Therapeutic Effects of Manual Therapy, Transcutaneous Electric Nerve Stimulation, and Forearm Brace on Lateral Epicondylitis: A Randomized Controlled Trial

Background: Epicondylopathia humeri radialis is often diagnosed by general practitioners. Usually, the therapy comprises transcutaneous electrical nerve stimulation and the application of a forearm brace. Manual therapy is prescribed beyond transcutaneous electrical nerve stimulation and forearm brace, and it is performed by specialized physiotherapists. However, data comparing the effectiveness of all methods are scarce. In this study, the therapeutic effects of manual therapy were compared to those of transcutaneous electrical nerve stimulation and forearm brace along with a combination of all three. Methods: Fifty-two patients diagnosed with epicondylopathia humeri radialis by a general practitioner were randomized into three treatment arms: 19 patients received a combination of manual therapy, transcutaneous nerve stimulation, and forearm brace; 18 patients received manual therapy only; and 15 patients wore a forearm brace and received transcutaneous nerve stimulation. The primary outcomes included the range of motion and pain intensity. The secondary outcomes were elbow function and psychological well-being. Primary and secondary outcomes were measured before treatment (0), and 4-and 8-weeks post-treatment using the Patient Rated Tennis Elbow Evaluation Questionnaire and the Short Form Health Survey Questionnaire. Results: The range of motion and pain intensity did not differ between the intervention groups. Conclusions: Manual therapy alone is as effective as combination therapy with transcutaneous nerve stimulation and the use of a forearm brace for epicondylopathia humeri radialis. Hence, there is evidence supporting the inclusion of manual therapy in the guidelines for treating patients with epicondylopathia humeri radialis. registration:

supporting the inclusion of manual therapy in the guidelines for treating patients with epicondylopathia humeri radialis.
Trial registration: German Clinical Trial Register: DRKS, trial registration number: 00021137, date of registration: 24/03/2020 (retrospectively registered) Background Epicondylopathia humeri radialis (EHR)-also termed lateral epicondylitis or tennis elbow-is a painful disease of the tendon insertions of the lateral elbow. 1 Guidelines from the American College of Occupational And Environmental Medicine (ACOEM) acknowledge braces and transcutaneous electrical nerve stimulation (TENS) as therapies for EHR, but there have been no recommendations endorsing or opposing these methods. 2 The ACOEM guidelines do not recommend mobilization. In Germany, EHR is commonly treated by physiotherapists with manual therapy (MT), as prescribed by physicians, even though the exclusive treatment of EHR with MT is not recommended in the current guidelines. 1 Furthermore, German guidelines recommend "epicondylitis-bandages," although there is little evidence supporting this method of treatment. 3 TENS was used in combination with a forearm brace (FB), as this is widely used for treating EHR in Germany.
A literature review was conducted in PubMed using broad MeSH-terms, such as manual therapy (MT), epicondylalgia, epicondylopathia, and epicondylitis (Table 1). MT included the terms manual therapy, manual medicine, physiotherapy, thrust technique, myofascial technique, manipulation, and muscle energy techniques.  8 Therefore, the relaxation of muscles using MT 9 is indicated. Dommerholt et al. 10 described myofascial pain as a prevalent type of musculoskeletal pain accepted by the International Association of Pain. The presence of trigger points (TRP) can be con rmed by magnetic resonance imaging (MRI) and sonography studies. Manual TRP-release is a special type of MT that appears to increase the pain threshold. However, MT of the cervical spine and cervicothoracic junction has been reported as ineffective for the treatment of EHR. 4 In a randomized, double-blind study, 5 craniosacral therapy, a special type of MT, was found to be effective in treating EHR. Thus, the results of these studies indicate that MT is a very effective treatment for EHR.
A second literature search of PubMed included the keywords epicondylopathia, epicondylalgia, epicondylitis, TENS, epicondylopathia, epicondylalgia, epicondylitis, and forearm brace ( Table 2). One study reported that low-frequency electricity is an effective treatment for EHR. 13 Bandages have been reported to have minimal effects, except for braces in uencing the extensor muscles. 11 Therefore, forearm extensor braces were used in this study.
Herein, the therapeutic effect of MT performed by specialized physiotherapists compared to the combination of FB and TENS was examined. Although pain medications (including nonsteroidal antiin ammatory drugs [NSAIDs]) are recommended in the German guidelines, they were not included in this study.

