|Year : 2021 | Volume
| Issue : 4 | Page : 191-197
The effectiveness of hyaluronic acid injection in the treatment of lateral epicondylitis among adults: A systematic review
Roberto F Calupitan1, Carl Froilan D. Leochico2, Gilmore C Senolos1, Reynaldo R Rey-Matias2
1 Department of Physical Medicine and Rehabilitation, St. Luke's Medical Center, Quezon City, Philippines
2 Department of Physical Medicine and Rehabilitation, St. Luke's Medical Center, Quezon City; Department of Rehabilitation Medicine, College of Medicine and Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
|Date of Submission||04-Jun-2021|
|Date of Decision||10-Aug-2021|
|Date of Acceptance||31-Aug-2021|
|Date of Web Publication||15-Nov-2021|
Dr. Carl Froilan D. Leochico
Department of Physical Medicine and Rehabilitation, St. Luke's Medical, Center, 279 E. Rodriguez Sr. Ave, Quezon City, 1112 Metro Manila
Source of Support: None, Conflict of Interest: None
Background: Lateral epicondylitis is common and may negatively impact activities of daily living. Currently, various conservative treatments are available including physiotherapy, pharmacotherapy, and interventional physiatry. Among the interventional procedures, periarticular hyaluronic acid (HA) injection is an emerging treatment option, but it lacks firm evidence to support its use. Objective: The objective of the study was to determine the effectiveness and safety of HA in reducing pain and improving function of patients with lateral epicondylitis. Methods: We conducted a systematic review in January 2020. Randomized controlled trials identified from various electronic databases were included if they involved the following: Adults with lateral epicondylitis, periarticular injection of HA with or without other medications, and reported outcomes on pain, function, and adverse effects. Assessment of risk of bias was performed using the Cochrane Collaboration Tool. Pertinent data were extracted from the eligible studies for data analysis. Results: Among the 42 studies identified, we included two trials with a total of 388 participants followed up within 6–12 months. The trials employed similar techniques in administering HA, although they used different doses and preparations. The control groups used either normal saline or corticosteroid. In both trials, there were statistically significant improvements in pain and function in favor of HA. No serious adverse event was reported. Conclusion: Albeit with promising intermediate and long-term effects for lateral epicondylitis, HA remains to have limited evidence regarding its effectiveness and safety. We recommend further research to determine the most optimal HA preparation, dosage, and technique for lateral epicondylitis that will help standardize our procedures.
Keywords: Hyaluronic acid, injection, pain, physical medicine and rehabilitation, systematic review, tennis elbow
|How to cite this article:|
Calupitan RF, Leochico CF, Senolos GC, Rey-Matias RR. The effectiveness of hyaluronic acid injection in the treatment of lateral epicondylitis among adults: A systematic review. J Int Soc Phys Rehabil Med 2021;4:191-7
|How to cite this URL:|
Calupitan RF, Leochico CF, Senolos GC, Rey-Matias RR. The effectiveness of hyaluronic acid injection in the treatment of lateral epicondylitis among adults: A systematic review. J Int Soc Phys Rehabil Med [serial online] 2021 [cited 2022 Jan 28];4:191-7. Available from: https://www.jisprm.org/text.asp?2021/4/4/191/330493
FNx01Roberto F. Calupitan and Carl Froilan D. Leochico first authors.
| Introduction|| |
Lateral epicondylitis, a common reason for consultation in Physical and Rehabilitation Medicine, is an overloading-induced injury attributed to the repetitive use of the common extensor muscles of the forearm that may negatively impact activities of daily living and work due to pain and functional limitations., It occurs in 1%–3% of the general population and 7% among manual laborers, affecting individuals usually aged 42–54 years without sex predilection. Currently, we can offer various conservative treatment options for lateral epicondylitis, ranging from physiotherapy and pharmacotherapy to interventional physiatry. Among the interventional procedures, periarticular hyaluronic acid (HA) injection is an emerging treatment option, but it lacks firm evidence to support its use. The choice of treatment largely depends on the patient's clinical needs and preferences, clinician's experience, and current evidences.
