Inflammation Impact on Pain in Knee Osteoarthritis

Inflammation Clinical Trial

Official title:

Inflammation Impact on Pain in Patients With Knee Osteoarthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03389906
• Other study ID #: N-20160045
• Status: Completed
• Phase: N/A
• Start date: December 1, 2017
• Est. completion date: December 1, 2020

Study information

• Verified date: August 2021
• Source: Northern Orthopaedic Division, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: December 1, 2020
• Est. primary completion date: December 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Inflammation
• Osteo Arthritis Knee
• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Other:
• Gold
Approximately 72000, 20-40 my-meter diameter, sterilised gold particles (=20 mg) will be provided in vials (The Berlock® Gold Implants). 5-10 ml of synovial fluid is aspirated (20G needle) from most affected OA-knee. The vial of gold particles are mixed with the synovial fluid, and the mix of gold and synovial fluid is injected intra-articularly into the patients knee.

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg

Sponsors (2)

Lead Sponsor	Collaborator
Sten Rasmussen, MD, PhD	Aalborg University

Country where clinical trial is conducted

Denmark, 

References & Publications (37)

Andrew D, Greenspan JD. Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol. 1999 Nov;82(5):2649-56. — View Citation

Arendt-Nielsen L, Egsgaard LL, Petersen KK, Eskehave TN, Graven-Nielsen T, Hoeck HC, Simonsen O. A mechanism-based pain sensitivity index to characterize knee osteoarthritis patients with different disease stages and pain levels. Eur J Pain. 2015 Nov;19(1 — View Citation

Arendt-Nielsen L, Egsgaard LL, Petersen KK. Evidence for a central mode of action for etoricoxib (COX-2 inhibitor) in patients with painful knee osteoarthritis. Pain. 2016 Aug;157(8):1634-1644. doi: 10.1097/j.pain.0000000000000562. — View Citation

Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. Pain. 2010 Jun;149(3):573-581. doi: 10.1016/j.pain.2010.04.003. Epub 2010 Apr 24. — View Citation

Arendt-Nielsen L, Skou ST, Nielsen TA, Petersen KK. Altered Central Sensitization and Pain Modulation in the CNS in Chronic Joint Pain. Curr Osteoporos Rep. 2015 Aug;13(4):225-34. doi: 10.1007/s11914-015-0276-x. Review. — View Citation

Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee — View Citation

Christensen MM, Danscher G, Ellermann-Eriksen S, Schiønning JD, Rungby J. Autometallographic silver-enhancement of colloidal gold particles used to label phagocytic cells. Histochemistry. 1992;97(3):207-11. — View Citation

Clark P, Tugwell P, Bennet K, Bombardier C, Shea B, Wells G, Suarez-Almazor ME. Injectable gold for rheumatoid arthritis. Cochrane Database Syst Rev. 2000;(2):CD000520. Review. — View Citation

Courtney CA, Kavchak AE, Lowry CD, O'Hearn MA. Interpreting joint pain: quantitative sensory testing in musculoskeletal management. J Orthop Sports Phys Ther. 2010 Dec;40(12):818-25. doi: 10.2519/jospt.2010.3314. Epub 2010 Oct 22. Review. — View Citation

Danscher G, Stoltenberg M. Silver enhancement of quantum dots resulting from (1) metabolism of toxic metals in animals and humans, (2) in vivo, in vitro and immersion created zinc-sulphur/zinc-selenium nanocrystals, (3) metal ions liberated from metal imp — View Citation

Danscher G. In vivo liberation of gold ions from gold implants. Autometallographic tracing of gold in cells adjacent to metallic gold. Histochem Cell Biol. 2002 May;117(5):447-52. Epub 2002 Apr 13. — View Citation

Forestier J. Rheumatoid arthritis and its treatment by gold salts. The lancet 1934;224:646-648.

