Clinical UM Guideline


Subject: Hyaluronan Injections
Guideline #:  CG-DRUG-29 Publish Date:    02/27/2019
Status: Reviewed Last Review Date:    01/24/2019


This document addresses the use of hyaluronan injections for the replacement or supplementation of naturally occurring intra-articular lubricants in individuals with musculoskeletal conditions. This therapy may also be referred to as viscosupplementation. 

Clinical Indications

Not Medically Necessary:

Intra-articular injections of hyaluronan for all joints including, but not limited to, the knee, ankle, shoulder, hip, temporomandibular joint, or thumb is considered not medically necessary.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Hyaluronan or derivative, Durolane, for intra-articular injection, 1 mg


Hyaluronan or derivative, GenVisc 850, for intra-articular injection, 1 mg


Hyaluronan or derivative, Hyalgan or Supartz, for intra-articular injection, per dose


Hyaluronan or derivative, Hymovis, for intra-articular injection, 1 mg


Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose


Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose


Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg


Hyaluronan or derivative, Gel-One, for intra-articular injection, per dose


Hyaluronan or derivative, Monovisc, for intra-articular injection, per dose


Hyaluronan or derivative, Gel-Syn, for intra-articular injection, 0.1 mg


Hyaluronan or derivative, TriVisc, for intra-articular injection, 1 mg



ICD-10 Diagnosis



All diagnoses

Discussion/General Information

Osteoarthritis is a degenerative condition of the joints and is the most common form of arthritis. Osteoarthritis commonly affects the hands and the weight-bearing joints, such as the knees, hips, feet and spine. The specific causes of osteoarthritis are unknown, but it is believed to be both mechanical and molecular events in the affected joint. Afflicted joints experience loss of synovial fluid, a protective substance which aids in absorbing shock and lubrication in the joints. Low synovial fluid levels and other mechanisms cause a progressive breakdown of the cartilage lining the ends of bones that are necessary for proper cushioning and smooth function of joints. Because of this breakdown of cartilage, bones rub against each other causing pain, loss of movement, and further destruction of the joint. The severity of osteoarthritis can range from very mild to very severe. Onset is gradual and usually begins after age 40. It is estimated that osteoarthritis affects 13.9% of adults aged 25 and older and 33.6% of adults aged 65 and older in the United States. The most prevalent osteoarthritis occurs in the knee. There is no cure for osteoarthritis and current treatment focuses on relieving symptoms and improving function. The injections are considered to be a device by the United States Food and Drug Administration (FDA) and several have been approved via the premarket approval process.

Proposed use of hyaluronan for osteoarthritis of the knee is derived from demonstration of benefit of varying degrees in a number of trials and meta-analyses of randomized trials. However, many analyses have not shown a clinical benefit beyond the effect seen with placebo, and evidence from recent large, double-blinded, and high-quality trials suggests the clinical benefit of hyaluronan is of minimal benefit over intra-articular placebo (Bannuru, 2015). Intra-articular hyaluronan may be associated with potential side effects such as pain flare-ups and joint infection, and the use of hyaluronan remains controversial in clinical practice.

In a 2014 study by van der Weegen and colleagues, the authors evaluated the effectiveness and safety of hyaluronic acid compared to placebo. This was a multi-center, double-blind, placebo controlled study in which 196 participants with osteoarthritis of the knee received either hyaluronic acid injections (n=99) or saline placebo injections (n=97). Participants received three weekly injections and were followed for 6 months. Efficacy was evaluated using 100-mm visual analog scores (VAS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score and recording of limitations in sports and work activities. Both treatment groups showed an improvement in pain and functional scores from baseline to 6 months follow-up. Pain during 50 m walking improved from 56.4 to 38.1 for the hyaluronic acid group and from 58.2 to 39.6 in the placebo group. WOMAC scores improved from 39.0 to 29.3 points for the hyaluronic acid group and from 40.8 to 28.8 points in the placebo group. While symptoms and function improved from baseline, neither treatment group showed a significant difference in any outcome at any follow-up time.

In a 2015 study by Wang and colleagues, 78 participants with osteoarthritis of the knee were randomized to either an intervention group of hylan G-F 20 injections (n=39) or a control group who received usual care for osteoarthritis of the knee (n=39). Participants had magnetic resonance imaging of the knee at baseline, 12 months and 24 months following treatment or usual care. A total of 55 participants completed the 24 month follow-up. At that time, the group that received the hylan G-F 20 showed a decreased annual rate of medial and lateral tibial cartilage volume loss compared to the control group. This study has limitations which include non-randomization and a lack of placebo control group. There was also a 29% rate of loss to follow-up. The authors conclude that larger, randomized studies will need to be done to further examine the benefit of repeated injections over a longer time.

