BlueCross and BlueShield of Montana Medical Policy/Codes
Hyaluronan Injections for Osteoarthritis of the Knee
Chapter: Medicine: Treatments
Current Effective Date: April 06, 2012
Original Effective Date: August 15, 1998
Publish Date: April 06, 2012
Revised Dates: June 7, 2002; October 15, 2003; April 11, 2007; March 1, 2010; April 6, 2012

Intra-articular injection of hyaluronan (HA) into osteoarthritic joints is thought to replace HA, restore the viscoelastic properties of the synovial fluid, and improve pain and function. The majority of studies to date have assessed HA injections for knee osteoarthritis, and this is the U.S. Food and Drug Administration (FDA) -approved indication. Other joints, such as the hip and shoulder, are currently being investigated for intra-articular HA treatment of osteoarthritis (OA).

Hyaluronan (HA) is a naturally occurring macromolecule that is a major component of synovial fluid and is thought to contribute to its viscoelastic properties. Chemical crosslinking of hyaluronan increases its molecular weight; crosslinked hyaluronans are referred to as hylans. In osteoarthritis (OA), the overall length of HA chains present in cartilage and the HA concentration in the synovial fluid are decreased. Intra-articular injection of HA (IAHA) has been proposed as a means of restoring the normal viscoelasticity of the synovial fluid in patients with OA. This treatment has been called viscosupplementation.

Six preparations of intra-articular (IA) hyaluronan have been approved by the FDA as an alternative to nonsteroidal anti-inflammatory drug therapy in the treatment of OA of the knee (Synvisc® and Synvisc-One®, Genzyme; Hyalgan®, Fidia; Supartz®, Smith and Nephew; OrthoVisc®, Anika; and Euflexxa®, previously named Nuflexxa, Savient). All products are manufactured from rooster combs except for Euflexxa and Orthovisc, which are produced from bacterial fermentation. Also, Synvisc undergoes additional chemical crosslinking to create hylans with increased molecular weight (6,000 kDa) compared to Hyalgan (500-730 kDa) and Supartz (620-1170 kDa). The differing molecular weights of the products lead to different half-lives; the half-life of Hyalgan or Supartz is estimated at 24 hours, while the half-life of Synvisc may range up to several days.

Currently, no curative therapy is available for OA, and thus the overall goals of management are to reduce pain and prevent disability. Intra-articular hyaluronic acid is “indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy, and to simple analgesics, e.g., acetaminophen.” The product inserts further indicate that Synvisc® and Euflexxa® should be injected intra-articularly into the knee joint once per week for a total of 3 injections over a 2- to 3-week period. In contrast, 5 weekly injections are recommended for the Hyalgan® and Supartz® products, and 3–4 weekly injections are recommended for OrthoVisc®. In February 2009, the FDA approved the use of single-dose hylan G-F 20 (Synvisc-One™) for the treatment of OA of the knee.

In 2000, the FDA approved removal of a precautionary statement from the package inserts for Hyalgan and Synvisc that stated that the safety and efficacy of repeat courses have not been established.

The FDA has not approved intra-articular hyaluronan for joints other than the knee.


Prior authorization is recommended for intra-articular hyaluronan injections. To authorize, call the Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service Department at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review is performed if services are not prior authorized.

Medically Necessary

BCBSMT considers intra-articular hyaluronan injections medically necessary for treatment of painful osteoarthritis of the knee in patients who have insufficient pain relief from conservative nonpharmacologic therapy and simple analgesics.

Repeated courses of intra-articular hyaluronan injections of the knee may be considered medically necessary under the following conditions:

  • Significant pain relief achieved with the prior course of injections; and
  • At least 6 months have passed since completion of the prior course.


BCBSMT considers the use of intra-articular hyaluronan injections in joints other than the knee investigational.

Federal Mandate

Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.

Policy Guidelines

Appropriate candidates for hyaluronan injections are those who have failed conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or who have contraindications to NSAID therapy. Plans may also require candidates for hyaluronan injections to have failed intra-articular injections of corticosteroids.

A course of hyaluronan injections is defined according to labeled indications for each product; one formulation involves a single injection, others use multiple injections. For example, Synvisc-One® is a single 6-mL injection treatment regimen. For a single course of treatment, the single injection formulation should not be followed with subsequent doses of the multiple-injection formulations.

