Use of Sonophoresis with Corticosteroids in Carpal Tunnel Syndrome: Systematic Review and Meta-Analysis

Carpal tunnel syndrome is a neuropathic disease. It is one of the most frequent musculoskeletal pathologies affecting the upper limbs. One of most frequently used non-surgical treatments is corticosteorids. There are several alternatives for corticosteroids administration. One of them is phonophoresis, this being an effective and painless method of treatment. A systematic review and meta-analysis have been conducted over the use of phonophoresis with corticosteroids for the treatment of carpal tunnel syndrome compared to other non-surgical treatment methods. Keywords from Medical Subjects Headings (MeSH) were used in the following databases: Wos, Scopus, CINHAL, SciELO and PeDro. A total of 222 potentially relevant articles were retrieved. Eleven articles analysing the efficacy of phonophoresis with corticosteroids in reducing pain symptoms in individuals with carpal tunnel syndrome were included, 10 of which were used to conduct the meta-analysis. A conclusion could not be reached as to the application of phonophoresis with corticosteroids being better than other treatment methods, except for the perception of pain and an improved motor and sensory nerve conduction in cases of mild to moderate carpal tunnel syndrome.


Introduction
Carpal tunnel syndrome (CTS) is a neuropathic disease that occurs at the wrist area when the median nerve is affected. It is one of the most frequent musculoskeletal pathologies affecting the upper limb [1]. It features a high prevalence among the working force and it reaches a rate in the general population of 276/100,000 individuals [2]. Symptoms may include a sensation of tingling, numbness and paresthesia, as well as pain and weakness in the area of the hand innervated by the median nerve [3]. Surgical treatment is reserved for severe cases or when conservative treatment is not successful [4]. One of most frequently used non-surgical treatments is corticosteorids injections [5]. Due to the direct inoculation into the injury, it is highly effective in mild cases and in the short term, but it shows arguable results in the long term [6]. There are several alternatives to corticosteroids administration. One of them is phonophoresis, this being an effective and painless method of administration [7]. It is applied by using the cavitation effect produced by an ultrasonic wave allowing drug penetration [8]. This method of administration has been used since 1950. From then on, its functional characteristics have been modified and improved [9]. The advantages observed with this method of treatment include less harmful effects on organs, due to a reduced systemic concentration of drugs, reduced side effects, and an improved adherence of patients to therapy, since it is a painless technique [10,11].
In spite of the systematic reviews that exist on this subject [12][13][14][15], no meta-analysis focused on phonophoresis with corticosteroids compared to other non-surgical techniques Table 1. Search strategy in the databases used.

Elegibility Criteria
The eligibility criteria were established based on the PICO [17] model: (P) Populationsubjects diagnosed with carpal tunnel syndrome; (I) Intervention-treatment consisting in phonophoresis with corticosteroids. (C) Comparator-sham and other treatments; (O) Outcomes-related to pain and/or nerve conduction. Studies not being clinical trials or conducted on humans were excluded. No language or date restriction were used.

Studies Selection and Data Abstraction
Two reviewers (F.J.M.V. and G.G.M.) conducted the studies selection process, eliminated duplicates, and reviewed and systematically abstracted data. A third reviewer (V.P.C.) helped to reach an agreement in case of dispute. For this, the Mendeley reference manager version 1.19.8.0 was used.
Data abstracted from each of the studies included were: (i) authors and publication date; (ii) subjects' related data (number of subjects, sex, age, number of bilateral cases, study groups and degree of injury); (iii) data related to assessment (measuring tools used, number and timing of assessments); (iv) data related to the intervention with phonophoresis (type of intervention, type and quantity of active ingredient used); (v) parameters of techniques used, duration and frequency of the intervention; (vi) achieved outcomes.

Assessment of the Methodological Quality of the Studies
For methodological assessment purposes, the PEDro [18] scale was used. This scale comprises 11 items related to selection, performance, detection, information, and allocation. Each item scores one point if the studies meet the criteria, except item 1, which is not used for final calculation purposes. A score higher than or equal to 6 is considered a level of evidence 1 (10-9: excellent; 8-6: good) and a score lower than or equal to 5 is considered a level of evidence 2 (5-4: fair; below 4: poor) [19].

Statistical Analysis
The IT tool Review Manager (RevMan) was used to conduct the meta-analysis. Version 5.4. The Cochrane Collaboration, 2020 [20]. Data were gathered by variable and form of drug administration. Generic inverse variance was applied for the analysis of each subgroup. When grouping could not be done, mean difference was applied. When I 2 value was above 50% the random effect model was used. The effect size was obtained through the Z value in the Test for overall effect and its p value (p < 0.05 significant; p > 0.05 non-significant). Sensitivity analysis has been conducted for all studies included in all the variables subject to analysis. To verify the homogeneity of studies, the value for p of Heterogeneity (p < 0.05 Homogeneity; p > 0.05 Heterogeneity) was used. The risk of bias was estimated through the Begg and Egger tests, with the epidemiological data analysis programme (EPIDAT) [21], in addition to the funnel plots outcomes.