In a 2016 study by Tammachote and colleagues, the authors evaluated the efficacy of a single injection of hylan G-F 20 and triamcinolone acetonide for relieving pain and improving function in participants with osteoarthritis of the knee. In this single-center, prospective, double-blind, randomized controlled trial, 99 participants were randomized to either hylan G-F 20 (n=50) or triamcinolone acetonide (n=49). With a follow-up period of 6-months, primary outcome measures included knee pain, functional improvement, and knee range of motion. Knee pain was analyzed using a 100-mm VAS. Knee function was measured using 3 dimensions of the modified WOMAC. Range of motion of the knee was measured with a goniometer. In evaluation of pain relief, the triamcinolone acetonide group had better overall pain improvement in the first week after injection. The participants in both groups showed pain relief after injections that lasted up to 6 months. At 6 months, the mean change in VAS was -29 points (95% confidence interval [CI], -36.4 to -22.7 points) in the hylan G-F 20 group and -30 points (95% CI, -36.0 to -22.8 points) in the triamcinolone acetonide group (p<0.0001). Both treatment groups had similar overall change in the mean modified WOMAC scores. Two weeks after injection, the triamcinolone acetonide group had better mean functional improvement compared to the hylan G-F 20 group. At the end of 6 months, the mean modified WOMAC scores improved from 43 to 21 points (95% CI, 16.7 to 29.2 points) in the hylan G-F 20 group and from 39 to 21 points (95% CI, 11.0 to 24.3 points) in the triamcinolone acetonide group. Range of motion of the knee was not different between the two treatment groups at any time during the study. After 6 months, those treated with hylan G-F 20 improved mean knee flexion by 6° and those treated with triamcinolone acetonide improved mean knee flexion by 8°. This study is limited by the lack of a placebo group, however the authors note that “both corticosteroid and hyaluronic acid injections have superior efficacy compared with a placebo injection.”

Waddell and colleagues (2016) used retrospective data to analyze predictors of total knee replacement. While the authors purported that total knee replacement was delayed for more than 7 years in 75% of individuals with grade 4 osteoarthritis of the knee treated with hylan G-F 20 in an orthopedic practice, the analysis did not use a control group and lacked randomization; thus any conclusion on the causality of the association remains confounded by individual and surgeon preference. The incidence of total knee replacement in individuals treated with hylan G-F 20 was low (25%), suggesting the surgical eligibility and member preference may have been strong predictors for the decision to undergo or delay total knee replacement vs. attempt treatment with hylan G-F 20.

While limited data purports an association with intraarticular hyaluronic acid injection use and longer time to knee arthroplasty, it is unclear whether the duration of delay is clinically significant, and there is no evidence suggesting that intraarticular hyaluronic acid injection use leads to a decrease in knee arthroplasty utilization (Ong, 2016).

In 2015 meta-analysis, Bannuru and colleagues reported on the efficacy of treatments for osteoarthritis of the knee evaluating pain, function and stiffness. A total of 137 studies made up of 33,243 participants were included in the analysis. Inclusion criteria into the analysis included randomized controlled trials that compared at least two interventions (acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, intra-articular corticosteroids, intra-articular hyaluronic acid, oral placebo, and intra-articular placebo). Pain-related outcomes were analyzed in 129 trials. In these trials, all of the interventions were better than oral placebo, reporting that intra-articular placebo was better than oral placebo. Physical function outcomes were analyzed in 76 trials. All interventions except for intra-articular corticosteroids were superior to oral placebo. A total of 55 trials were analyzed for stiffness outcomes. Intra-articular hyaluronic acid was reported to be better than intra-articular placebo; however intra-articular placebo was not better than oral placebo. The authors concluded that all treatments except for acetaminophen showed significant pain improvement and intra-articular treatments were more effective than the non-steroidal anti-inflammatory drugs (NSAIDS), noting that the effect of hyaluronic acid injection seems to derive from the use of intra-articular delivery.