When determining the timing of repeated courses, the prior course is assumed to have been completed at the date of the last injection of the series of injections.

The procedure may be billed using a combination of CPT codes to describe the procedure and J codes to describe the hyaluronic acid product.

CPT code

  • 20610

The initial office visit to initiate hyaluronan therapy may be billed using an evaluation and management CPT code; however, the use of both CPT code 20610 and an evaluation and management CPT code during subsequent visits for the sole purpose of hyaluronan injections is not routinely warranted.

The following HCPCS codes are specific to the various hyaluronan products:

  • J7321: Hyaluronan or derivative, Hyalgan or Supartz, for intra-articular injection, per dose
  • J7323: Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose
  • J7324: Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose
  • J7325: Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg
  • J7326: Hyaluronan or derivative, Gel-One, for intra-articular injection, per dose


The most recent literature search was performed for the period June 2010 through December 2011. The following is a summary of key findings.


This policy is based in part on a 1998 TEC Assessment on intra-articular hyaluronan (IAHA) for osteoarthritis (OA) of the knee (1) that offered the following conclusions:

  • There are 13 randomized controlled trials (RCTs) comparing IAHA to placebo. These trials include 1,350 patients. Although the quality of this evidence is somewhat limited by a variety of methodologic flaws, the preponderance of evidence is consistent in suggesting that a small incremental benefit is associated with IAHA treatment over the benefit achieved with placebo-control treatments.
  • The 2 available studies comparing IAHA treatment to pharmacologic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) suggest that IAHA has comparable effectiveness to NSAIDs.
  • There are inadequate data to determine the net effect of multiple courses of IAHA on health outcomes.

Originally, the policy suggested that multiple courses of therapy would be considered investigational; the policy was revised to delete that statement, in part due to a U.S. Food and Drug Administration (FDA) labeling change for Hyalgan. The original labeling for both Hyalgan and Synvisc, at the time of their 1997 FDA approval, included the following statement in the Patient Information section:

“The safety and effectiveness of repeat treatment cycles [of Hyalgan and Synvisc] have not been established.”

In 2000, the FDA approved revised labeling for Hyalgan by deleting the above statement regarding repeat treatment cycles. Therefore, the current labeling for Hyalgan is silent on the issue of multiple courses of therapy. In support of the labeling change to Hyalgan, the manufacturers cited 2 studies, although no study has specifically focused on the multiple courses of therapy. Scali conducted an uncontrolled study of 75 patients with OA of the knee who received 5 weekly intra-articular (IA) injections of 2-mL Hyalgan repeated every 6 months, for a total of 25 IA injections over 2 years. (2) Over the course of the study, progressive reduction was noted in various symptoms, including pain, stiffness, and analgesic intake. There were no serious systemic side effects. Kotz and Kolarz conducted an open-label, multicenter study of 108 patients with knee OA who received 5 weekly injections of Hyalgan, 14 of whom began a new treatment cycle after 4 to 8 months due to pain recurrence. (3) Six of these patients completed the second cycle follow-up of 12 months. Patients who received a second treatment cycle showed further improvement. There were no significant systemic adverse effects. In other international studies of both Synvisc and Hyalgan, multiple treatment courses for knee OA have been reported, but the studies do not permit separate assessment of the effectiveness of multiple courses of therapy. (4, 5) In 2000, the policy was revised such that no statement was made regarding multiple courses of therapy. In 2003, an explicit statement was added, identifying multiple courses of therapy as investigational. This revision was made based on the panel consensus that controlled trials are required to determine the effectiveness of multiple courses of therapy, particularly given the unclear method of action of hyaluronan (HA).