Based on prior studies, HA injection for lateral epicondylitis shows promising results, owing to its anti-inflammatory and lubrication properties.,,,, HA is the primary component of synovial fluid and provides lubrication and shock absorption for arthritic joints. Its mechanism of action for tendinopathies, however, is not well established. Nonetheless, HA can potentially: (a) reduce the surface friction between tendons; (b) prevent influx of inflammatory mediators; (c) promote analgesia by desensitizing nociceptors; and (d) upregulate the vascular endothelial growth factor and type IV collagen, thereby accelerating tendon healing, among others., Relevant research has focused on producing a biocompatible and effective form of HA that can enhance the regeneration of injured soft tissues such as tendons and ligaments. HA similar to naturally produced hyaluronan can be vital in tissue repair across all phases of healing. There are several prior reviews on interventional procedures for lateral epicondylitis, but only a few explores the effectiveness and safety of HA.,,, Our present study primarily aimed to determine the effectiveness of HA in terms of pain control and functional improvement among adults with lateral epicondylitis. Secondarily, we aimed to determine the safety of HA injections. In this systematic review, we also summarized the parameters that prior studies used for the different experimental and control medications injected for lateral epicondylitis.
| Methods|| |
Our study followed the guidelines included in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Consensus Statements and was done in January 2020., We included studies published in English language between 1973 and January 2020. We considered studies eligible for analysis if they met the following criteria following the PICOS model to answer our aforementioned research objectives: (a) population: adults aged at least 18 years with lateral epicondylitis, regardless of duration; (b) intervention: local periarticular injection of HA with or without corticosteroids, nutraceuticals (glycosaminoglycans), or anesthetics; (c) comparison: local injection of placebo or other agents such as corticosteroids or plasma-rich protein; (d) outcomes: pain, function, and adverse effects; and (e) study design: randomized controlled trials (RCTs). We then tried to access the full text of eligible studies for critical appraisal and analysis. When necessary, we E-mailed the authors of studies without accessible full text and requested for a copy of their article. Two authors performed independent screening of the articles for inclusion, and in case of disagreements we achieved resolutions through discussions with a third author.
We conducted an initial search of relevant studies using the following computerized bibliographic databases: PubMed/MEDLINE, PubMed Central, The Cochrane Library, Scopus, ClinicalTrials. Org, Physiotherapy Evidence Database, Google Scholar, Latin American and Caribbean Health Sciences Literature, and Health Research and Development Information Network Database of the Philippines. Although the preliminary application of HA for clinical disorders appeared toward the end of the 1970s, our search included any related publications from January 1973 to January 2020 in order to be thorough. Furthermore, we checked for ongoing similar studies through the PROSPERO database, which did not yield any search result. Our search strategy varied slightly across databases but generally included the following terms: (”hyaluronic acid” or “sodium hyaluronate” or “hyaluronan”), (”lateral epicondylitis” or “lateral epicondylosis” or “lateral epicondylalgia” or “lateral tendinosis” or “tennis elbow”), and (”randomized control trial” or “controlled trial”) as either Medical Subject Heading (MeSH) terms, keywords, or subject headings. We combined related terms using the Boolean “OR” and “AND.”
Using the Cochrane Collaboration Tool, two authors independently assessed the risk of bias and methodological quality of eligible studies, whose authors were contacted to obtain further information, if necessary. Finally, we extracted pertinent data from the eligible studies for analysis.
| Results|| |
We retrieved a total of 42 articles from the databases. From these, we excluded 13 duplicates, 5 ongoing studies, and two abstracts without full text available despite attempts to contact the authors. Twenty-two articles underwent further review, and twenty were further excluded for not meeting the eligibility criteria [Figure 1]. As a result, two studies were critically appraised and analyzed.