A 2015 meta-analysis by Richette and colleagues analyzed 8 randomized controlled trials which studied intra-articular hyaluronic acid injections for osteoarthritis of the knee. The studies compared hyaluronic acid injection to a placebo saline injection. The primary outcome was the intensity of pain (using VAS) and secondary outcome was knee function at 3 months. For pain intensity, the standardized mean difference was −0.21 (95% CI −0.32 to −0.10) favoring intra-articular hyaluronic acid injection. Five (5) of the trials had information about functional outcomes with a standardized mean difference of −0.12 (95% CI −0.22 to −0.02). Limitations to this meta-analysis are potential for publication bias since only published trials were included, a short follow-up time of 3 months, and the studies did not separately distinguish the different types of hyaluronic acid only assessing hyaluronic acid as a whole.

In 2015, Campbell and colleagues performed a systematic review of overlapping meta-analyses comparing different treatment of knee osteoarthritis to intra-articular hyaluronic acid. The purpose was to determine which meta-analyses provided the best current evidence and identify potential causes of disagreement. The included studies had varied levels of evidence ranging from level I to level IV. All of the included studies compared the use of intra-articular hyaluronic acid to oral NSAIDS, intra-articular corticosteroids, intra-articular platelet-rich plasma, or intra-articular placebo. A total of 14 meta-analyses were included in the review with 4 of the 14 having industry funding. Of the 10 studies that looked at the effects of intra-articular hyaluronic acid versus intra-articular placebo, 5 found an improvement in pain and 4 found an improvement in function. However, 3 meta-analyses found no difference between hyaluronic acid and placebo in terms of pain and 4 studies found no difference in function. There were 3 studies which examined the efficacy of intra-articular hyaluronic acid to oral NSAIDS; none of these studies showed clinically relevant differences between the two treatments. In the studies which compared intra-articular hyaluronic acid injections to intra-articular corticosteroid injections, the corticosteroids initially provided better relief of pain 4 week following the injection, but the intra-articular hyaluronic acid showed more positive effects 5-13 weeks following injections. Both intra-articular hyaluronic acid injection and intra-articular platelet-rich plasma showed improvements in knee function at 2 and 6 months following injection, the effects of the intra-articular platelet-rich plasma were more robust. In the studies which compared different formulations of hyaluronic acid products, no definitive conclusions could be made about the best product. The authors note that because of the high prevalence of osteoarthritis of the knee, many clinical trials, systematic reviews, and meta-analyses have been conducted in an attempt to determine the best non-operative treatment, “however, a clear gold standard has not been identified.” As noted by the authors, the quality of the systematic review is limited by the quality of the studies included in the review, including methodological limitations inherent to those studies.

Bhandari and colleagues (2017) published a review of 8 meta-analyses on intra-articular hyaluronic acid therapy for mild-to-moderate knee osteoarthritis. The meta-analyses included were published within 5 years of the review, only included randomized control trials, and evaluated the effects of intra-articular hyaluronic acid therapy compared with intra-articular placebo or non-interventional controls for knee osteoarthritis. While the authors found statistically significant improvements in pain, function and stiffness outcomes for hyaluronic therapy compared with placebo or nonintervention in meta-analyses considered, the analysis did not address questions surrounding clinical significance. In addition, many of the underlying studies used in the reviewed meta-analyses included methodological limitations such as insufficient blinding, non-uniform methodology, small study samples, and inappropriate or no control group, as well as potential for publication bias.

Other authors have also published literature reviews regarding the use of hyaluronan injections for the treatment of osteoarthritis of the knee (Jevesvar, 2015; Nguyen, 2016). The positive results are inconsistent, and supportive meta-analyses are limited by wide-heterogeneity of the published literature (including insufficient blinding, non-uniform methodology, small study samples, and inappropriate or no control group), as well as potential for publication bias. Many analyses have not shown benefit beyond the effect seen with placebo, and the treatment effect demonstrated in positive analyses is often of questionable clinical significance. In reviewing the issue of clinical significance, demonstration of a clinically meaningful difference is mixed among meta-analyses, and in many publications, clinical importance is only achieved when the full therapeutic effect of hyaluronan is considered; that is, factoring in the placebo effect attributed to intra-articular administration.

In 2016, O’Hanlon and colleagues compared their systematic review and meta-analysis of the use of hyaluronic acid injections in individuals over the age of 65 who had osteoarthritis of the knee to a previous systematic review (Rutjes, 2012). While comparing the results of the two reviews, O’Hanlon and colleagues identified that differences in how adverse effects are synthesized resulted in differences in estimates of the risk of harms which leads to difference conclusions regarding benefits and harms for the use of hyaluronic acid. Only two of the same studies in the analyses of serious adverse effects were included in both the O’Hanlon and Rutjes review which could attribute to some of the differences in adverse effects. However, O’Hanlon also notes that there is a lack of standardized way to report adverse effects which can lead to differing conclusions about the benefits and harms of hyaluronic acid.

