seems to be as important as ultrasound parameters treatment success. 37 According to Byl et al., the diffusion of topically applied drugs through the skin can also be enhanced by preheating the skin to increase kinetic energy. 49 In our selected RCTs, three studies followed this principle. 40,44,45 The application of heat before treatment may have in uenced the results in these studies. On the basis of our analysis, the outcomes when preheating was applied were controversial.
Some studies showed improved outcomes, whereas others reported no differences when compared with outcomes without preheating application. Therefore, the exact effects of preheating the skin require further investigation.
Regarding WOMAC scores, study heterogeneity was high (I 2 = 84%, P < 0.00001). For this reason, sensitivity analysis was conducted. According to the Cochrane Handbook for Systematic Reviews of Interventions, heterogeneity may arise due to the presence of one or two outlying studies with results that con ict with those of the remaining studies. 34 If an obvious reason for the outlying result is apparent, the study might be removed with more con dence. 34 In the selected studies mentioning WOMAC score as an outcome, both Akinbo et al. and Kozanoglu et al. applied preheating on the treatment site before treatment. 44,45 They followed the principle of Byl et al. 49 However, this application may in uence treatment outcomes. As a result, these two outliners 44,45 were excluded from the analysis.
In a systematic review and meta-analysis, Wu et al. assessed the effectiveness and safety of different therapeutic ultrasound methods. 26 In the subanalysis of phonophoresis, three RCTs were examined. 42,43,45 [37][38][39][40][41][42][43][44][45] We examined the effect of phonophoresis on patients with knee osteoarthritis. We focused on the outcomes of VAS score, WOMAC score, range of motion, and walk tests and found that phonophoresis effectively improved such outcome measures.
This systematic review and meta-analysis has several strengths. First, this is the rst meta-analysis of RCTs that focused on the effects of phonophoresis in patients with knee osteoarthritis, with adequate evidence provided. Second, several studies are ongoing in this eld according to our electronic database search. Thus, the study results will serve as a reference for future studies. Third, multiple major databases were used for the selection of RCTs, without language restrictions. Fourth, the data and quality of selected studies were extracted and assessed, respectively, by at least two reviewers through a group consensus approach.
Our study had several limitations, which might limit the generalization of our results. First, heterogeneity was moderate to high for some outcomes. This might be because of varying disease severity, symptom durations, patient characteristics, and treatment protocols. Thus, further studies are required to establish a standardized treatment protocol. Second, different gel contents such as lidocaine or capsaicin that could be applied in the experimental group were not studied. Future studies should examine different contents of gel and measure their effects. Third, some studies did not mention blinding to therapeutics and the blinding of patients or assessors. Hence, some concerns regarding risk of bias may persist. Fourth, in the selected RCTs, follow-up durations were mostly short. One study had a 1-month follow-up, 39 and one study had a 3-month follow-up; 41 others provided follow-up data within 1 week after intervention. 37,38,40,42−45 Thus, more high-quality large-scale RCTs with long-term follow-ups are required to overcome these limitations.

Conclusion
This is the rst meta-analysis of RCTs that focused on the effect of phonophoresis in patients with knee osteoarthritis and provided adequate evidence. According to our analysis, phonophoresis might improve pain and functions in the short term. Furthermore, no adverse events were noted in the selected studies. Phonophoresis is a treatment option for patients with knee osteoarthritis. However, further high-quality, large-scale, and long-follow-up-period RCTs are required to con rm the bene t and long-term effects of this intervention.
Declarations Figure 1 Flowchart of article selection.

Figure 2
Study quality assessment.

Figure 3
Forest plot for changes from baseline determined using the visual analog scale (VAS).

Figure 4
Forest plot for changes from baseline determined using the Western Ontario and McMaster Universities Arthritis Index (WOMAC).

Figure 5
Forest plot for changes from baseline based on range of motion.

Figure 6
Forest plot for improvements in walk test scores.

Supplementary Files
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