|Figure 1: The study's Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of information|
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Based on [Figure 2], both studies that reached analysis were generally of high quality. The study of Tosun et al. had a low risk of bias in terms of performance (i.e., appropriate blinding of research participants and personnel), detection (i.e., appropriate blinding of outcome assessors), attrition (i.e., completeness of outcome data), and reporting (i.e., identification of prespecified outcomes). However, it had unclear risk of selection bias due to inadequate description of random sequence generation and allocation concealment. Similarly, the study of Petrella et al. also had a low risk of selection bias (i.e., appropriate randomization but lacked description of allocation concealment), performance bias (i.e., blinding of participants), attrition bias (i.e., completeness of outcome data and intention-to-treat analysis), and reporting bias (i.e., complete reporting of predetermined outcomes). However, its risk of detection bias was unclear due to the lack of information regarding blinding of outcome assessors. Both studies had unclear risks of other biases due to the lack of relevant data to ascertain such risks, if any.
|Figure 2: Assessment of included studies for risk of bias using the Cochrane Collaboration Tool|
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The characteristics of the population from the included studies are summarized in [Table 1]. This review analyzed 388 patients with a mean age of 47.01 ± 1.34 years and a clinical or radiologic diagnosis of lateral epicondylitis. The male patients comprised nearly 54% of the study population, and the chronicity of symptoms ranged from 8 to 20 months. The inclusion criteria for both studies were significant pain for at least 3 months at the lateral epicondyle during activities and a positive response to at least one of three provocative tests: Mill's test, Cozen's test, and Maudsley's test., The exclusion criteria, on the other hand, consisted of previous local injection treatments (e.g., corticosteroid, acupuncture, etc.) within the preceding 3 months, history or physical findings of local nerve entrapment, any systematic disease, or neuromuscular disorders., The previous use of oral medications for the treatment of lateral epicondylitis was not part of the exclusion criteria. In addition to these, Tosun et al. also included local tenderness to palpation distal and anterior to the lateral epicondyle and an age limit ranging from 18 to 60 years as a part of their study's inclusion criteria, while pregnancy or breastfeeding, a history of elbow surgery, coagulation disorders, autoimmune disease, allergy to local anesthetics or glycosaminoglycans, and physical therapy within the preceding 3 months were part of the exclusion criteria.
|Table 1: Characteristics of included studies and their population (n=388)|
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In terms of outcome measures, the study of Tosun et al. utilized the self-administered 15-item Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire, wherein each item was scored from 0 to 10, with higher scores indicating more severe condition. The sum of five pain items (e.g., at rest, during a task) constituted 50% of the total score for each participant, while the sum of ten functional disability items (e.g., basic and instrumental activities of daily living) divided by two accounted for the remaining 50%., The mean total scores of all participants at baseline and follow-ups for both experimental and control groups are presented in [Table 2]. Meanwhile, the study of Petrella et al. utilized the visual analog scale (VAS) to assess pain, and a 6-point Likert scale to assess function as follows: (1) patient-reported global assessment of elbow injury (0 = not satisfied, 5 = fully satisfied); (2) patient-reported assessment of normal function/activity (0 = no return to normal function, 5 = full return to normal function); and (3) physician-reported global assessment of elbow injury (0 = poor pain management and elbow function, 5 = good pain management and normal elbow function). The adverse events that occurred throughout the study period were tallied in both studies. The follow-ups ranged from 1 to 12 months postinjection.
|Table 2: Pain and functional outcomes for experimental and control groups in included studies (n=388)|
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Interventional treatment parameters for lateral epicondylitis
The studies made the use of the following concoctions in the experimental and control/comparator groups: (1) 1 mL solution of 1.6% HA (800 mg) + chondroitin sulfate (1 g per 50 mL) + prilocaine (0.6 mL) versus triamcinolone acetonide (1 mL; 40 mg/mL) + prilocaine (0.6 mL); and (2) 1% sodium hyaluronate in phosphate-buffered saline (1.2 mL; 12 mg) versus saline placebo (1.2 mL)., The two different HA preparations were given either in a single dose or two doses that were 1 week apart. Both studies made the use of an anatomy-guided approach and the fanning technique with the injections administered into the soft tissue 1–2 cm from the lateral epicondyle at the point of maximum tenderness. Aside from acetaminophen (maximum dose: 1500 mg/day), aspirin (325 mg/day), and cold application, no other home remedy was given throughout the study period.
