The use of gold and gold-containing compounds in medicine can be traced back thousands of years in certain cultures. Gold salts have previously been shown to reduce pain, swelling, and inflammation, but caution must be exercised when considering its use – gold salts have toxic effects on the kidneys, liver, and skin. Over the last decade, several studies have reported higher pain thresholds in both healthy and osteoarthritic animals following gold particle injections, with one study using intra-articular injections.
Now, a new exploratory and proof-of-concept study led by Sten Rasmussen (Department of Clinical Medicine, Aalborg University, Denmark) demonstrates how gold microparticles have a similar effect in humans. The administration of intra-articular gold microparticle injections in patients experiencing knee osteoarthritis was found to reduce pain and inflammation for up to two years.
Finding novel therapeutics for osteoarthritis is an important area, according to Philip Conaghan (professor of musculoskeletal medicine at the University of Leeds School of Medicine, UK). Conaghan is a rheumatologist with expertise in the treatment of osteoarthritis but was not involved in this current study.
“Osteoarthritis is in desperate need of new therapies that reduce pain and improve function,” Conaghan told PRF. “Gold has demonstrated molecular anti-inflammatory effects in animal studies, and rheumatologists are aware that gold was used for many years as a treatment for arthritis-associated inflammation.”
This research was published in the European Journal of Pain on 25 January 2022.
How Can Gold Be Used in Medicine?
Many ancient cultures used gold-based therapeutics for a variety of health conditions, such as skin ulcers and measles. During the 20th century, a variety of gold-based salts were used to treat rheumatoid arthritis, with good effect. In animal models, macrophages attach to the surfaces of gold particles and dissolve, releasing gold ions in the intracellular space. Mast cells, fibroblasts, and other macrophages take up these gold ions, which inhibits the release of the inflammatory mediator histamine (Danscher, 2002).
Toward the end of the 20th century, the reported benefits of using gold to treat rheumatoid arthritis were highly variable. Consequently, doubts about its clinical benefit grew, and its use declined. However, a review of randomized clinical trials comparing gold injections against placebo in patients with rheumatoid arthritis identified clinically and statistically significant short-term benefits for these patients (Clark et al., 2000).
Lead author Sten Rasmussen is no stranger to seeing gold microparticles used to treat osteoarthritis and other degenerative diseases.
“More than 20 years ago, my neighbor and colleague treated chronic degenerative lumbar spine patients with gold particles, as well as patients with osteoarthritis around the hip and knees. I often removed gold particles when performing lumbar spinal fusions or completing a hip or knee arthroplasty,” Rasmussen told PRF via email.
“But it was never documented or reported in a peer-reviewed journal whether the gold particle treatment was effective or not.”
Animal studies in dogs and horses in the early 21st century (Jæger et al., 2007Märki et al., 2018) showed the beneficial effects of gold microparticle injection, paving the way for human studies to explore potential anti-inflammatory and pain-reducing mechanisms.
“Based on the knowledge that gold ions accumulated in macrophages, I came up with the idea to treat osteoarthritis pain with intra-articular gold,” said Rasmussen.
Putting the Theory to the Test
Rasmussen and his colleagues recruited 30 patients with radiographically confirmed knee osteoarthritis (18 men and 12 women, mean age of 62 years) who reported experiencing pain for more than three months. Patients were excluded if they were currently receiving steroid or other anti-rheumatic treatment, or if they were experiencing chronic pain at other sites aside from their knee.
All patients completed three study visits: an initial appointment where baseline measures were recorded and treatment was administered, and two follow-up appointments at eight weeks and two years post-treatment.
During the initial visit, a small amount of synovial fluid was removed from the knee joint and mixed with pure gold microparticles prior to re-injection.
“Initially, we had planned to use hyaluronic acid as the carrier for the gold microparticles, but several studies have shown hyaluronic acid is effective in treating osteoarthritis pain,” Rasmussen explained.
“We wanted to prove that inflammation causes osteoarthritis pain. As gold is not analgesic, we predicted that any reduction in pain would be due to a reduction in inflammation. So we decided to use the patient’s synovial fluid as the carrier instead.”
The primary outcome measure for the study was the change in Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores at the eight-week follow-up compared to baseline. The WOMAC is a widely used questionnaire designed to measure pain, stiffness, and function in patients with knee or hip osteoarthritis.
Additional outcome measures included changes in the PainDetect questionnaire, quantitative sensory testing measures (including pressure pain threshold over the knee joint), and a weekly pain diary. Synovial fluid and blood samples were taken at two timepoints (before the injection of gold microparticles and at the eight-week follow-up) and subjected to proteome analysis to examine changes in gene and protein regulation following the treatment administration.
Gold Microparticles Are Associated With Reductions in Pain and Inflammation
Eight weeks after the injection of gold microparticles, patients reported lower scores on the WOMAC pain, stiffness, and activity subscales – representing lower levels of pain and stiffness, and improved function. Patients also reported lower scores on the PainDetect questionnaire, implying their pain was less severe compared to baseline. The improvements in WOMAC and PainDetect scores persisted when patients returned for their two-year follow-up.
Pressure pain thresholds – the point at which mechanically applied pressure is first perceived as painful – measured at the knee increased by 17.5% at the eight-week follow-up compared to baseline.
Complementing the questionnaires and quantitative sensory testing measures were the proteomic results of the synovial fluid samples. Nearly 40 different genes and proteins displayed a significant change eight weeks after the injection of gold microparticles. Most of these genes and proteins – which were associated with increased inflammation and degeneration – were downregulated compared to baseline levels.
Proteomic analysis revealed decreases in interleukin-6, a pro-inflammatory mediator with elevated levels in osteoarthritis patients. Decreases were also observed for cell division control protein 42 homolog (CDC42), a protein found to be associated with cartilage degeneration in mouse models of osteoarthritis. There were beneficial upregulations in gene and protein activity, such as Golgi membrane protein 1, that reduce inflammation through processes associated with immune cells.
Don’t Start Panning for Gold Straight Away
Although these findings may sound promising, there are important limitations that need to be considered. The main limitation is that this was a small and unblinded exploratory study without a control group, meaning the current study may overestimate the effects of the gold treatment.
“The osteoarthritis field is bedeviled by small, uncontrolled studies which have not translated to successful large randomized controlled trials,” Conaghan explained. “Overall, the pattern of pain response was very similar to that seen in most randomized control trials with both active and placebo arms.
“While these results are interesting, it would be important to understand both the potential toxicity and the scalability or cost of the potential therapy before considering a large trial,” Conaghan elaborated.
Rasmussen is aware of these limitations but is encouraged by the preliminary results. He has plans to continue this line of research in a more rigorous fashion.
“This study proves inflammation is a major cause of osteoarthritis pain, and that gold has a long-lasting effect. I am already planning a double-blinded randomized controlled trial [for the use of gold] with one- and two-year follow-ups.”
Only time will tell whether gold microparticles will provide a much-needed treatment option for patients with osteoarthritis or if it turns out to be fool’s gold.
Lincoln Tracy is a researcher and freelance writer based in Melbourne, Australia. You can follow him on Twitter – @lincolntracy.