Study Design
There were three treatment arms: MT, a combination of TENS and FB, and a combination of MT, TENS, and FB. The add-on effect of MT was evaluated by comparing TENS and FB to TENS, FB, and MT.
The primary and secondary outcomes were measured at baseline, and both at 4 and 8 weeks posttreatment.
The primary outcomes included range of motion (ROM) and the intensity of pain measured using the visual analog scale (VAS) (pain range: 1-10). The VAS is a valid and widely applied tool that is used for assessing musculoskeletal pain. 14 ROM was measured using exion and extension of the elbow in geometrical degrees using a goniometer. 15 The secondary outcomes included elbow function and psychological well-being, measured using the Patient Rated Tennis Elbow Evaluation Questionnaire (PRTEE) and the Short Form Health Survey Questionnaire (SF-36), respectively. The PRTEE characterizes the elbow function and pain using ten items related to joint malfunction and ve items related to pain. 16 Each item is scored (range: 0-10), and the sum of the scores is used as the total PRTEE score. For this study, the PRTEE items were translated into German and read aloud to the patients. SF-36 is widely used for the measurement of health-related quality of life (HRQOL) and contains eight domains: vitality, functional capability, pain, perception of health, physical, emotional, and social functioning, and physical well-being. 17 Scores for each domain range between 0 and 100, with 100 indicating full satisfaction; the total sum of the scores is used. The total scores and the subscores for pain and vitality were evaluated, and a version of the SF-36 that has been standardized for use in Germany was used in this study. 18 Before starting with the enrollment, the study was approved by the ethics committee ( Patients who ful lled the following inclusion criteria were consecutively enrolled in the study: between 18 and 65 years old, diagnosed with EHR (as described below), and provided informed consent. EHR was diagnosed if the reported pain was in the lateral region of the elbow and was provoked by extension of the hand (positive provocation test). Other diseases or injuries were excluded prior to the diagnosis, with structural causes excluded using X-ray imaging.
The exclusion criteria were as follows: injuries to the arm or cervical spine during 6 months prior to presentation, acute or chronic infection, rheumatic diseases, osteochondrosis dissecans, advanced osteoarthritis of the elbow, pregnancy, diabetes, malignancy, malformation in the upper extremities, circulatory disorder in the upper extremities, radicular syndrome at C6, chronic pain syndrome, psychiatric disorders, neuropathy, myopathy, the use of beta-blockers, statins, or NSAIDS, or incomplete data.
Of the 52 patients included in this study, 18 received MT, 15 received a combination of TENS and FB, and 19 received a combination of MT, TENS, and FB (Table 3). Patient recruitment was discontinued after attaining the required number of participants speci ed in the statistical analysis section.

Statistical Analysis
Statistical signi cance was set at P < 0.05. The number of patients required for repeated measures of variance (ANOVA) for three groups and three points of measurement on within-between-group effects assuming an alpha-error level of 5%, a level for the beta error of 20%, an assumed effect size of 0.25, and a power to detect between-group differences of 80% was calculated. ANOVA is a statistical method that calculates variances and test variables in order to obtain information on the laws behind the data to determine the differences between groups. The Statistical Package for Social Sciences software (IBM → ) was used for statistical calculations. The correlation between repeated measures was assumed to be 0.5, with the lowest boundary possible for non-sphericity corrections set at 0.5. The number of participants required for the total sample was 52. 19 One ANOVA per dependent variable was conducted.

Results
The demographic data for all patients are shown in Table 3. There were no signi cant differences between the treatment groups in terms of age or gender.
The PRTEE score (p = 0.004) and ROM (p = 0.001) signi cantly improved from baseline to 8 weeks posttreatment. However, there were no differences in PRTEE scores or ROM between the treatment groups.
Although there was a decrease in the VAS score over time, the change was not signi cant. Subjective HRQOL measured by the total SF-36 score did not change signi cantly over time and was not signi cantly different between the groups (Table 4). Also, the sub-scores for pain and vitality were not signi cantly different between the groups (data not shown). An additional le shows this in more detail [see Additional le 1].