Effectiveness of hyaluronic acid injection
Based on [Table 2], both studies showed a general trend of improvement in pain and function after HA injection across time. Petrella et al. observed statistically significant improvements (P < 0.05) in pain both at rest (VAS 8.5 ± 11.1 at baseline reduced to 2.4 ± 1.4 after 12 months) and when gripping (from 9.8 ± 1.1 to 2.9 ± 1.4). Better pain control translated to better functional outcomes, as evidenced by the significantly higher scores reported by both patients (Global Assessment of Elbow Injury: From 0.3 ± 1.1 to 4.8 ± 0.9); Assessment of Normal Function/Activity: From 1.1 ± 2.1 to 4.6 ± 0.3), and clinicians (Global Assessment of Elbow Injury (from 1.1 ± 1.0 to 4.7 ± 0.5). Statistically significant improvements (P < 0.05) were also noted in the control group in terms of pain at rest (VAS 8.4 ± 1.6 at baseline reduced to 7.7 ± 1.3 after 12 months) and when gripping (from 9.6 ± to 9.1 ± 1.1). Although more favorable results were seen in the experimental group, such improvements were also observed with the functional outcomes reported in the control group by both patients (Global Assessment of Elbow Injury: From 0.4 ± 1.1 to 1.1 ± 1.8); Assessment of Normal Function/Activity: From 1.7 ± 2.2 to 0.9 ± 1.9), and clinicians (Global Assessment of Elbow Injury: from 0.9 ± 1.2 to 1.3 ± 0.7) as well. These improvements were persistent throughout the course of 12 months.
Meanwhile, Tosun et al. found statistically significant reductions in PRTEE scores in the pain and functional disability subscales for both experimental and control groups after 3 and 6 months from injection. Comparing the treatment groups, however, the reductions seemed larger for the experimental group than for the control across subscales and follow-ups [Table 2].
The statistical pooling of treatment effects was not performed in this review as the individual studies evaluated different preparations of HA. The experimental and treatment groups in the studies varied also in terms of the composition of their treatment concoctions, amount or dose of each component, and number of injections.
Safety of hyaluronic acid injection
No serious adverse event was observed from the injections until the last follow-up in both studies. In the study of Petrella et al., 1.8% of the participants in the HA group reported postinjection pain [Table 3]. No subject withdrew or dropped out throughout the study period.
|Table 3: Adverse drug events associated with the treatment arms in included studies (n=388)|
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| Discussion|| |
We analyzed two RCTs of high quality (i.e., low risk of bias) in this systematic review, highlighting the paucity of evidence on the effectiveness and safety of HA injections for lateral epicondylitis. Nonetheless, our present study shows a trend toward larger benefits in pain and functional outcomes for the HA group compared to the non-HA group. Although periarticular injections into the lateral elbow seem effective and safe, HA injections are not commonly used as first-line treatment, but as an intervention to address refractory lateral epicondylitis.
In both studies, the beneficial effects on pain and function are shown to be statistically significant and clinically relevant, especially with HA injections. These effects are observed at short-term (<6 weeks) follow-up in one of the included studies and at intermediate (6 weeks to 6 months) and long-term (>6 months) follow-ups in both studies.,, However, it should be noted that, in the absence of a nontreatment cohort, it is difficult to determine whether the benefits are a result of the natural course of the condition, rather than the intervention alone. It is reported that lateral epicondylitis is self-limiting and can spontaneously resolved within a period of 1 year from its onset. When confronted with gray areas in actual practice, the physiatrist's clinical judgment and expertise should take precedence.
