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Hyaluronates and Viscosupplementation

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Introduction

Osteoarthritis (OA) is the most common chronic joint disorder and is associated with pain, disability and reduced levels of hyaluronic acid in affected joints. Intra-articular injections of sodium hyaluronate (also called viscosupplementation) have been shown to be safe and effective at relieving pain in osteoarthritis of the knee. They are being used extensively in the United States and the number of randomised controlled trials on their efficacy is growing.1 The United Sates Food and Drugs administration (FDA) has approved several intra-articular versions of sodium hyaluronate (HA), the first having been approved in 1997 for use in the knee. They have been classified in the United States as 'medical devices' rather than drugs. There are 8 licensed versions in the United Kingdom.

Products available

Products so far available include:

  • Non-cross-linked sodium hyaluronate:
    • Hyalgan, Supartz, Orthovisc- derived from chicken combs
    • Euflexxa-derived from a fermentation process involving a Streptococcus spp.
  • Cross-linked sodium hyaluronate:
    • Hylan G-F 20 or Synvisc
Mode of action

The mode of action is not fully understood. Although the substance persists in the joint only for days the benefits can last months. It is postulated that there may be a biological, possibly immunological, basis for this. Possible mechanisms include:

  • Increased endogenous hyaluronate2
  • Blocking of pain receptors
  • Inhibition of pain mediators (prostaglandins, bradykinin)
  • Anti-inflammatory effects
  • An effect on immune cells
  • Antioxidant action
  • Physical effects (viscosity, lubrication and elasticity)
Efficacy

A recent Cochrane review concluded that viscosupplements were:3

  • Comparable in efficacy to systemic treatments but with more local reactions and fewer systemic adverse events.
  • More long lasting in their beneficial effects (up to 26 weeks) than intra-articular steroids (although slower in onset of effect).4
  • Most effective between 5 and 13 weeks after injection.
  • Different in their effects between products (but without any clear comparisons possible between products).



Overall this review and others support the use of hyaluronates in the treatment of osteoarthritis of the knee.1,3,5 It does not yet seem possible to recommend one product above another.6

Viscosupplementation is expensive and not yet proven to be cost effective. It has not been shown to be more effective than NSAIDs, intra-articular steroids or physiotherapy. It has not been shown whether the benefits are sustained with repeat courses of treatment. It may be a costly and labour intensive alternative to these other options.

The NICE guidance for osteoarthritis has reviewed the efficacy of hyaluronates in some detail.7 They conclude that the research evidence on the efficacy of hyaluronates is difficult to interpret because of:

  • Different molecular weights of the hyaluronates.
  • Different injection schedules (ranging from once weekly to a series of five injections).
  • Poor trial design despite large numbers of studies, for example lack of intention-to-treat analyses, limitations in blinding.

On balance, the NICE guidance suggests a benefit for reducing pain up to 3 months after a series of three to five injections (although the effect size is generally small) BUT that the efficacy would have to be three to five times higher than the estimates from the trials before reaching the standard threshold for cost effectiveness to the NHS.7

Indications

Osteoarthritis of the knee where:

  • Current treatment not giving adequate pain relief
  • Other treatments such as anti-inflammatories are contraindicated
  • Surgical options not available
  • Patients on multiple oral medications

Hyaluronates are also being used in osteoarthritis of the hip, for example to delay surgery, but more studies are needed.8 There is even less experience of use in other joints.

Initiation and administration

The preparations are administered into the knee joint under aseptic conditions after aspiration of any effusion. Depending on the product used between 3 and 5 injections are given over several weeks. Usually no more than 3 treatments per year are recommended. It is important to emphasise to patients that:

  • It does not have an immediate effect
  • Local reactions after the injection are common (apply ice pack)
  • Avoid jogging, standing and heavy lifting for 48 hours after the injection
  • Beneficial effects may last for several months
  • Viscosupplementation does not work for all patients
  • It is very expensive and has not yet been demonstrated to be cost effective
Contraindications and cautions
  • Allergy to products from birds (for example feathers)
  • Children- Synvisc not tested in children
  • Pregnancy and breast feeding
Common interactions

None listed.

Side effects

They appear to be generally well tolerated. The most common side effect is injection site pain and/or swelling. Rashes appear to be rare. A Cochrane review concluded that within the constraints of trial designs no major safety issues were detected.3 Septic arthritis after hyaluronate injection has been reported but infection is uncommon.9


Document references
  1. Divine JG, Zazulak BT, Hewett TE; Viscosupplementation for knee osteoarthritis: a systematic review. Clin Orthop Relat Res. 2007 Feb;455:113-22. [abstract]
  2. Bagga H, Burkhardt D, Sambrook P, et al; Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol. 2006 May;33(5):946-50. [abstract]
  3. Bellamy N, Campbell J, Robinson V, et al; Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD005321. [abstract]
  4. Aggarwal A, Sempowski IP; Hyaluronic acid injections for knee osteoarthritis. Systematic review of the literature. Can Fam Physician. 2004 Feb;50:249-56. [abstract]
  5. Shoor S; Review: Viscosupplementation for knee osteoarthritis reduces pain and improves function. Evid Based Med. 2006 Feb;11(1):12.
  6. Kotevoglu N, Iyibozkurt PC, Hiz O, et al; A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatol Int. 2006 Feb;26(4):325-30. Epub 2005 Jun 15. [abstract]
  7. Osteoarthritis, NICE Clinical Guideline (January 2008); The care and management of osteoarthritis in adults
  8. Conrozier T, Vignon E; Is there evidence to support the inclusion of viscosupplementation in the treatment paradigm for patients with hip osteoarthritis? Clin Exp Rheumatol. 2005 Sep-Oct;23(5):711-6. [abstract]
  9. Albert C, Brocq O, Gerard D, et al; Septic knee arthritis after intra-articular hyaluronate injection. Two case reports. Joint Bone Spine. 2006 Mar;73(2):205-7. Epub 2005 Jun 23. [abstract]

Internet and further reading
  • Osteoarthritis, Clinical Knowledge Summaries (2008)
  • Osteoarthritis, NICE Clinical Guideline (January 2008); The care and management of osteoarthritis in adults
Acknowledgements EMIS is grateful to Dr Richard Draper for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2009.
Document ID: 4026
Document Version: 2
Document Reference: bgp25973
Last Updated: 8 May 2009
Planned Review: 8 May 2011

The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest. Find out more about updating.

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