VIENNA — Data do not back the use of diacerein or resveratrol for managing the pain of knee osteoarthritis (OA), according to the results of two well-performed, multicenter, double-blind, randomized controlled clinical trials.
During the News in Therapies session at the OARSI 2024 World Congress, the null findings of the DICKENS study and ARTHROL trial were presented alongside a reappraisal of the possible role of botulinum toxin.
DICKENS Study of Diacerein
“The role of diacerein in the treatment of OA is controversial,” acknowledged Dawn Aitken, PhD, associate professor at the University of Tasmania in Hobart, Tasmania, Australia. “There are only a few acceptable quality trials to date, and the results are inconsistent,” Dr. Aitken added.
Indeed, a Cochrane review performed in 2014 had concluded that there was “low-quality evidence that diacerein had a small beneficial effect on pain,” she said. The reported overall effect size on a 100-mm visual analog scale, based on a meta-analysis of 10 trials, has been just −8.65 mm, equating to just a 9% pain reduction.
Bruce Jancin/MDedge News
Dr. Dawn Aitken
At the time the DICKENS study was conceived, diacerein was recommended by a number of international guidelines for the management of hip and knee OA, although further, higher-quality studies were needed.
Diacerein blocks interleukin-1 beta, which is one of the key inflammatory markers of OA, so Dr. Aitken and collaborators postulated that perhaps it would work better if used in patients with an inflammatory phenotype.
They set about to test their hypothesis by recruiting 260 individuals with knee OA and MRI-detected effusion synovitis. The participants were then randomly allocated to treatment with either diacerein or a matching placebo for 24 weeks.
Individuals in the diacerein group were treated with an oral dose of 50 mg once daily for the first 2 weeks. If tolerated, the dose was increased to 50 mg twice daily.
No significant improvement in the primary endpoint of knee pain was seen comparing diacerein with placebo, with mean values of 53.2 mm and 56.4 mm, respectively, at 24 weeks using a 0-100 mm visual analog scale where 0 represented no pain and 100 represented the worst pain. It followed that there was no significant difference in the change from baseline to week 24 (−19.9 mm vs −18.6 mm; P = .77).
There was also no difference in the secondary endpoints, which included Western Ontario and McMaster Universities Arthritis Index pain, function, and stiffness. In fact, placebo-treated patients appeared to do better in terms of resolution of effusion synovitis as measured by a repeat MRI and quality of life, Dr. Aitken reported.
“These findings do not support the use of diacerein in treating patients with knee OA and effusion synovitis,” Dr. Aitken concluded.
ARTHROL Trial of Resveratrol
Similarly, negative results were reported for resveratrol from the ARTHROL trial, with 55% of the resveratrol- and 55% of placebo-treated individuals achieving a 20% reduction in knee pain intensity at 3 months. The actual change in knee pain from baseline to 3 months was −15.7 for resveratrol and −15.2 for placebo on a numerical rating scale that went from 0 (no pain) up to 100 (worst pain).
Resveratrol is found naturally in grapes, peanuts, pine cones, and Chinese knotweed, and there is a growing body of evidence that it may have pleiotropic effects, said investigator Christelle Nguyen, PhD, MD, a professor of physical and rehabilitation medicine at Université Paris Cité, Paris, France.
It’s available in a powder form over the counter as a treatment for multiple ailments, but more recently, became available as an oral formulation. Dr. Nguyen and colleagues wanted to know if this would make a difference to OA knee pain when added to usual care.
A double-blind, multicenter, placebo-controlled randomized trial was therefore conducted that involved 142 people with knee OA who had been experiencing knee pain for at least 1 month. The participants were equally randomly allocated to receive either oral resveratrol given as two caplets of 20 mg twice daily for the first week, then once daily for a total of 6 months, or a matched placebo.
There was also no effect of resveratrol vs placebo on a host of secondary outcomes measured at 3 and 6 months.
The interpretation is that oral resveratrol may not be effective in this indication or have a biologic effect on the pain pathway, Dr. Nguyen said.
Sara Freeman/Medscape Medical News
Dr. Christelle Nguyen
“Our findings do not support the use of [trans-resveratrol] supplementation in this patented formulation for reducing knee pain in adults with painful knee OA,” she concluded.
Botulinum Toxin: Over But Not Out?
Dr. Nguyen separately reported data from a new systematic review and meta-analysis on the use of intra-articular (IA) botulinum toxin type A (BoNT-A) for knee OA pain.
Seven of the 14 randomized controlled trials included in the meta-analysis had looked specifically at knee OA outcomes in the short, intermediate, and long term.
Results showed a nonsignificant trend favoring BoNT-A use, with the standard mean difference in pain of 0.35 (−0.82; 0.12), −0.27 (−0.61; 0.08), and −0.43 (−1.12; 0.26) for short-, intermediate-, and long-term use, respectively.
In contrast, pain reductions were seen with BoNT-A in three trials that included people with OA of the shoulder or base of the thumb. This begs the question as to whether botulinum toxin may still have a role to play, Dr. Nguyen said in an interview.
“It seems like there may be a positive effect for the shoulder joint and base of the thumb,” she told this news organization.
“So, basically, we found differences between large and small to intermediate joints,” Dr. Nguyen added. “It questions the dilution of botulinum toxin into the joint. If it’s a big joint, maybe the dilution is too high,” she suggested.
This hypothesis will be tested in the upcoming RHIBOT II trial that will begin recruitment later this year. This is a follow-on from the RHIBOT trial that was published in The Lancet Rheumatology 2 years ago.
Meanwhile, the use of botulinum toxin is off-label, Dr. Nguyen said. “We use it in our clinics only when first-line treatment had failed for base of thumb OA.” It’s not offered as a stand-alone intervention, and the IA injections need to be given by someone with experience, she said.