In people with osteoarthritis of the knee, there is a large body of poor quality evidence to suggest that intra-articular injection of hyaluronan/hyaluronic acid (HA) derivatives provide short-term symptomatic relief. Several poor quality studies found that intra-articular HA may reduce pain and improve function compared with placebo, with the greatest effect being up to 13 weeks after injection. Compared with intra-articular corticosteroids, data from three small RCTs suggests that HA may be more effective at reducing pain at 5–13 weeks. No significant differences in adverse effects were found between HA derivatives and placebo. Heterogeneity between trials is partially due to the number of different HA derivatives available. The National Institute for Health and Clinical Excellence (NICE) Guideline Development Group decided that HA use is not currently a cost-effective option for the NHS.

• NICE investigated the efficacy and safety of intra-articular injection of HA (compared with placebo or corticosteroid injection) with respect to symptoms, function, and quality of life in adults with osteoarthritis.
• Two Cochrane reviews were found of people with osteoarthritis of the knee [Bellamy et al, 2006a; Bellamy et al, 2006b]. Four RCTs were found that were published subsequently. One of these RCTs was excluded by NICE due to multiple methodological limitations and the other three RCTs reinforced the findings of the Cochrane reviews, and so are not discussed further.
• The first Cochrane review (40 RCTs, n = 5257) assessed the effects of viscosupplementation (intra-articular hyaluronan and hyaluronan derivatives) compared with intra-articular placebo in people with osteoarthritis of the knee [Bellamy et al, 2006b]. Literature searches were performed up to the end of 2005.
• Intra-articular HA injection compared with placebo:
• In people with osteoarthritis of the knee, the evidence suggested that compared with placebo, HA derivatives generally had superior efficacy in a range of outcomes (pain relief, stiffness in knee, function improvement, patient global assessment, and quality of life) at various time points, but especially in the 5- to 13-week post-injection period.
• The adverse event profiles were generally found to favour placebo. No major safety issues were identified, but sample sizes were limited.
• In people with osteoarthritis of the hip, no significant differences were reported in efficacy and function outcomes between HA and placebo at any time point.
• The effect of HA compared with placebo on weight-bearing pain at:
• 1–4 weeks post injection: significantly improved (22 RCTs: WMD –7.7, 95% CI –11.3 to –4.1, p < 0.0001).
• 5–13 weeks post injection: significantly improved (17 RCTs: WMD –13.0, 95% CI –17.8 to –8.2, p < 0.00001).
• 14–26 weeks post injection: significantly improved (nine RCTs: WMD –9.0, 95% CI –14.8 to –3.2, p = 0.002).
• At 45–52 weeks post injection: no improvement was found (as indicated by three RCTs).
• The effect of HA compared with placebo on Lequesne Index at:
• 1–4 weeks post injection: significantly improved (four RCTs: WMD –0.8, 95% CI –1.5 to –0.2, p = 0.02).
• 5–13 weeks post injection: significantly improved (four RCTs: WMD –1.4, 95% CI –2.0 to –0.7, p < 0.0001).
• At 14–26 weeks post injection or later: no significant difference was found.
• The second Cochrane review (28 RCTs, n = 1973) evaluated the efficacy and safety of intra-articular corticosteroids in people with osteoarthritis of the knee [Bellamy et al, 2006a]. Literature searches were performed up to the beginning of January 2006. Studies differed in the type of HA used, mode of HA production, type of corticosteroid used, treatment regimens, trial design, trial size, and trial duration. The efficacy of HA was often difficult to interpret because of some of these confounders. The Cochrane review pooled all data for symptoms, function and adverse effects but quality of life outcomes were not reported.
• Intra-articular HA injection compared with intra-articular corticosteroid:
• In people with osteoarthritis of the knee, no significant difference in pain levels was found between intra-articular corticosteroids and HA at 1–4 weeks after injection. However, HA was significantly more effective than corticosteroids in reducing pain at 5 and 13 weeks, suggesting that intra-articular HA may have a more prolonged effect:
• At 1–4 weeks after injection (three RCTs [n = 85]: WMD –4.90, 95% CI –9.91 to +0.10, p = 0.05).
• At 5–13 weeks after injection (three RCTs: WMD –7.73, 95% CI –12.81 to –2.64, p = 0.003).
• In people with osteoarthritis of the hip and hand, no significant differences between HA and intra-articular corticosteroids were reported at any time point by the two studies evaluating efficacy and function outcomes.
• There were no significant differences in adverse event outcomes between HA and intra-articular corticosteroids.
• When economically evaluating the role of HA, the NICE Guideline Development Group found that despite the (generally small) beneficial effect of HA, from a cost-effectiveness perspective 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 for the NHS.

[National Collaborating Centre for Chronic Conditions, 2008]