Discussion
Signi cant improvements were observed within 2 months in all treatment arms. Elbow function and ROM improved independent of the treatment, indicating that MT is as effective as TENS and FB for EHR. However, the results of this study also reveal that MT had no additional effect when combined with TENS and FB.
According to Mohr et al.,20 the pain of EHR is not exclusively caused by structure-associated lesions, such as the bulging of extensor-sinews, edema, or other MRI ndings. The presence of these lesions on MRI also does not correlate with subjective pain ratings. 21 Manual therapy addresses not only the elbow bones but the functional chains in the musculoskeletal system that are associated with her as well. The functional chains may represent segmental dysfunctions in the cervical spine or TRP in the shoulder or the extensor muscles of the forearm. Physiotherapists were prompted to diagnose and treat functional chains and TRP, which may affect the therapeutic effect of MT observed in this study. The target structures for MT include joints (especially in the elbow and cervical spine), muscles (TRP within the shoulder belt), and the fascia of the upper extremity.
Cloward et al. 22 described referred pain after irritation of the intervertebral discs of the cervical spine that resembled EHR, as it radiated into the arm and shoulder (the Cloward -zones) after irritation of the intervertebral discs between C4 and C6. The intensity of the structures on T1-weighted MRIs has been reported not to be correlated with the patient's subjective pain. 21 These results support the hypothesis of the nociceptive supply of the intervertebral discs in the cervical spine, which may account for the pain radiating to the elbow. Yamashita et al. 23 reported mechanosensitive afferent nerves of lumbar facet joints and the surrounding tissue in rabbits that included proprioceptors with low thresholds and high line velocity and nociceptors with high thresholds and low line velocity. MT on joints may alter proprioceptive inputs at the spinal cord, which may contribute to its therapeutic effect in patients with EHR.
TRP provide another promising mechanism for the treatment with MT. According to Simons et al., 24 TRP are de ned as areas within the muscle that can produce referred pain. TRP differ from non-tensed muscles, as they have reduced distances to the endomysium, fragmented or worn-out muscle bers, atrophy of type II bers, and necrosis. 25 TRP have been reported to have a higher pH and higher concentrations of bradykinin, substance P (SP), calcitonin gene-related peptide (CGRP), tumor necrosis factor-alpha, interleukins 1b, 6, and 8, norepinephrine, and other in ammatory mediators. Active TRP possessed the highest concentrations of these mediators, 26 and taut-bands (tensed regions of muscle tissue) have been identi ed on magnetic resonance elastography. 25 The manipulation of TRP during MT may alter nociception in these regions, which may contribute to its therapeutic effect.
Buchmann et al. 27 measured the changes in tension within TRP before and during neuromuscular blockage (general anesthesia) and found that segmental interneuronal changes may play a role in the pathophysiology of TRP. Fernandez-Carnero et al. 28 described both central and peripheral mechanisms of sensitization of TRP in the forearm for patients with EHR compared to those of healthy controls.
There are no studies speci cally focusing on pain development in the elbow, as it relates to the fascia.
Tesarz et al. 29 reported that the thoracolumbar fascia (TLF) is important for deep back pain in a rat model, as the concentrations of SP and CGRP in the outer fascia and subcutis were elevated. The hyperexcitability of spinal neurons and deep structures of the back (muscles and TLF) generated new receptor elds after a second injection of nerve growth factor suggesting that the development of back pain is a complex interaction that involves the fascia. 30 This type of interaction may also be present in EHR pain, and MT may alter the afferent input from these target tissues on a segmental neuronal level.
Generally, the results of previous studies do not support the theory of a single, local cause of EHR pain.
On the contrary, the results indicate that spinal neuronal mechanisms of sensitization also contribute to EHR pain, suggesting that MT on target tissues may affect the segmental neuronal level of arousal and, therefore, contribute to the nociceptive turnover in the perception of pain.
The present study has some limitations. First, the PRTEE has not been validated for use in Germany and was translated for the purpose of this study. Due to its high reliability and international approval, the usefulness of the PRTEE was assumed in the study and was, therefore, administered to the participants. Second, MT was provided by different therapists, and no data is available regarding the experience of or speci c methods used by the therapists. Third, although forearm braces are commonly used in Germany, there is no evidence from randomized controlled trials supporting their use. Finally, this study did not evaluate the use of concomitant medications, such as analgesics. Future research to further evaluate this subject area is necessary.

Conclusion
Patients with EHR are likely to suffer from functional chains in the musculoskeletal system, which can be effectively treated with MT. MT alone is as effective as combination therapy with TENS and FB for EHR. Hence, there is evidence to support the inclusion of MT in the guidelines for treating patients with EHR. Ethics approval and consent to participate:

List Of Abbreviations
The study was approved by the ethics committee (University of Rostock, Germany, number of registration: A2012-0146, at 19/12/2012). Informed consent to participate in the study was obtained from the participants. We con rm that all methods were performed in accordance with the relevant guidelines and regulations of the ethics committee.

Consent for publication:
Not applicable. The requirement for informed consent for publication was waived as no patientidentifying information was included in this study.