In 2004, a TEC Special Report on IAHA for OA of the knee (6) offered the following conclusions:

  • To date, there appears to have been 28 randomized placebo-controlled clinical trials of hyaluronan and 3 published systematic reviews of hyaluronan. Despite observed flaws in the studies, all of the reviews conclude that hyaluronan demonstrates an effect on the symptoms of OA. One review by Lo et al. (7) concludes that the effect is small and possibly subject to publication bias.
  • The evidence base regarding the comparison between hyaluronan and alternative treatments has not been advanced significantly since the 1998 TEC Assessment, with only 1 study confirming the prior conclusion that hyaluronan is about as effective as NSAIDs. However, this literature base remains small, and the quality of the evidence is fair to poor.
  • There is no rigorous controlled evidence regarding the effectiveness of repeated treatments of hyaluronan. Case series showing improvement of symptoms after repeated treatments could be due to either placebo effects or selection bias.
  • Overall, the review shows that the evidence is still consistent with that presented in the 1998 TEC Assessment. The evidence shows a statistically significant effect in almost all studies, although the magnitude and clinical significance of the effect may be small.
  • There are inadequate data to determine the clinical efficacy of hyaluronan injections in joints other than the knee.

In 2005, a Cochrane review of viscosupplementation for OA of the knee was published that evaluated a total of 63 clinical trials identified from a literature review conducted up to April 2004. (8) Overall, the review concluded hyaluronan is safe and effective in improving joint pain and function and global patient function in the treatment of OA of the knee. Included in the 63 trials evaluated for the review were 37 trials comparing hyaluronan/hylan products to placebo. The pooled analyses for these 37 trials demonstrated that hyaluronan treatment was more effective than placebo, most notably in the 5 to 13 weeks after treatment. Five trials were evaluated that compared hyaluronan (HA) to NSAIDs. In the analysis of this comparison, HA was found to be comparable in efficacy to NSAIDs. In 9 trials comparing HA to corticosteroid injections, analysis demonstrated longer term benefits with HA than with corticosteroid injections. The authors noted that the clinical effects of the HA products have considerable heterogeneity and therapeutic variability. However, conclusions about the clinical effectiveness of products could not be drawn given the limited data comparing products head-to-head.

Another 2005 systematic review and meta-analysis by Arrich and colleagues evaluated 22 randomized controlled trials (RCTs) through April 2004 on hyaluronic acid injections for OA of the knee. (9) The authors’ analysis found pain relief from OA of the knee related to movement was only slightly better with hyaluronic acid injections than placebo but was of borderline clinical significance. Also, pain at rest and joint function were not improved with hyaluronic acid injections. The authors emphasized the poor methodologic quality of the trials and thereby concluded that there was no proof that hyaluronic acid injections provide clinically relevant benefits, and they may even increase the incidence of adverse events.

The conclusions of the Cochrane review are consistent with the 2004 TEC Special Report. While hyaluronan has some beneficial effect, the magnitude and clinical significance of the effect may be small. As noted in the Cochrane review, further research would be useful, such as head-to-head comparisons of the various HA products, longer term trials (up to 1 year), and trials examining repeated courses of treatment with HA. The Arrich et al. review also found improvement in pain with hyaluronic acid injections but emphasized that the benefits were borderline in clinical significance. However, the Arrich trial reviewers concluded that the evidence was not sufficient to demonstrate the clinical effectiveness of hyaluronic acid injections. Therefore, the authors recommended hyaluronic acid injections not be used for the treatment of pain in OA of the knee until large clinical trials determine the clinical benefits on defined clinical endpoints versus the risk of adverse events.

An April 2006 update of the Cochrane review of viscosupplementation for OA of the knee evaluated a total of 76 clinical trials identified from a literature review conducted up through the first week of January 2006. (10) The Cochrane review came to the same conclusions it had made previously, as noted earlier, including that HA treatment was more effective than placebo, most notably in the 5 to 13 weeks after treatment. In a meta-analysis of literature reviewed in a search conducted through October 2004, Pagnano and Westrich concluded that repeat courses of HA for OA of the knee were as safe and effective as a single course of HA injections. (11) Pseudoseptic reactions were more frequently reported with hylan G-F 20 (Synvisc) than with sodium hyaluronate (Hyalgan, Supartz, Euflexxa). However, as noted in the 2004 TEC Special Report, there is no rigorous controlled evidence regarding the effectiveness of repeated treatments with HA.