Xing and colleagues (2017) assessed the risk of bias of 31 systematic reviews which evaluated the safety and efficacy of hyaluronic acid for the treatment of osteoarthritis of the knee. Risk of bias was assessed using the ROBIS tool. For the studies found to have low risk of bias, methodological quality of the studies was evaluated according to the Cochrane Handbook and the evidence quality of each primary outcome was determined by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The authors noted there were 13 systematic reviews found to have low risk of bias, 16 systematic reviews with high risk of bias, and 2 systematic reviews with unclear risk of bias. Using the Cochrane Handbook, methodological quality assessment identified limitations to the current evidence which included insufficient information on randomization methods and allocation concealment, insufficient blinding, and incomplete outcome data and selective reporting over-estimated the pooled effects. There were 42 statistical comparisons from the 13 systematic reviews with low risk of bias that were assessed by GRADE approach. There were three items with high quality, eight with moderate quality, 12 with low quality and 19 with very low quality. There are limitations to this study including disregarding non-English language literatures and only the evidence quality of primary outcomes in systematic reviews with low risk of bias were evaluated.

In 2012, the American College of Rheumatology (ACR) published their recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee (Hochberg, 2012). For individuals with symptomatic knee osteoarthritis they recommend an exercise program, counseling for weight loss if the individual was overweight and use of acetaminophen or NSAIDs (unless there are contraindications to these drugs). The ACR recommendations do not advocate the use of intraarticular hyaluronate for the initial management of knee osteoarthritis; if an individual does not have a satisfactory response to acetaminophen or NSAIDs, then the use of tramadol, duloxetine, or intraarticular hyaluronate is “conditionally recommended”.

The American Academy of Orthopaedic Surgeons (AAOS) published their Clinical Practice Guideline for Treatment of Osteoarthritis of the Knee in 2013. In their recommendations, the AAOS states that they “cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee.” It was noted that the recommendation was based on lack of efficacy, not on potential harm.

The Osteoarthritis Research Society International (OARSI) published guidelines for the non-surgical management of knee osteoarthritis in 2014; the evidence-based consensus recommendations lists intra-articular hyaluronic acid as a treatments of “uncertain appropriateness.” Appropriate treatment modalities recommended for individuals with knee osteoarthritis include biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management.

The American Medical Society for Sport Medicine (AMSSM) published a consensus statement in 2016 recommending the use of hyaluronic acid for the appropriate individuals with knee osteoarthritis. The recommendation is based on network meta-analysis of 11 articles showing a small, but statistically significant improvement for participants treated with hyaluronic acid compared to those treated with intra-articular corticosteroids or placebo. Potential for bias was present among the majority of studies included in the meta-analysis, including incomplete data reporting, selective reporting or the absence of blinding of participants and personnel.

In 2017, a workgroup of clinicians published Appropriate Use Criteria (utilizing existing literature supplemented with expert opinion) for use of hyaluronic acid in the treatment of osteoarthritis of the knee (Bhadra and colleagues). The authors found that hyaluronic acid is appropriate for 6 of 17 described clinical scenarios – namely individuals with mild to moderate disease, including those who have experienced an incomplete response or have failed other therapies. The authors concede that evidence on hyaluronic acid is limited – that when compared with active treatments, effects are smaller or there are no clear differences. While the authors conclude that hyaluronic acid injections play a positive role in the treatment of knee OA, they also note that additional research is needed.

In conclusion, there is debate on the effectiveness of hyaluronan injections for treatment of osteoarthritis of the knee. There is a lack of consensus on the ideal treatment regimen regarding the number of injections and the interval between injections, as well as the use of repeated treatment cycles making it difficult to establish effectiveness of hyaluronan. There are also differences in available hyaluronan products including source, molecular weight, concentration and volume. With differing protocols for the treatment of osteoarthritis of the knee with hyaluronan injections, different dosages, different formulations, and the timing of injections not being uniform and varying across trials, it is difficult to assess the overall treatment effect of hyaluronan for osteoarthritis of the knee.