Results
A total of 222 potentially relevant articles were retrieved ( Figure 1). Eleven articles analysing the efficacy of phonophoresis with corticosteroids in reducing pain symptoms in individuals with carpal tunnel syndrome were included, 10 of which were used to conduct the meta-analysis ( Figure 1).
The total sample included 434 subjects. The average was 39.5 subjects (a bracket between 31 and 54 subjects). Only four studies [22][23][24][25] identified the prevalence of women, but not the others. The age range of subjects was 39-54 years. The bilateral pathology is present in a range of 22.5% and 44.6% of subjects, except for four studies which do not reflect it [22,[25][26][27]. Carpal tunnel syndrome has been diagnosed at a mild to moderate level, except for five studies which do not refer to it [25,[27][28][29][30].
Concerning the tools used for diagnosis purposes, all of the studies included the Boston Carpal Tunnel Questionnaire (BCTQ) scale [33] which consists of a 19-item selfadministered questionnaire with two subscales: a subscale measuring symptom severity (11 items) and a scale assessing functional status (eight items) and/or nerve conduction studies (NCS) on the median nerve [34] where major motor latency (LMMotor) is analysed, sensory major latency (LMSensor), sensory nerve action potential amplitude (SNAPam), motor nerve action potential amplitude (CMAPam), sensory nerve conduction velocity (CNVS) and motor nerve conduction velocity (CNVM) are measured. Some of them used the visual analogue scale (VAS) for patient self-assessment of pain sensation [35], as well as the dynamometer for measuring grip strength [23,[25][26][27]29,31] and pinch strength [23,25,26,31], evaluation of manual dexterity [23,27,29], Phalen and Tinel's tests [28,29], degree of paresthesia [23,26], ecographic analysis of the cross-sectional area of the median nerve [28], as well as the Semmes-Weinstein test and the Duruoz Hand Index [29]. The total sample included 434 subjects. The average was 39.5 subjects (a bracket between 31 and 54 subjects). Only four studies [22][23][24][25] identified the prevalence of women, but not the others. The age range of subjects was 39-54 years. The bilateral pathology is present in a range of 22.5% and 44.6% of subjects, except for four studies which do not reflect it [22,[25][26][27]. Carpal tunnel syndrome has been diagnosed at a mild to moderate level, except for five studies which do not refer to it [25,[27][28][29][30].
Concerning the tools used for diagnosis purposes, all of the studies included the Boston Carpal Tunnel Questionnaire (BCTQ) scale [33] which consists of a 19-item selfadministered questionnaire with two subscales: a subscale measuring symptom severity (11 items) and a scale assessing functional status (eight items) and/or nerve conduction studies (NCS) on the median nerve [34] where major motor latency (LMMotor) is analysed, sensory major latency (LMSensor), sensory nerve action potential amplitude (SNAPam), motor nerve action potential amplitude (CMAPam), sensory nerve conduction velocity (CNVS) and motor nerve conduction velocity (CNVM) are measured. Some of them used the visual analogue scale (VAS) for patient self-assessment of pain sensation [35], as well as the dynamometer for measuring grip strength [23,25-27,29,31] The assessment of different diagnosis tools was conducted before and after the intervention. In some studies a subsequent evaluation after four weeks [26,31], two months [24], and three months [23][24][25][27][28][29][30] was included.
Steroideal active ingredients enhancing phonophoresis efficacy compared to other treatment methods were: betamethasone valerate 0.1% [28,29] compared to phonophoresis with diclofenac diethylammonium and local injection with betamethasone dipropionate. Betamethasone 0.1% [27] compared to the use of a splint. Dexamethasone sodium phosphate 0.4% [26,31] compared to its application with iontophoresis, although Aygül R et al. [24] do not find significant variations using the same active ingredient and comparing both methods, except in the case of using a lower drug concentration (0.1%). Dexamethasone 0.1% [30] compared to ultrasounds with contact gel.
With regard to the parameters used for the application of phonophoresis with corticosteroids, most of the studies [22,[25][26][27]31,32] applied a 1 MHz frequency, except for three of them which used 3 MHz [24,28,29], and two studies which do not state it [23,30]. With regard to the emission mode, the continuous mode [25,27,32] and the pulsed mode [26,31] are used or it is not specified [22][23][24][28][29][30]. The intensity applied was 1 W/cm 2 in all of the studies except in two of them in which it reached 1.5 W/cm 2 [28,29] and another one applying 0.1 W/cm 2 [30]. The time of emission was 10 min per session in most studies, except for four of them in which the session took five minutes [22,26,30,31]. Table 2 shows the main characteristics of the studies included in this systematic review. In relation to quality from a methodological perspective, the average resulting from all the studies is considered as good (7/10) (Table 3). C1: Eligibility criteria were specified. C2: Subjects were randomly allocated to groups. C3: Allocation was concealed. C4: Groups were similar at baseline regarding the most important prognostic indicators. C5: There was blinding of all subjects. C6: There was blinding of all therapists who administered the therapy. C7: There was blinding of all assessors who measured at least one key outcome. C8: Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups. C9: All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analysed by "intention to treat". C10: The results of between-group statistical comparisons are reported for at least one key outcome. C11: The study provides both point measures and measures of variability for at least one key outcome.

