Hyaluronates and Viscosupplementation

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 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

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)

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

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.

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

• Allergy to products from birds (for example feathers)
• Children- Synvisc not tested in children
• Pregnancy and breast feeding

None listed.

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