A study by DeGroot and colleagues (2012) enrolled 64 participants to randomly receive either a single injection of hyaluronic acid for ankle osteoarthritis or a single injection of normal saline solution. In this randomized, double-blind, placebo-controlled study, a total of 56 participants completed the study (8 participants withdrew from the study). The primary outcome measure was the change from baseline using the American Orthopaedic Foot & Ankle Society (AOFAS) clinical rating score. Participants were rated at baseline, 6 weeks following injection and 12 weeks following injection. Secondary outcome measures were the change from baseline in the Ankle Osteoarthritis Scale (AOS) score and a self-reported visual analog score. Both groups (active treatment and placebo) had improvements in the primary outcome measure at 12 weeks. The mean AOS scores in the active treatment group improved from baseline by 5.0 points at 6 weeks and 5.3 points at 12 weeks. The mean AOS scores in the placebo group improved by 8.4 points at 6 weeks and 14.8 points at 12 weeks. Using the visual analog score, the pain scores in the active group improved from baseline by 6.4 points at 6 weeks and 4.1 points at 12 weeks. In the placebo group, the visual analog scores improved by 3.0 points at 6 weeks and 11.1 points at 12 weeks. The authors noted that both the active treatment group and placebo group had improvements in scores at 12 weeks, but the improvements in the groups were not significantly different and a single dose of hyaluronic acid is not superior to a single dose of normal saline for the treatment of ankle osteoarthritis.

A prospective study by Lucas and colleagues (2013) reported on 18 individuals with osteoarthritis of the ankle who received a series of 3 injections of viscosupplementation. The participants were evaluated at 4 and 12 months and then annually using the AOFAS score. The AOFAS scores increased from 61.8 ± 15 before receiving the injections to 74.4 ± 14.5 after 4 months and 73.7 ± 16.6 after 12 months. A literature search identified trials focusing on osteoarthritis of the ankle, but trials remain limited to small group sizes (Cohen, 2008; Karatosun, 2008; Salk, 2006; Witteveen, 2010) and retrospective studies (Han, 2014).

A 2015 Cochrane report by Witteveen and colleagues assessed the benefits and harms of conservative treatment for osteoarthritis of the ankle. The conclusions were that since simple analgesics are recommended for osteoarthritis of the hip and knee it would be reasonable to use these to treat osteoarthritis of the ankle. Based on a low quality of evidence it was unclear if there is a benefit or harm to using hyaluronan as a treatment of osteoarthritis of the ankle compared to placebo at 6 months and results were inconclusive when hyaluronan was compared to other treatments.

Blaine and colleagues (2008) reported on the results of a multi-institutional randomized study of 660 individuals with shoulder pain related to glenohumeral osteoarthritis, rotator cuff tear or adhesive capsulitis. All participants had failed prior management with physical therapy, at least one corticosteroid injection and the administration of oral pain medications. Baseline pain levels ranged from 40 to 90 mm on a 100 mm visual analog scale. Limitation of active range of motion in at least one of several directions was also required. Participants were randomized to either a course of 3 or 5 injections of hyaluronan or placebo injection. The primary outcome was improvement in shoulder pain at 13 weeks; the secondary outcome was the maintenance of pain relief through the 26-week follow-up. A total of 456 participants completed the 26 weeks of follow-up; 20% had discontinued the study at week 26. Using an intent-to-treat analysis, at week 13 (the primary outcome measure), all three groups showed significant reductions in pain from baseline that were not significantly different from one another. At week 26, the 3-injection hyaluronan group did show a small but statistically significant reduction in pain compared to the placebo group. Specifically, compared to the placebo group, the difference in mean reduction from baseline was 7.2 mm on a 100 mm scale for the 3-injection group. This trial did not meet its primary outcome, and the questionable clinical significance of the modest improvements noted at other time points is another limitation of this study.

Another study reported on 39 individuals with osteoarthritis of the shoulder who received injections of Hylan G-F 20 (Noel, 2010). Baseline visual analog scores ranged from 40/100 to 90/100. Each participant received 1 intra-articular injection of Hylan G-F 20. Participants could be scheduled for a second injection at the 1-month, 2-month, or 3-month visit. Participants were reevaluated at 7 days and 1, 2, 3, and 6 months following the injection. Thirty-three individuals received an initial injection, and 16 individuals required a second injection. Four participants left the study due to unacceptable pain (which left 29 total participants). Visual analog score decreased from 61.2 mm at baseline to 37.1 mm at 3 months following an injection. In this particular study 52% of participants reported good pain relief following 1 injection; however the authors did state that “controlled trials are needed to confirm our results and determine optimal treatment schedule.”

Qvistgaard and colleagues (2006) reported on the results of a randomized placebo-controlled trial of hyaluronan injections in 101 individuals with osteoarthritis of the hip compared to corticosteroid or saline injection. The researchers reported that over the 3-month evaluation period, the participants who received hyaluronan injections reported only a small reduction in pain with walking compared to those injected with corticosteroid who reported significant pain reductions with walking.