Study Groups Included in the Meta-Analysis
Twelve meta-analyses grouped by variable were made (Figures 2-13 C1: Eligibility criteria were specified. C2: Subjects were randomly allocated to groups. C3: Allocation was concealed. C4: Groups were similar at baseline regarding the most important prognostic indicators. C5: There was blinding of all subjects. C6: There was blinding of all therapists who administered the therapy. C7: There was blinding of all assessors who measured at least one key outcome. C8: Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups. C9: All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analysed by "intention to treat". C10: The results of between-group statistical comparisons are reported for at least one key outcome. C11: The study provides both point measures and measures of variability for at least one key outcome.

Study Groups Included in the Meta-Analysis
Twelve meta-analyses grouped by variable were made (Figures 2-13).                              The sensitivity analysis for all the studies in every analyzed variable does not significantly modify the outcomes, therefore, our analysis is solid. As for LMSensor, when removing the study by Aygül, R. et al. I, the outcome changes in favour of phonophoresis. However, it should be noted that this outcome was already remarkably close to significance (−0.81, 0.01).
Studies analysed for the variables pain, BCTQ Sensorial, BCTQ Total, LMMotor, LMSensor, Grip strength and CNVS were considered homogeneous. The rest of the studies for the remaining variables were heterogeneous (Figures 14-25).    The sensitivity analysis for all the studies in every analyzed variable does not significantly modify the outcomes, therefore, our analysis is solid. As for LMSensor, when removing the study by Aygül, R. et al. I, the outcome changes in favour of phonophoresis. However, it should be noted that this outcome was already remarkably close to significance (−0.81, 0.01).
Studies analysed for the variables pain, BCTQ Sensorial, BCTQ Total, LMMotor, LMSensor, Grip strength and CNVS were considered homogeneous. The rest of the studies for the remaining variables were heterogeneous (Figures 14-25).  The sensitivity analysis for all the studies in every analyzed variable does not significantly modify the outcomes, therefore, our analysis is solid. As for LMSensor, when removing the study by Aygül, R. et al. I, the outcome changes in favour of phonophoresis. However, it should be noted that this outcome was already remarkably close to significance (−0.81, 0.01).
Studies analysed for the variables pain, BCTQ Sensorial, BCTQ Total, LMMotor, LMSensor, Grip strength and CNVS were considered homogeneous. The rest of the studies for the remaining variables were heterogeneous (Figures 14-25).  The sensitivity analysis for all the studies in every analyzed variable d significantly modify the outcomes, therefore, our analysis is solid. As for LMSenso removing the study by Aygül, R. et al. I, the outcome changes in favour of phonop However, it should be noted that this outcome was already remarkably significance (−0.81, 0.01).
Studies analysed for the variables pain, BCTQ Sensorial, BCTQ Total, LM LMSensor, Grip strength and CNVS were considered homogeneous. The res studies for the remaining variables were heterogeneous (Figures 14-25).