In 2007, the TEC Evidence-based Practice Center published a technology assessment for the Agency for Healthcare Research and Quality (AHRQ) on the treatment of primary and secondary OA of the knee. (12)

The report concluded that:

  • Results from 42 trials (n=5,843) generally show positive effects of viscosupplementation on pain and function scores compared to placebo for patients with primary OA of the knee. However, the evidence on viscosupplementation is accompanied by considerable uncertainty due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported.
  • Trials of hylan G-F 20 (Synvisc, 6,000 kDa), the highest molecular weight cross-linked product, generally reported better results than other trials.
  • There was no evidence for differential effects according to subgroups defined by age, sex, primary/disease, BMI [body mass index]/weight, or disease severity.
  • Minor adverse events accompanying intra-articular injections are common, but the relative risk accompanying hyaluronan injections over placebo appears to be small. The risk of local adverse events appears to increase with prior courses of treatment. Pseudoseptic reactions associated with hyaluronans appear relatively uncommon but can be severe.

In 2009, Bannuru et al. conducted a meta-analysis of 7 RCTs published between 1987 and 2004 that compared pain relief achieved with IAHA or intra-articular (IA) corticosteroids in 610 patients with OA of the knee. (13) Trial quality was fair, heterogeneity was moderate (I2, 37-49% at various time points), and publication bias was suggested by an asymmetric funnel plot and positive Egger test. At week 2, the effect size favored corticosteroids (0.39 [95% confidence interval (CI): -0.65, -0.12]); at week 4, the effect size suggested equal efficacy (-0.01 [95% CI: -0.23, 0.21]); and at week 8, there was a non-significant effect size favoring IAHA (0.22 [95% CI: -0.05, 0.49]). At weeks 12 and 26, statistically significant effect sizes favoring IAHA were found (0.35 [95% CI: 0.03, 0.66], and 0.39 [95% CI: 0.18, 0.59], respectively).

Bannuru et al. published another meta-analysis of IAHA for knee OA in 2011. (14) This meta-analysis evaluated 54 randomized clinical trials published between 1983 and 2009, 49 of which compared the effects over time of IAHA to placebo for pain relief in a total of 6,962 patients. Trial quality and conduct varied. By week 4, the effect size favored IAHA (0.31; 95% CI 0.17, 0.45), peaked at 8 weeks (0.46; 95% CI 0.28, 0.65), and decreased by week 24 to a lesser residual effect (0.21; 95% CI 0.10, 0.31). The authors noted the therapeutic effect was also consistent on multivariate analysis of the subset of high quality trials (2,570 participants) adjusting for correlation between time points.

In 2009, the FDA approved the use of single-dose hylan G-F 20 (Synvisc-One™) for the treatment of knee OA. This approval was based on a double-blind, randomized clinical trial that compared a single 6-mL IA injection of either hylan G-F 20 or saline in 253 osteoarthritic knees. (15) At 26 weeks, there was a significant reduction in pain (>20%) in both groups as measured by the Western Ontario and McMaster University (WOMAC) A (pain) subscale. The improvement at 26 weeks in the treatment group was greater than in the control group (-0.84 vs. -0.69, respectively, p=0.047), and the magnitude of the improvement is similar to that noted in trials with 3 to 5 injections of hylan G-F 20 versus placebo when the scores are adjusted for the overall scale. The difference between groups, while statistically significant at 26 weeks, had not shown statistical significance at 12 weeks. Thus, this formulation appears to provide improvements similar to those noted for existing agents.

A multicenter, placebo-controlled, double-blind RCT administered 5 weekly Hyalgan or saline placebo IA injections to 335 patients with OA of the knee (335 knees) and assessed survival of response at 3, 6, 9, and 12 months. (16) Survival of response was defined using the Lequesne algofunctional index (LFI), an international index for scoring pain and function in OA using a 0-24 point scale. The LFI is a modification of the WOMAC Index of Osteoarthritis, a 24-item self-administered questionnaire that assesses pain, stiffness, and function in OA patients. The LFI is not as well-validated as the WOMAC. In this study, a 1-point decrease in LFI score defined the onset of improvement, and a 1-point increase in LFI score defined recurrence. These changes may not be clinically relevant. There was no statistically significant difference between groups in the time to recurrence (Hyalgan group, 172 days; placebo group, 204 days, p=0.26). The total number of adverse events in the Hyalgan and placebo groups was 133 and 178, respectively. Local injection site pain, joint pain exacerbation, and “infections in general” were reported more often in the placebo group.

