The aim of this study is to use gold particles as a model compound to modulate specifically and selectively the function of macrophages and mast cells and investigate how this modulates pain and pain sensitization in the osteoarthritic knee assessed by mechanistic pain assessment technologies

Osteoarthritis (OA) of the knee and hip is the most common musculoskeletal joint disease worldwide. Although a major symptom of OA is chronic joint pain, which has a significant effect on patients' quality of life, the pain mechanisms remain largely unknown.

Recently, clinical studies have suggested the existence of a neuropathic component in OA pain [5]. Accumulating evidence has been indicating that painful OA patients show peripheral and central sensitization [3,16]. Quantitative sensory testing (QST) is a relevant way to assess peripheral and central sensitization in joint pain [9]. The majority of studies have administered mechanical stimuli, and the most commonly used modality have been pressure. A recent review concluded that that people with OA have lower Pressure Pain Thresholds (PPT), facilitated temporal summation and impaired conditioned (CPM) compared with healthy controls [5]. Also, recent evidence have link QST profiles to the development of chronic pain [29,38], which emphasises the importance of studying the central nervous system.

Inflammation markers have been correlated with the pain intensity [35], and systemic inflammation can leads to sensitization of peripheral nociceptors [1]. Recently it was reported that higher preoperative levels of TNF-α, MMP-13 and IL-6 in synovial fluid may indicate a smaller improvement in pain 2 years after TKR [15].

Injectable solutions of gold-thio-compounds have been used to treat rheumatoid arthritis for nearly 100 years [13,21]. Several studies suggest that gold ions reduces pain, joint swelling, inflammation, and increase joint motility [24,31,33]. Gold salt therapy (auranofin; RidauraR) has been vetted by the FDA and approved (May 1985) and recommended by the American College of Rheumatology as a Disease Modifying Anti Rheumatic Drug - DMARD (https://www.rheumatology.org).

Gold salts, whether injected or given orally, have been shown to be effective [33,37] in reducing joint pain. Studies report patients going to total remission [28] and others report a 30% reduction in symptoms [20,27]. In addition, Clark et al., 1997 [8] concluded in a Cochrane meta-analysis that systemic treatment with gold was highly effective compared to placebo.

The use of gold salt given systemically have been criticized, since when gold compounds are made to circulate systemically via the circulatory system after oral or parenteral administration, the gold ions reach essentially all tissues and organs. In some patients, organs that are not involved in the arthritic disease, such as the kidneys, liver, and skin are adversely affected by gold. About 30% of patients develop such remote-organ "side effects" and discontinue gold treatment [20]. In addition, newer drugs have been developed with efficacy almost equal to gold ions in many patients, and less toxic.

To overcome the toxicity, a method that captures the efficacy of the gold ions but eliminates the remote side effects have been developed[10,23]. Briefly, the method isolates the gold ions within the affected joints by injecting solid gold metal directly into the diseased joint, whereby a very slow dissolution and local diffusion deliver the therapeutic gold ions to affected areas within the joint. In this therapy, 99.99% pure gold implants are injected into the body.

Individual single beads are implanted with a 15-16 gauge needle based on an X-ray picture in deeply anesthetized animals close to the capsule of the affected joint(s) (videos www.goldtreat.com). Over 3000 dogs, and more than 100 horses have had this treatment for osteoarthritis at 50+ veterinary clinics and hospitals throughout Europe. (www.goldtreat.com ). Success rates of 50 - 70% are quoted (www.goldtreat.com), and a double-blind, placebo controlled study on dogs showed improvement in over 80% of the dogs, which continues for 18 months [18] as the gold particles remain in the joint[26].

The systemic concentration of released gold ions is low but clinically effective and because the gold ions do not spread in the organism, but instead stay local, the technique is safe [12]. The trials to date indicate that only one local application is needed to obtain lifelong clinical effect [12].

To date it is still debated how much the inflammation per se contributes to pain in osteoarthritis. A variety of studies have investigates various aspects such as synovitis but still no clear associations to pain have been found[30]. Many studies have attempted to modulate the effect of the inflammatory mediators on the pain receptors by e.g. interacting with the arachidonic acid pathways[4]. As such compounds have both peripheral and central effects it is difficult to use such compounds a specific modulators of specific local inflammatory processes. No compounds have so far been used to modulate selectively the local organelles specifically involved in the inflammatory processes of joint pain.

Gold particles seems as the only known method to obtain such a local effect on one specific element involved in the inflammatory process - the macrophages and the mast cells.

If a foreign object gets embedded in the body, macrophages will attack the object and digest it.

If the foreign object has a diameter bigger than 20 microns the macrophage cannot engulf it. Instead the macrophages create a membrane on the surface of the foreign body and starts a chemical attack in order to dissolve it.

If the foreign body consist of gold the macrophages will cause release of gold ions from the foreign body.

Gold ions, taken up by the macrophages, causes them to malfunction[10,11,23]. As the macrophage is 'conductor' of the inflammatory process it causes a drastic restraint of the inflammation and finally bring it to a stop[22,25]. The released gold ions will be taken up by the macrophages themselves, but also diffuse out into the surrounding tissue where they are taken up by other cells as well e.g. mast cells and other connective tissue cells[7,32]. When the gold ions accumulate in the secretory granules of mast cells it blocks histamine release and thereby decrease the local oedema and additionally suppresses pain.

The amount of bio-released gold ions are related to the intensity of inflammation. Only few gold ions are released in immunological nonreactive tissue. This means that if a local inflammation that has been treated with gold implants, the increase in macrophages will cause an immediate inhibition of the inflammation.

The combined effect of gold ions on macrophages and mast cells is together believed to causes the significant reduction in pain following treatment with metallic gold particles. If this principle can be validated it may provide important information for development of new and better treatments for e.g. joint pain.

Recently, Seifert et al.[34] called for studies providing new insights into the mode of action of gold ions and suggest investigating the effects on key mechanisms involved in arthritis or other inflammatory conditions.

Inclusion Criteria:

• Knee OA diagnosed based on the American College of Rheumatology criteria, KL (Kellgren-Lawrence) X-ray grade ≧ 2, pain for > 3months, maximal pain intensity VAS (visual analogue scale) ≧ 5 (0-10 scale) for the most painful knee during the last week. Knee joint effusion that can be aspirated

Exclusion Criteria:

• Pregnancy
• Drug addiction defined as the use of cannabis, opioids or other drugs
• Previous neurologic, musculoskeletal or mental illnesses
• Lack of ability to cooperate
• Current use of medications that may affect the trial e.g. analgesics, anti-inflammatory drugs
• Recent history of acute pain affecting the lower limb and/or trunk
• Past history of a chronic pain condition
• Participation in other pain trials throughout the study period

Inflammatory markers may be shared with other researchers

After publication information is available.

At the reasonable request to Sten Rasmusssen. (sten.rasmussen@rn.dk;s_rasmussen@dcm.aau.dk