Discussion
The prevalence of women observed during this review, as well as the subjects' range age, is in line with the epidemiological studies carried out in the past [36][37][38][39]. The presence of a higher quantity of women may be due to their prevalence in types of employment prone to suffer from this pathology [39]. Furthermore, the age range stated does not imply that this pathology cannot be found in other age groups [40].
Regarding the bilateral occurrence of the pathology, the average ratio resulting from this review is slightly lower than that stated in other searches [37,39]. This may be due to having excluded this profile of patients in certain studies, whether by exclusively selecting the dominant hand [27] or by randomly selecting one of the hands [22].
Although all of the studies included in this review state the efficacy of phonophoresis when applied with corticosteroids in carpal tunnel syndrome, a consensus has not been reached as to its therapeutical preeminence compared to other types of treatment.
Therefore, when comparing the application of phonophoresis with corticosteroids to other methods, this is not decisive concerning an improvement of the studied variables. When compared to injections, it is observed that electrophysiologic parameters and pain improve with injections, but this is not the case when applying phonophoresis. This is in contrast with Soyupek F et al. [29], who observed improved physiologic parameters but not pain relief.
When comparing this application to iontophoresis, it is observed that phonophoresis provides higher benefits [31], and more particularly to the electrophysiologic parameters [26]. This contradicts other studies [24,27], in which no statistically significant differences are found between both methods. Phonophoresis features higher or equivalent efficacy when compared to the application of splints [27][28][29] or low level laser [22], respectively.
Clinical symptoms and functionality improve both after the application of corticosteroids via phonophoresis and the application of phonophoresis without any drug.
Concerning evaluation tools, much heterogeneity exists. The reason may be found in the lack of a standardised protocol for this purpose [1,41]. Three methods were the most frequently used out of the different methods described: (1) the Boston Carpal Tunnel Questionnaire [33] scale due to its high reliability and validity, as well as its ability to be rendered and adapted to other languages [42][43][44][45][46]; (2) the electrophysiologic study on the velocity of the median nerve conduction according to the American Association of Electro-diagnostic Medicine (AAEM) guidelines [34]. While its proved objective validity, high specificity and sensitivity [47], some authors recommend to use it in addition to other instruments [5,48]. This is due to potential false negatives in a ratio ranging from 16 to 34% [1]; and (3) the visual analogue Scale, which is highly recommended for measuring pain [49]. The reason why these tests are more frequently observed may be due to the poor diagnostic utility of other evaluation tools as described by Li Pi Shan R et al. [50], despite the fact that the rest of the diagnostic instruments used in the studies have been to a lower or greater extent credited in other research activities [51][52][53][54][55][56][57].
As for the active ingredients, there is also a great heterogeneity. Anti-inflammatory and analgesic actions of dexamethasone valerate have been already described in other studies [58,59]. When comparing the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to corticosteroids, Soyupek F et al. [28,29] describe a higher efficacy of dexamethasone valerate compared to diclofenac, which is in line with the studies conducted by Iannitti et al. [59].
Bakhtiary AH et al. [26,31] describe a higher efficacy of dexamethasone sodium phosphate when applied with phonophoresis than iontophoresis, in contrast with Aygül R et al. [24], who do not observe any significant difference. This may be due to the latter using a lower concentration of the active ingredient. However, the studies conducted by Akinbo SR et al. [60] did not find significant differences either when comparing both methods applied to knee arthritis using this same active ingredient at similar ratios to those applied in the studies by Bakhtiary AH et al.
With regard to the parameters used in phonophoresis, our outcomes do not allow us recommend the use of 1 MHz frequency instead of 3 MHz [12]. This may be due to the penetration efficacy mostly depending on the amount of energy applied and the time of application [61]. Even so, the use of high frequencies is justified, as they increase the density of the energy necessary to improve skin permeability [62]. Nonetheless, frequencies lower than 1 MHz allow deeper drug penetration, this being relevant for transdermal drug administration [9]. It is likely that no differences are observed in relation to the use of various intensities (W/cm 2 ), which is in line with the outcomes observed during a systematic review conducted by Huisstede BM et al. [12].
The meta-analysis proves that, although no statistically significant relation is established between the use of phonophoresis compared to other kinds of drug administration, there is indeed a significant trend in the case of pain, LMMotor and LMSensor. This suggests that using phonophoresis may be beneficial in the case of patients suffering from pain or for whom nerve conduction, both motor and sensory, is altered.
No other systematic reviews or meta-analysis have been found for comparing our outcomes.

Review Strengths and Limitations
A systematic review and a meta-analysis have been conducted by following a specific methodology. Sensitivity analysis shows stability for the final measure obtained. All the studies found have been reviewed without using any filters. Clinical trials have been used showing a medium-high methodological quality.
The literal translation of studies drafted in Turkish or Persian could indicate a general or biased overview of the global construction the authors wished to convey.
For the analysis of some variables, the number of studies were scarce. Although variables could be categorised into groups, it was observed that some of them were measured on different nerves, which could have an impact on extremely specific assessments. We recommend the use of updated clinical practice guidelines as far as the electrophysiologic studies is concerned [34], and a large consensus on the most relevant parameters to be asessed.

Conclusions
The application of corticosteroids by phonophoresis do not seem better that other treatments according with the results, except for the perception of pain and an improved motor and sensory nerve conduction in case of mild to moderate carpal tunnel syndrome.
Concerning the evaluation tools, for the active ingredients and phonophoresis parameters, much heterogeneity does exist. For future studies we recommend these variables to be homogenised in order to achieve more conclusive outcomes and parameters to conform to the treatment objectives.