In a systematic review for osteoarthritis of the hip (Fernández López, 2006), two independent reviewers applied a series of inclusion and exclusion criteria to the studies located in the search, and selected only those that included more than 20 participants; had a follow-up period of more than 1 week; and exclusively assessed the efficacy and/or effectiveness of hyaluronan in those with confirmed osteoarthritis of the hip. A total of eight studies consisting of clinical trials and one review, met the inclusion criteria. Only two of the trials were controlled: one compared two hyaluronan products of different molecular weights; and the other compared hyaluronan injections with corticoids and a placebo. Pain relief was estimated to be around 40-50% by most studies, although the duration of this post-treatment effect was not known. The researchers concluded that based on available evidence, hyaluronan injections as a treatment of osteoarthritis of the hip should be used under careful supervision by the clinician and only in those instances where other treatments have failed. The researchers noted that methodological limitations include short follow-up periods, dissimilar ways of measuring outcomes and the absence of a control group in many of the studies.

Another systematic review (van den Bekerom, 2008) sought to identify studies relating to the use of viscosupplementation as a treatment for osteoarthritis of the hip. Sixteen articles addressing the efficacy of viscosupplementation in a total of 509 participants with osteoarthritis of the hip were included. The products evaluated included Hylan G-F 20, Hyalgan, Ostenil, Durolane, Fermatron and Orthovisc. While the researchers concluded that viscosupplementation might have a beneficial effect in relieving pain in individuals suffering with osteoarthritis of the hip, additional comparative studies are needed before it can be recommended as standard therapy in osteoarthritis of the hip.

Richette and colleagues (2009) reported the findings of a multicenter, randomized, parallel-group, placebo-controlled trial which evaluated the efficacy and tolerability of a single intra-articular injection of hyaluronic acid for the treatment of osteoarthritis of the hip. A total of 85 participants were randomized to either the hyaluronic acid group (n=42) or placebo group (n=43). At the end of 3 months no difference in efficacy was noted between the two groups. The findings indicated that a single intra-articular injection of hyaluronic acid was no more effective than placebo in treating the symptoms of osteoarthritis of the hip. However, the value of the study results were limited by the small number of participants included in each study arm and the fact that the hyaluronic acid injections were administered only once versus the multiple injections typically administered for other indications.

A retrospective review by Migliore and colleagues (2012) reported on 224 participants who received injections of hylan G-F 20 and who were then followed to see if total hip replacement was required. Of the study participants, 56 were classified as being candidates for total hip replacement and 168 participants were classified to not being candidates for a total hip replacement. Following injections, 84 participants later required total hip replacement (32 of these participants came from the non-surgical candidate group). Survival time (in months) was the amount of time between start of treatment with injections and total hip replacement, if performed. Twelve-month survival was achieved by 206 participants, 24-month survival was achieved by 170 participants, and 5-year survival was achieved by 69 participants. This study is limited by its retrospective design and lack of a control group. The authors also note that intra-articular treatment is known to have a placebo effect and additional studies are needed to gain further insight into functional and clinical improvement.

A 2016 study by Rivera reports on 207 participants with osteoarthritis of the hip who received a single intra-articular injection of hyaluronic acid. Participants were assessed prior to the injection, and at 3, 6, and 12 months following the injection. Primary outcome measure was the score on the Modified Brief Pain Inventory with a pain severity score of 0-10. Participants were also evaluated using the Harris Hip Score from 0-100 which addressed pain domain, function domain, range of motion domain, and no deformity domain. Visual analog scale was also used to assess pain scores. A total of 121 participants filled out the questionnaires for Modified Brief Pain Inventory and Harris Hip Score at 1 year following the injection while 104 participants completed the questionnaire for visual analog score. The Modified Brief Pain Inventory mean score at the initial assessment was 4.07 and 2.55 between 6-12 months. The mean Harris Hip Scores ranged from 68.35 at initial evaluation to 81.76 between 6-12 months. The visual analog scores were reported as “a statistically highly significant improvement” between initial evaluation and the 3 month follow-up. This study has limitations including a loss of participants from initial evaluation to the 12-month post injection follow-up, and lack of a control group. Randomized trials are needed.

The American College of Rheumatology has no recommendation for the use of intraarticular hyaluronate injections for the management of osteoarthritis of the hip (Hochberg, 2012).