In a double-blind, placebo-controlled RCT from investigators in Turkey, 45 patients with OA of the knee (48 knees) were randomly assigned to receive 2 weekly IA injections of Orthovisc or saline placebo. (17) At 1, 3, 5, and 14 weeks, there was no difference in visual analog scale (VAS) for pain or in overall WOMAC Index.

A double-blind, active-controlled RCT administered 5 weekly injections of IAHA (Ostenil®, unavailable in the U.S.) or IA corticosteroid (triamcinolone) to 42 patients with OA of the knee (42 knees) and assessed pain, instrumented gait analysis (GA), and functional electromyography of the muscles stabilizing the knee joint at 1 and 12 weeks. (18) Drop-outs in the corticosteroid group were 25% compared to 5% in the IAHA group. By as-treated analysis, there were no significant differences between the two groups in any outcome measure except for 2 of 13 parameters of GA; a significant improvement (decrease) in ground reaction forces was seen in the corticosteroid group at 12 weeks. Adverse reactions were not reported.

Results from an RCT on the effects of repeat IAHA for knee OA (the AMELIA project) were published in 2011. (19) In this trial of 306 patients, 5 injections of IAHA or placebo were given weekly for 4 treatment cycles. Patients were followed a total of 40 months, including a 6-month follow-up after the first and second cycles and a 1-year follow-up after the third and fourth cycles. Patients were not permitted to use non-steroidal anti-inflammatory medications 1 week before follow-up evaluations, nor were they permitted to receive corticosteroid injections in the treatment knee during the entire study period. After each treatment cycle, more patients in the IAHA group progressively responded (from 71.1% to 80.5%) compared to the placebo group (from 67.8% to 65.8%) according to Osteoarthritis Research Society International (OARSI) 2004 criteria. At the end of follow-up, 120 patients responded to IAHA or 22% more than the 100 patients that responded to placebo (relative risk [RR] 1.22, 95% CI 1.07 to 1.41; p=0.004). Adverse events included local bleeding, mild pain, or allergic reaction and occurred at a rate of 0.029 per cycle in both groups. Serious adverse events did not occur. The authors noted repeated injections of IAHA progressively increased the number of patients responding and demonstrated a positive carry-over effect for up to 1 year but whether this suggests remission or alteration of the course of OA could not be determined.

Two studies from Switzerland compared IAHA with high molecular weight hylan (Synvisc). An RCT (20) compared 3 injections of either high molecular weight HA (Synvisc), medium molecular weight HA (Orthovisc), or low molecular weight HA (Ostenil, unavailable in the U.S.) in 660 patients with OA of the knee. At 6 months, there was no difference between groups in any outcome measure. This RCT was one of 13 trials included in the second Swiss study, a meta-analysis (21) that found no superior effectiveness of hylan over hyaluronic acids. In 2 randomized controlled, non-inferiority trials, published in 2011, different hyaluronans were also compared and found to have similar outcomes. In one trial of 381 patients, highly purified hyaluronic acid (Sinovial®) was found to be equivalent to 0.8% hylan G-F20 (Synvisc®). (22) In the other trial of 276 patients, a medium' molecular weight hyaluronan product (F60027, Structovial) was also found to be equivalent to hylan G-F 20 (Synvisc®). (23)


The evidence on IAHA injections in the ankle consists of a few small RCTs and case series. DeGroot et al. reported on an RCT of 64 patients with ankle OA that compared a single IAHA to a single IA saline injection. (24) At 6 weeks and 12 weeks, there were no significant differences in improvement between treatment groups on the American Orthopaedic Foot & Ankle Society clinical rating score, the Ankle Osteoarthritis Scale score, and the patient-reported visual analog pain scale (VAS).

Migliore and colleagues conducted a review of 7 studies on IAHA for ankle OA, identified from the period of 2006-2009, that included 3 small RCTs with a total of 75 patients, and 4 case series. For 2 of the RCTs, IAHA was compared to saline injection, and the results showed benefit on some outcome measures but not others. The third RCT compared IAHA to exercise therapy and reported no differences in outcomes. (25) The authors were unable to do a meta-analysis due to the limited number of studies and study heterogeneity.