Optimal hyaluronic acid treatment protocol
The use of different types, molecular weights, doses, concentrations, and administration techniques of interventional HA for lateral epicondylitis varies in the literature. Hence, the therapeutic and adverse effects may also vary, regardless of whether these effects are accurately identified and reported.,
In other studies, corticosteroid is mixed with HA, but the former carries the potential to undermine the accurate assessment of the effect of the latter for lateral epicondylitis. The anti-inflammatory effects of corticosteroids may falsely exaggerate the beneficial effect of HA. Another possible confounder is the mixing of other substances such as local anesthetic or chondroitin sulfate with HA, as in the study of Tosun et al. By adding volume to the injectate, anesthetic agents may contribute to the distribution of HA within the target and nearby tissues, possibly diluting the effect of HA. Chondroitin sulfate, on the other hand, possesses anti-inflammatory, viscoelastic, and hydration properties, which may contribute to the effectiveness of HA.,
The injection sites and techniques used in the included studies also vary. Guided by bony landmarks (i.e., blind technique), Petrella et al. employed the fanning technique, wherein the injectate was administered as the needle was withdrawn from the point of maximal tenderness after a single puncture. Currently, there is no study that confirms the superiority of any needling technique over another., With no consensus on the standard HA concentration, preparation, and administration for different clinical phases and presentations of lateral epicondylitis, the heterogenous eligibility criteria and methodologies in the literature may persist and make conducting any meta-analysis on the topic challenging.
The postinjection instructions to participants were similar in both studies. With the exception of acetaminophen, aspirin, and cold application, other medications and treatment options were prohibited throughout the study period.,
Outcome measures for lateral epicondylitis
Using the outcome measures in the included studies, one may find the data to be seemingly comparable [Table 2]. However, a certain degree of heterogeneity in their scoring systems may present an inherent problem in arriving at sound conclusions. The PRTEE in the study of Tosun et al. offers reliable psychometric properties, but using this as the sole outcome measure for pain and functional disability may confer lack in objectivity because of subjective patient reports., Hence, it is difficult to compare their study's clinical outcomes with those of Petrella et al., who considered both patient- and clinician-reported outcomes. Such differences in clinical outcomes make it difficult to assemble a well-structured quantitative review or meta-analysis. It may be helpful to have a consensus that recommends the most clinically relevant and appropriate outcome measures for lateral epicondylitis that can be utilized in future-related studies. Evidence-based medicine indeed plays an integral role in clinical practice to incorporate the clinician's experience and patient's values, alongside inconclusive or sometimes mixed evidence available so far.
Review strengths and limitations
In this review, we did not perform a meta-analysis due to the clinical heterogeneity (e.g., various types of HA preparations, concentrations, administrations, and different outcome assessments) of the included studies. Nonetheless, we were able to conduct direct and descriptive comparisons of the outcomes from each included study and present gaps in the existing body of literature on the topic.
Aside from the small number of included studies, our review had several limitations. First, the accuracy of information presented was dependent on the quality of the primary studies that were assessed using the risk-of-bias table. Although the table provided assessments on randomization and concealed allocation, it lacked the ability to further evaluate data validity as important parameters such as sample size and length of follow-up were not included. Second, the two included studies had a large disparity in sample size (i.e., 57–331), accounting for heterogeneity in patient characteristics and potential confounding factors. Third, the variations in HA preparations and treatment protocols made head-to-head comparisons difficult. Finally, the lack of a universally agreed set of outcome measures prevented us from combining the studies suitable for a meta-analysis. Given the limited high-quality publications available, the stringent inclusion and exclusion criteria employed in our review might also need to be modified in future similar reviews.
| Conclusion|| |
Our review shows that periarticular HA injections may be beneficial and safe for adults with chronic lateral epicondylitis, with effects lasting until the intermediate (>6 weeks) and long-term (>6 months) follow-ups. Although the current evidence seems promising, it remains limited. Hence, further high-quality research is recommended not only to accurately determine its effectiveness but also to better characterize or standardize the optimal HA preparation, dosage, and technique that clinicians can use for this common musculoskeletal condition.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]