Clinical UM Guideline


Subject: Hyaluronan Injections in the Knee
Guideline #:  CG-DRUG-29 Publish Date:    03/29/2018
Status: Revised Last Review Date:    05/04/2017


This document addresses the use of hyaluronan injections for the replacement or supplementation of naturally occurring intra-articular lubricants in individuals with osteoarthritis in the knees (also referred to as viscosupplementation).

Note: Please see the following related document for additional information:

Clinical Indications

Not Medically Necessary:

The use of intra-articular injections of hyaluronan is considered not medically necessary for osteoarthritis of the knee and for all other knee conditions.


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, per dose


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



ICD-10 Diagnosis



All knee conditions

Discussion/General Information


Osteoarthritis is the degeneration of cartilage and the underlying bone within a joint. This can lead to pain and joint stiffness. The specific causes of osteoarthritis are unknown, but it is believed to be both mechanical and molecular events in the affected joint. 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.”


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 hyaluronan injection seems to derive from the use of intra-articular delivery. 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).


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.


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.


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. Meta-analyses have been published regarding the use of hyaluronan injections for treatment of osteoarthritis of the knee (Bhandari, 2017; Jevsevar, 2015; Nguyen, 2016; Zhao, 2016). In 2015, Jevsevar et al published a systematic review of 19 large, high-quality randomized controlled trials (minimum 30 participants per subgroup) comparing hyaluronan with usual care, totaling 4400 participants, and found high heterogeneity among trials. Double-blinded, sham-controlled trials had much smaller treatment effects than trials that were not sufficiently blinded, and in double-blinded trials, overall treatment effect was less than half the defined minimal important difference. 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.




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.



Peer Reviewed Publications:

  1. Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015; 162(1):46-54.
  2. Bhandari M, Bannuru RR, Babins EM, et al. Intra-articular hyaluronic acid in the treatment of knee osteoarthritis: a Canadian evidence-based perspective. Ther Adv Musculoskelet Dis. 2017; 9(9):231-246.
  3. Hunter DJ. Viscosupplementation for osteoarthritis of the knee. N Engl J Med. 2015; 372(11):1040-1047.
  4. Jevsevar D, Donnelly P, Brown GA, Cummins DS. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am. 2015; 97(24):2047-2060.
  5. Johal H, Devji T, Schemitsch EH, Bhandari M. Viscosupplementation in knee osteoarthritis: evidence revisited. JBJS Rev. 2016; 4(4):e11-e111.
  6. Nguyen C, Lefèvre-Colau MM, Poiraudeau S, Rannou F. Evidence and recommendations for use of intra-articular injections for knee osteoarthritis. Ann Phys Rehabil Med. 2016; 59(3):184-189.
  7. Ong KL, Anderson AF, Niazi F, et al. Hyaluronic acid injections in Medicare knee osteoarthritis patients are associated with longer time to knee arthroplasty. J Arthroplasty. 2016; 31(8):1667-1673.
  8. Tammachote N, Kanitnate S, Yakumpor T, Panichkul P. Intra-articular, single-shot hylan G-F 20 hyaluronic acid injection compared with corticosteroid in knee osteoarthritis: a double-blind, randomized controlled trial. J Bone Joint Surg Am. 2016; 98(11):885-892.
  9. van der Weegen W, Wullems JA, Bos E, et al. No difference between intra-articular injection of hyaluronic acid and placebo for mild to moderate knee osteoarthritis: a randomized, controlled, double-blind trial. J Arthroplasty. 2015; 30(5):754-757.
  10. Waddell DD, Joseph B. Delayed total knee replacement with Hylan G-F 20. J Knee Surg. 2016; 29(2):159-168.
  11. Wang Y, Hall S, Hanna F, et al. Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet Disord. 2011; 12:195.1-9.
  12. Zhao H, Liu H, Liang X, et al. Hylan G-F 20 versus low molecular weight hyaluronic acids for knee osteoarthritis: a meta-analysis. BioDrugs. 2016; 30(5):387-396.

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 April 26, 2017.
  2. 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 April 26, 2017.
  3. Jüni P, Hari R, Rutjes AWS, et al. Joint corticosteroid injection for knee osteoarthritis. Cochrane Database Syst Rev. 2015;(10):CD005328.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Arthritis. October 2015. Available at: Accessed on April 26, 2017.
  2. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Osteoarthritis. May 2016. Available at: Accessed on April 26, 2017.


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.







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



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



Medical Policy & Technology Assessment Committee (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.