There is a very limited amount of evidence on IAHA injections in the foot. Munteanu and colleagues reported on an RCT of a single IAHA injection in 151 patients with first metatarsophalangeal joint OA. (26) At 1, 3, and 6 months’ follow-up, there were no significant differences between the IAHA and placebo groups on the Foot Health Status Questionnaire.


Two small RCTs that enrolled a total of 100 patients evaluated HA injections compared to steroid injections for arthritis of the thumb. (27, 28) Fuchs et al. (28) reported that steroid injections were superior at 2-3 weeks post-treatment but that IAHA was superior at 6 months’ follow-up. Stahl et al. (27) reported essentially equivalent outcomes between steroid injections and IAHA, although IAHA was superior to steroids for some aspects of fine motor function. The results of these trials are not sufficient to determine the efficacy of IAHA for thumb arthritis and are not sufficient for determining comparative efficacy to steroids.


There are a number of small RCTs and systematic reviews that evaluate IAHA for OA of the hip. The largest RCT randomized 101 patients to receive either HA injections or saline. (29) There was a small reduction in pain with walking in patients treated with HA injections over the 3-month evaluation period, whereas patients injected with corticosteroid had larger and significant pain reductions with walking. (29) Two systematic reviews (30, 31) identified this study, which did not show significant benefit of viscosupplementation over placebo, and one RCT comparing hyaluronans of different molecular weights. Although the case series reviewed in these papers suggested that HA “might have a beneficial effect in relieving pain” in patients with hip osteoarthritis, in the absence of comparative studies, efficacy could not be evaluated.

A 2008 systematic review of 2 RCTs and 9 cohort studies (32) concluded that viscosupplementation therapy with HA appears to be “a safe and effective method in the treatment of hip OA resistant to conventional treatment modalities.” However, the authors recommend future studies with a large number of patients to confirm results and to answer questions about doses, intervals between doses, and the number of injections needed to achieve a therapeutic and safe effect.

One industry-sponsored RCT published since that review (33) compared a single 2.5 mL IAHA (Adant, 900 kDa, unavailable in the U.S.) to saline injection for treatment of hip OA in 85 patients. At 3 months, there were no significant differences between groups in any outcome measure. The number of patients who experienced mild to moderate treatment-related adverse events (injection-site pain, pain flare, hematoma, pruritus) did not differ between groups.

In another industry-sponsored, single-center, randomized, double-blind, active-controlled trial, published in 2009,forty-two patients with OA of the hip were randomly assigned to receive 2 monthly injections of high-molecular weight IAHA (Hyalubrix® - unavailable in the U.S.; 1,500-3,200 kDa) or IA mepivacaine, a local anesthetic. (34) At 3 and 6 months, there was a significant decrease in the LFI in the IAHA group compared to the mepivacaine group (5.15 vs. 6.53, respectively, at 3 months, p<0.001; 3.94 vs. 6.41, respectively, at 6 months, p<0.05). Of note, 2 patients with the most severe OA (Kellgren-Lawrence radiologic grade IV) were randomly assigned to the mepivacaine group. The only reported adverse event was injection-site pain occurring in 1 patient in each group.

Atchia and colleagues reported on a randomized, controlled trial (RCT) of 77 patients with hip OA who were potential candidates for total hip replacement. (35) In this study, patients were randomized to receive standard care or an injection of saline, hyaluronan or methylprednisolone and followed for 8 weeks. Significant improvement was only seen in the steroid group in the numerical rating scale for worst pain, and the Western Ontario and McMaster Osteoarthritis Index for pain and function. No improvements were reported in the IAHA group.


An industry-sponsored RCT (36) of 660 patients with persistent shoulder pain due to glenohumeral joint OA, rotator cuff tear, and/or adhesive capsulitis compared 3 weekly injections versus 5 weekly injections of sodium hyaluronate (Hyalgan) versus 5 weekly injections of saline. Approximately 60% of patients had OA, although the majority of those with OA also had rotator cuff disorders or capsulitis. Sixty-nine percent (n=456) of the patients had a follow-up visit at 26 weeks. There was no significant difference among groups in the primary outcome measure, shoulder pain with movement at 13 weeks. Analysis of predefined, stratified subgroups revealed no significant differences in reported pain at 13 weeks but a significant decrease in reported pain in both treatment groups at 26 weeks compared to placebo among patients with OA. In those without OA, there was no significant improvement with either regimen. Of note, this appears to be an as-treated analysis of the OA subgroup data. Differences in range of motion among groups were judged to be not clinically important.

