Intra-articular hyaluronic acid produces a small but significant non-clinically meaningful reduction in knee pain in osteoarthritis
The use of intra-articular hyaluronic acid (HA) gives rise to a small but significant increase in knee osteoarthritis pain compared to placebo although this reduction is less than the minimal clinically important difference and therefore does not support its use. This was the conclusion of a systematic review and meta-analysis by Swiss and Canadian researchers.
Osteoarthritis is a degenerative or ‘wear and tear’ condition and which globally affects around 16% of the population aged 15 and over and 22⋅9% of those aged 40 and over. One form of treatment which has been termed viscosupplementation, is intra-articular hyaluronic acid and although it seems to be provide clinically meaningful benefits to a large number of patients, emerging evidence indicates that the apparent effectiveness is largely a result of other factors, including the placebo effect. Nevertheless, a 2021 economic evaluation suggested that intra-articular hyaluronic acid may reduce the use of pain medications, such as non-steroidal anti-inflammatory drugs and opioids and thus potentially decreasing the overall treatment costs for knee OA over time. Furthermore, a recent US study found that despite the 2013 American Academy of Orthopaedic Surgeons clinical practice guideline recommending against the clinical utility of hyaluronic acid, services continued to be widely implemented among Medicare beneficiaries. With its widespread use yet apparent lack of evidence, for the present study, the research team decided to perform a systematic review and meta-analysis to examine the evidence on the clinical benefits and safety of the intervention.
The researchers searched for randomised or quasi-randomised trials in which at least 75% of participants had clinically or radiologically confirmed knee osteoarthritis and where outcomes such as pain, function or adverse events were reported. They set the primary outcome as pain intensity and function and serious adverse events as the two secondary outcomes. Continuous outcomes were analysed as standardised mean differences (SMDs) such that when the SMD was > 0, this was indicative of a better outcome for HA. The researchers also determined that the minimal clinically important difference for HA was -0.37.
Hyaluronic acid and pain intensity
A total of 169 trials with 9,423 participants (mean age of 62 years, 59% women) and a mean disease duration of 5.2 years were included in the analysis. The median follow-up time for patients after their HA injection was 13 weeks and 12 weeks for functional assessment.
Based on 24 trials (8997 randomised patients), there was a small, significant but non-clinically relevant reduction in pain intensity after HA injection (SMD = -0.08, 95% CI -0.15 to -0.02, p = 0.02). Based on a 100 mm visual analogue pain scale, this equated to a 2 mm reduction in scores compared to placebo.
For the secondary outcome of function, the pooled estimate was a SMD of -0.11 (95% CI -0.18 to -0.05, p = 0.001) which again was much lower than the minimally important difference. In terms of adverse effects, the use of HA was associated with a significant increased risk of serious adverse events compared to placebo (relative risk = 1.49, 95% CI 1.12 – 1.98, p = 0.003). Overall, 3.7% of patients receiving HA and 2.5% of those given a placebo experienced a serious adverse event.
The authors concluded that HA was associated with a clinically irrelevant reduction in pain intensity and suggested that their findings do not support the broader use of this intervention for knee osteoarthritis.
Pereira TV et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis BMJ 2022