Extract proved effective in managing knee pain but made no mark on effusion-synovitis

A randomized, double-blind, placebo-controlled trial found that extract from the curcuma longa (CL) plant — or turmeric, as it’s known in the kitchen — bested placebo in reducing knee pain in patients with symptomatic knee osteoarthritis (OA); however, it had no notable impact on knee structural measures, researchers found.

Given the lack of approved disease-modifying drugs on the market for osteoarthritis and the limitations of traditional therapy options, including acetaminophen and nonsteroidal anti-inflammatory drugs, there is a need for safe and effective drugs to control OA symptoms, explained Benny Antony, PhD, of the Menzies Institute for Medical Research at the University of Tasmania in Tasmania, Australia, and colleagues, whose study was published in Annals of Internal Medicine. And, since effusion-synovitis assessed via magnetic resonance imaging (MRI) and ultrasonography is associated with structural and clinical progression of OA, Antony and colleagues reasoned that CL extract — particularly its principal component, curcumin, which the investigators noted is “highly pleiotropic, with anti-inflammatory, analgesic, antioxidant, anticancerous, and wound-healing properties” — might be an ideal treatment for OA patients with local inflammation.

So, Antony and colleagues set out to assess the efficacy of CL extract versus placebo for reducing knee symptoms and effusion-synovitis among OA patients.

“Compared with placebo, CL modestly but statistically significantly reduced knee pain over 12 weeks, as assessed by both VAS [visual analogue scale] and WOMAC [Western Ontario and McMaster Universities Osteoarthritis Index], with no increase in adverse events; however, it did not change effusion–synovitis volume or cartilage composition as assessed by MRI,” Antony and colleagues reported.

The study by Antony and colleagues was conducted in a single center and recruited 70 participants from southern Tasmania, Australia who had symptomatic knee OA and ultrasonography-defined effusion-synovitis. Of these, 36 participants were randomized to receive two 500 mg capsules of CL extract per day over the course of 12 weeks, while the remaining 34 participants were randomized to placebo. In order to be eligible for the study, patients had to be more than 40 years old and have knee pain of at least 40 mm on a VAS, clinical knee OA defined according to the American College of Rheumatology clinical criteria, and ≥4 mm effusion depth in the suprapatellar region on ultrasound. Following clinical and ultrasonographic examination, one of the patient’s knees was nominated as the “study knee” to be evaluated over the course of the trial; if both knees proved eligible, the more symptomatic knee was chosen.

Study participants were asked to continue therapy with medications they were receiving at baseline for the duration of the trial, and they were asked to keep their medication use as stable as possible during the study; “any medication changes were documented with the reason, drug name, and dose and were classified as commenced or increased, discontinued or decreased, or stable use or non-use,” they wrote.

The two primary endpoints were changes in knee pain on VAS and effusion-synovitis volume on MRI, while the key secondary endpoints were change in WOMAC pain and cartilage composition values. Antony and colleagues noted that they estimated the sample size on the basis of the minimum clinically important difference (MCID) for VAS knee pain. They powered the study to detect an MCID of 18 mm between CL and placebo on the 100-mm VAS pain scale.

“CL improved VAS pain compared with placebo by −9.1 mm (95% CI, −17.8 to −0.4 mm [P= 0.039]) but did not change effusion–synovitis volume (3.2 mL [CI, −0.3 to 6.8 mL]). CL also improved WOMAC knee pain (−47.2 mm [CI, −81.2 to −13.2 mm]; P= 0.006) but not lateral femoral cartilage T2 relaxation time (−0.4 ms [CI, −1.1 to 0.3 ms]),” Antony and colleagues reported. Adverse event incidence was similar between the CL (n=14 [39%]) and placebo groups (n=18 [53%]; P=0.16), they added; while the risk for reporting at least one adverse event was 17 percentage points lower in the CL group than in the placebo group (CI, −40.1 to 6.1 percentage points), this difference was not clinically significant (P=0.149). Two adverse events in the CL group and 5 in the placebo group were considered treatment related.

Notably, nine participants in the placebo group began or increased pain medication treatment over the course of the study compared with four in the CL group; meanwhile, four participants in the CL group and none in the placebo group discontinued or decreased their use of pain medication.

Antony and colleagues pointed out that the effect of 9.1 mm between the treatment groups indicated a moderate effect size for pain reduction with CL extract, but they noted that this result was “a magnitude smaller than the MCID (18 mm) for which the study was powered.” While this might suggest that the pain reduction seen in this study is not of clinical importance, the study authors pointed out that the first recommended drug therapy in knee OA treatment guidelines until 2019 was paracetamol, “which reportedly showed only a 3.7-mm difference on a 100-mm scale and had a less favorable safety profile.”

The most commonly used drug categories, including acetaminophen, cyclooxygenase-2 (Cox-2) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDS), have SMDs ranging from 0.18 to 0.44,” they added. “The pattern of increased pain medication use in the placebo group and decreased use in the CL group may have reduced the between-group difference in change in pain in our study. Overall, these results suggest that the modest effect on knee pain in our study may be clinically relevant and that CL may be a treatment option for man-aging knee osteoarthritis symptoms.”

The study data were contrary to the authors’ hypothesis that CL would work best in patients with more local inflammation — change in effusion-synovitis volume and cartilage composition were similar between the CL and placebo groups, “indicating that CL had no effect on the structural measures of osteoarthritis,” they wrote. “In post hoc analyses, participants with a lower effusion–synovitis volume at baseline had reductions in pain whereas pain did not change for those with a higher effusion–synovitis volume, which is an important hypothesis-generating finding. A possible explanation is that participants with a higher effusion–synovitis volume may have more severe disease.”

The study authors pointed out that the study’s relatively short duration and moderate sample size were both limitations. They also noted that the effect on pain, while statistically significant, was only moderate, making the clinical importance of the reduction uncertain. “Multicenter trials with larger sample sizes are needed to assess the clinical significance of these findings,” Antony and colleagues wrote.

  1. Curcuma longa (CL) extract outperformed placebo in reducing knee pain in patients with knee osteoartiritis.

  2. Note that CL extract did not change effusion–synovitis volume or cartilage composition as assessed by MRI, and that the effect on pain, while significant, was only moderate and therefore has uncertain clinical importance.

John McKenna, Associate Editor, BreakingMED™

The trial received partial funding from Natural Remedies Pvt Ltd; Natural Remedies provided Curcuma longa extract and placebo capsules.

Antony reports grants and non-financial support from Natural Remedies Pvt Ltd, during the conduct of the study.

Cat ID: 158

Topic ID: 90,158,393,438,730,141,192,94,158,68,925