A meta-analysis of 19 blinded RCTs published between 1988 and 2008 examined the use of IAHA for chronic painful shoulder in a total of 2,120 patients. (37) A variety of shoulder disorders were included, e.g., adhesive capsulitis, rotator cuff tear, shoulder impingement syndrome, and frozen shoulder. Sample size ranged from 20 to 660 patients, mean trial duration was 3.5 weeks, and mean Jadad score was 3.5 ± 1.5. Ten trials (1,435 patients) reported pain outcomes. The combined effect size (standardized mean difference) for categorical and continuous pain ratings favored IAHA (0.39, (95% CI: 0.26, 0.53)). There was no heterogeneity and no evidence of publication bias. Because the studies included in the meta-analysis were of short duration and included a variety of shoulder diseases, they do not provide conclusive evidence of the effectiveness of IAHA in OA of the shoulder.


Data from small pilot studies, and case series have been reported using hyaluronan for arthritis of the spine and for lateral condylitis of the elbow (tennis elbow).

Ongoing Clinical Trials

A search of online site in January 2012 identified 4 open Phase III or IV trials evaluating IAHA for OA of the knee (NCT01372475, NCT01295580, NCT01335321 and NCT01510535).

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers (6 reviewers) while this policy was under review in 2011. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Most reviewers agreed with the conclusions of this policy. In addition, those providing input supported the interval between and criterion for repeat injections. In response to a question about total number of treatment courses, there was no consensus; several noted that continued patient improvement with repeat treatment is an important finding.


Intra-articular injection of hyaluronan (IAHA) into osteoarthritic joints is thought to replace hyaluronan, restore the viscoelastic properties of the synovial fluid, and improve pain and function. The largest amount of evidence is on treatment of OA of the knee. Individual trials show inconsistent results in pain and functional outcomes for IAHA compared to placebo or active control. Meta-analyses of RCTs, however, support the clinical effectiveness of IAHA in OA of the knee. In general, studies report that IAHA had later onset but longer duration of action compared to intra-articular corticosteroid injections. A recent RCT found repeated injections of IAHA progressively increased the number of patients responding to IAHA. A positive carry-over effect for up to 1 year was also noted after repeated injections of IAHA. Therefore, based on a compilation of available evidence, IAHA injections for osteoarthritis of the knee appear to reduce pain and improve health outcomes and may be considered medically necessary.

IAHA continues to be investigated for off-label uses in other joints. Current evidence on these off-label uses is limited, consisting of small RCTs and case series. Some RCTs on IAHA injections for OA of the ankle, foot, hand and shoulder have shown treatment benefits; however, these studies are not consistent in reporting improvements that are significantly greater than placebo and/or control treatments. RCTs on IAHA injections for OA of the hip have also been inconsistent, with some RCTs reporting improvements in outcomes with IAHA hip injections and others reporting no improvement. Currently, given the limited and inconsistent available data, these uses are considered investigational.

Practice Guidelines and Position Statements

In 1995, the American College of Rheumatology (ACR) published guidelines for the treatment of osteoarthritis (OA) of the knee, which recommended acetaminophen as first-line therapy, followed by low-dose ibuprofen, and then full-dose nonsteroidal anti-inflammatory drugs (NSAIDs), when necessary. In 2000, the ACR published updated guidelines on the management of hip and knee OA. (38) These guidelines recommend nonpharmacologic approaches and drug therapy for management of hip and knee OA. Intra-articular hyaluronan or glucocorticoids are considered alternative approaches to oral agents for knee OA based on studies demonstrating effectiveness in reducing knee pain. However, the guidelines note there aren’t any studies demonstrating the efficacy of intra-articular hyaluronan or glucocorticoids for hip OA.