Temporomandibular Joint (TMJ)
A study by Li and colleagues (2015) reported observations of TMJ condylar changes and function of the joint for individuals with osteoarthritis of the TMJ who received hyaluronic acid injections. A total of 141 individuals were randomized to one of two study groups: the superior or inferior joint space injection group. The participants received hyaluronic acid injections once every 2 weeks for a total of 3 injections. Participants were evaluated at 3 and 9 months post injection with cone-beam computed tomography and clinical exam. TMJ function was assessed by mandibular movement, maximal mouth opening, protrusive and lateral excursion, tenderness of masticatory muscles, tenderness of the TMJ, and TMJ noise. At the 3-month visit, 126 participants were available for follow-up. In the superior group 44 participants and 51 participants in the inferior group showed reparative remodeling. Severe degenerative changes were noted in 13 participants in the superior group and 5 participants in the inferior group. No change was found in 8 participants in the superior group and 4 participants in the inferior group. Most of the participants showed improvement in TMJ function. A total of 74 participants were available at the 9-month follow-up and most of the available participants showed better condylar morphology than at the 3-month visit and most also had improved TMJ function. At the 3-month visit, new bone formation was noted in many of the participants. Some of the participants who were found to have severe degenerative changes at 3 months showed reparative remodeling at 9 months. While this study suggested that the use of hyaluronic acid injections of the joint space in treating TMJ osteoarthritis is effective, there are some limitations to the study including the large number of participants lost to follow-up and no placebo control.

A prospective trial by Korkmaz and colleagues (2016) studied 51 participants with temporomandibular joint derangements. Participants were assigned to one of three treatment arms: single injection of hyaluronic acid (n=13), double injection of hyaluronic acid (n=13), or splint therapy (n=12), and a self-selected control group (n=13). The purpose of the study was to evaluate pain, TMJ noise, quality of life, maximum mouth opening, and jaw movements. Participants were assessed 6 months following treatment. All treatment groups showed improvement in pain, noise, quality of life, and maximum mouth opening when compared to baseline. The participants who received double injections of hyaluronic acid showed more improvement for pain and maximum mouth opening compared to the splint therapy group. While improvement was noted across all treatment groups, the study is limited by a small number of participants, a short follow-up period and participation was at a single institution.

Current literature related to hyaluronic acid injections for use in temporomandibular joint disease is limited to small group sizes with short-term follow-up and inconsistent protocols when administering hyaluronic acid. Randomized trials with larger participant groups and longer follow-up are necessary to determine superiority of one specific treatment over another. Furthermore, the mechanism of potential therapeutic action remains unknown (Hepguler, 2002).

Similarly, randomized controlled trials comparing hyaluronan and corticosteroid injection in individuals with osteoarthritis of the thumb have reported superior results associated with the corticosteroid injection (Fuchs, 2006; Stahl, 2005). 


Intra-articular injections: A medical procedure using a hypodermic needle to inject a substance, such as a drug, into the space between two bones.

Osteoarthritis: A degenerative condition of the joints that causes destruction of the material in the joints that absorbs shock and allows proper movement.

Temporomandibular joint (TMJ): The joint where the lower jaw meets the skull.

Viscosupplementation: Intra-articular injections commonly used to treat osteoarthritis; thought to increase joint lubrication. 


Peer Reviewed Publications:

  1. Alpaslan GH, Alpaslan C. Efficacy of temporomandibular joint arthrocentesis with and without injection of sodium hyaluronate in treatment of internal derangements. J Oral Maxillofac Surg. 2001; 59(6):613-618.
  2. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol. 1998; 25(11):2203-2212.
  3. Arrich J, Piribauer F, Mad P, et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ. 2005; 172(8):1039-1043.
  4. Bannuru RR, Natov NS, Dasi UR, et al. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis meta-analysis. Osteoarthritis Cartilage. 2011; 19(6):611-619.
  5. Bannuru RR, Natov NS, Obadan IE, et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum. 2009; 61(12):1704-1711.
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  7. Bertolami CN, Gay T, Clark GT, et al. Use of sodium hyaluronate in treating temporomandibular joint disorders: a randomized, double-blind, placebo-controlled clinical trial. J Oral Maxillofac Surg. 1993; 51(3):232-242.
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  11. Blaine T, Moskowitz R, Udell J, et al. Treatment of persistent shoulder pain with sodium hyaluronate: a randomized, controlled trial. A multicenter study. J Bone Joint Surg Am. 2008; 90(5):970-979.
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  13. Campbell KA, Erickson BJ, Saltzman BM, et al. Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis of the knee: a systematic review of overlapping meta-analyses. Arthroscopy. 2015; 31(10):2036-2045.
  14. Cohen MM, Altman RD, Hollstrom R, et al. Safety and efficacy of intra-articular sodium hyaluronate (Hyalgan) in a randomized, double-blind study for osteoarthritis of the ankle. Foot Ankle Int. 2008; 29(7):657-663.
  15. DeGroot H 3rd, Uzunishvili S, Weir R, et al. Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 2012; 94(1):2-8.
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  27. Karatosun V, Unver B, Ozden A, et al. Intra-articular hyaluronic acid compared to exercise therapy in osteoarthritis of the ankle. A prospective randomized trial with long-term follow-up. Clin Exp Rheumatol. 2008; 26(2):288-294.
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  29. Korkmaz YT, Altintas NY, Korkmaz FM, et al. Is Hyaluronic acid injection effective for the treatment of temporomandibular joint disc displacement with reduction? J Oral Maxillofac Surg. 2016; 74(9):1728-1740.
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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Orthopedic Surgeons. Clinical practice guideline. Treatment of osteoarthritis of the knee. May 2013. Available at: Accessed on December 24, 2018.
  2. American Medical Society for Sports Medicine. Scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. 2016. Available at: Accessed on December 24, 2018.
  3. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006; (2):CD005321.
  4. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012; 64(4):465-474. Available at: Accessed on December 24, 2018.
  5. Jüni P, Hari R, Rutjes AWS, et al. Joint corticosteroid injection for knee osteoarthritis. Cochrane Database Syst Rev. 2015(10):CD005328.
  6. National Institute of Dental and Craniofacial Research of the National Institutes of Health. TMJ (Temporomandibular Joint and Muscle Disorders). Available at: Accessed on December 24, 2018.
  7. Osteoarthritis Research Society International. Guidelines for the non-surgical management of knee osteoarthritis. 2014. Available at: Accessed on December 24, 2018.
  8. Witteveen AG, Hofstad CJ, Kerkhoffs GM. Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle. Cochrane Database Syst Rev. 2015(10):CD010643.
Websites for Additional Information
  1. Arthritis Foundation. Osteoarthritis: Available at: Accessed on December 24, 2018.
  2. Centers for Disease Control and Prevention. Osteoarthritis. September 2017. Available at: Accessed on December 24, 2018.
  3. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Osteoarthritis. May 2016. Available at: Accessed on December 24, 2018.
  4. National Library of Medicine. Health Encyclopedia: Osteoarthritis. Available at: Accessed on December 24, 2018.
  5. National Library of Medicine. Health Encyclopedia: TMJ disorders. Available at: Accessed on December 24, 2018.

Intra-articular injections

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Discussion/General Information and References sections.



Updated Coding section with 01/01/2019 HCPCS changes; added J7318, J7329; removed C9465 deleted 12/31/2018.



Updated Coding section with 04/01/2018 HCPCS changes; added C9465.



MPTAC review. Moved content of DRUG.00017 Hyaluronic Injections in Joints Other Than the Knee into this Clinical UM Guideline. Title changed. Scope of document revised to include all joints. Revised NMN statement to include all joints. Updated Coding, Description, Discussion/General Information, Definitions, References, Websites for Additional Information, and Index sections.



Updated Discussion/General Information, References, and Index sections. The document header wording updated from “Current Effective Date” to “Publish Date.”



MPTAC review. Revision to Clinical Indications section that the use of hyaluronan is NMN for osteoarthritis of the knee and all other knee conditions. Updated Coding, Discussion/General Information and References sections. Removed Clinically Equivalent Cost Effective section.



MPTAC review. Updated Clinically Equivalent Cost Effective section.



MPTAC review. Changed title of the “Preferred Agents” section to “Clinically Equivalent Cost Effective Agents.” Updated Coding section to remove codes C9471 and Q9980 deleted 12/31/2016.



MPTAC review. Added new section addressing preferred agents. Removed Hylan G-F 20 from Clinical Indications. Updated Discussion/General Information, Reference and Index sections. Updated Coding section with 01/01/2017 HCPCS changes.



MPTAC review. Updated Reference section. Updated Coding section with 04/01/2016 HCPCS changes.



Updated Coding section with 01/01/2016 HCPCS changes; removed ICD-9 codes.



MPTAC review. Updated References and Index.



Updated Coding section with 01/01/2015 HCPCS changes.



MPTAC review. Updated References.



MPTAC review. Initial document development.