The Osteoarthritis Research Society International (OARSI) guidelines, (39) developed by consensus after review of existing guidelines and systematic reviews, recommend:

Injections of IA [intra-articular] hyaluronate may be useful in patients with knee or hip OA [osteoarthritis]. They are characterised by delayed onset, but prolonged duration, of symptomatic benefit when compared to IA injections of corticosteroids.

The recommendation is made with a strength of 64% (CI: 43–85%).

The 2009 Bannuru et al. meta-analysis (13), noted above, was cited in a 2010 evidence update by OARSI. (40) In an accompanying editorial, OARSI authors note that IAHA “has a time-dependent trajectory of therapeutic effect. Thus, the time point at which its outcome is assessed will influence its apparent effectiveness.” (41)

The American Academy of Orthopaedic Surgeons’ (AAOS) 2008 guideline on the non-arthroplasty treatment of OA of the knee indicates a recommendation cannot be made for IAHA for mild to moderate symptomatic knee OA. (42) The guideline notes available evidence is inconclusive. However, this AAOS guideline does indicate intra-articular corticosteroid injections are suggested for short-term pain relief for symptomatic knee OA based on fair evidence.

The 2009 AAOS Clinical Practice Guideline on glenohumeral joint osteoarthritis (43) includes a weak grade C recommendation that “the use of injectable viscosupplementation is an option when treating patients with glenohumeral [shoulder] osteoarthritis.” Grade C recommendations are based on poor-quality evidence. In this instance, the recommendation is based on a single case series of 30 patients with OA of the glenohumeral joint who received 3 weekly IA injections of Synvisc. (44) At 1, 3, and 6 months, clinically significant improvements were seen in pain, function, and quality of life measures.

Guidelines published by the National Institute for Health and Clinical Excellence (NICE) do not recommend IAHA injections for the treatment of OA because “the cost-effectiveness estimate is outside the realms of affordability” to the National Health Service. (45) However, guideline developers state, “Overall, the evidence suggests that hyaluronans and hylan derivatives seem to be superior to placebo in terms of efficacy and quality of life outcomes in patients with OA in the knee at different post-injection periods but especially at the 5- to 13-week post-injection period.” Toxicity of IAHA was noted to be small.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered please note that member contract language will take precedence over medical policy when there is a conflict.

ICD-9 Codes

715.16, 715.26, 715.36,715.96

ICD-10 Codes
M17.0 – M17.9, 3E0U3GC
Procedural Codes: 20610, J7321, J7323, J7324, J7325, J7326
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  14. 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):611-9.
  15. Chevalier X, Jerosch J, Goupille P et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis 2010; 69(1):113-9.
  16. Jorgensen A, Stengaard-Pedersen K, Simonsen O et al. Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis 2010; 69(6):1097-102.
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  18. Skwara A, Peterlein CD, Tibesku CO et al. Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study. Knee 2009; 16(6):466-72.
  19. Navarro-Sarabia F, Coronel P, Collantes E et al. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis 2011; 70(11):1957-62.
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  24. Degroot H, 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 2012; 94(1):2-8.
  25. Migliore A, Giovannangeli F, Bizzi E et al. Viscosupplementation in the management of ankle osteoarthritis: a review. Arch Orthop Trauma Surg 2011; 131(1):139-47.
  26. Munteanu SE, Zammit GV, Menz HB et al. Effectiveness of intra-articular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first metatarsophalangeal joint osteoarthritis: a randomised placebo-controlled trial. Ann Rheum Dis 2011; 70(10):1838-41.
  27. Stahl S, Karsh-Zafrir I, Ratzon N et al. Comparison of intraarticular injection of depot corticosteroid and hyaluronic acid for treatment of degenerative trapeziometacarpal joints. J Clin Rheumatol 2005; 11(6):299-302.
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  35. Atchia I, Kane D, Reed MR et al. Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis. Ann Rheum Dis 2011; 70(1):110-6.
  36. 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 2008; 90(5):970-9.
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April 2012  Policy updated with literature review; Rationale section extensively reordered; reference numbers 14, 19, 22-26, 35, 38 and 42 added; policy statements changed from not medically necessary to investigational
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Hyaluronan Injections for Osteoarthritis of the Knee