Freynhagen R, Baron R, Gockel U, Tölle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20. — View Citation

Gandhi R, Santone D, Takahashi M, Dessouki O, Mahomed NN. Inflammatory predictors of ongoing pain 2 years following knee replacement surgery. Knee. 2013 Oct;20(5):316-8. doi: 10.1016/j.knee.2012.10.015. Epub 2012 Nov 14. — View Citation

Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum. 2012 Sep;64(9): — View Citation

Guy W, Bonato RR. Manual for the ECDEU assessment battery. : US Department of Health, Education, and Welfare, National Institute of Mental Health, 1970

Jaeger GT, Larsen S, Søli N, Moe L. Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Vet Scand. 2007 Mar 23;49:9. — View Citation

Jinks C, Jordan K, Croft P. Osteoarthritis as a public health problem: the impact of developing knee pain on physical function in adults living in the community: (KNEST 3). Rheumatology (Oxford). 2007 May;46(5):877-81. Epub 2007 Feb 17. — View Citation

Jones G, Brooks PM. Injectable gold compounds: an overview. Br J Rheumatol. 1996 Nov;35(11):1154-8. Review. — View Citation

Kean TA. Rheumatoid Arthritis and Gold Salts Therapy. Ulster Med J. 1934 Oct;3(4):284-9. — View Citation

Labens R, Lascelles BD, Charlton AN, Ferrero NR, Van Wettere AJ, Xia XR, Blikslager AT. Ex vivo effect of gold nanoparticles on porcine synovial membrane. Tissue Barriers. 2013 Apr 1;1(2):e24314. doi: 10.4161/tisb.24314. — View Citation

Larsen A, Kolind K, Pedersen DS, Doering P, Pedersen MO, Danscher G, Penkowa M, Stoltenberg M. Gold ions bio-released from metallic gold particles reduce inflammation and apoptosis and increase the regenerative responses in focal brain injury. Histochem C — View Citation

Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J; METGO Study Group. A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid ar — View Citation

Leonaviciene L, Kirdaite G, Bradunaite R, Vaitkiene D, Vasiliauskas A, Zabulyte D, Ramanaviciene A, Ramanavicius A, Ašmenavicius T, Mackiewicz Z. Effect of gold nanoparticles in the treatment of established collagen arthritis in rats. Medicina (Kaunas). 2 — View Citation

Lie KI, Jæger G, Nordstoga K, Moe L. Inflammatory response to therapeutic gold bead implantation in canine hip joint osteoarthritis. Vet Pathol. 2011 Nov;48(6):1118-24. doi: 10.1177/0300985810381910. Epub 2010 Sep 22. — View Citation

Meier FM, Frerix M, Hermann W, Müller-Ladner U. Current immunotherapy in rheumatoid arthritis. Immunotherapy. 2013 Sep;5(9):955-74. doi: 10.2217/imt.13.94. Review. — View Citation

Menninger H, Herborn G, Sander O, Blechschmidt J, Rau R. A 36 month comparative trial of methotrexate and gold sodium thiomalate in the treatment of early active and erosive rheumatoid arthritis. Br J Rheumatol. 1998 Oct;37(10):1060-8. — View Citation

Petersen KK, Arendt-Nielsen L, Simonsen O, Wilder-Smith O, Laursen MB. Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement. Pain. 2015 Jan;156(1):55-61. doi: 10 — View Citation

Petersen KK, Siebuhr AS, Graven-Nielsen T, Simonsen O, Boesen M, Gudbergsen H, Karsdal M, Bay-Jensen AC, Arendt-Nielsen L. Sensitization and Serological Biomarkers in Knee Osteoarthritis Patients With Different Degrees of Synovitis. Clin J Pain. 2016 Oct; — View Citation

Rau R, Herborn G, Menninger H, Sangha O. Radiographic outcome after three years of patients with early erosive rheumatoid arthritis treated with intramuscular methotrexate or parenteral gold. Extension of a one-year double-blind study in 174 patients. Rhe — View Citation

Sadauskas E, Jacobsen NR, Danscher G, Stoltenberg M, Vogel U, Larsen A, Kreyling W, Wallin H. Biodistribution of gold nanoparticles in mouse lung following intratracheal instillation. Chem Cent J. 2009 Nov 20;3:16. doi: 10.1186/1752-153X-3-16. — View Citation

Sanders M. A review of controlled clinical trials examining the effects of antimalarial compounds and gold compounds on radiographic progression in rheumatoid arthritis. J Rheumatol. 2000 Feb;27(2):523-9. Review. — View Citation

Seifert O, Matussek A, Sjögren F, Geffers R, Anderson CD. Gene expression profiling of macrophages: implications for an immunosuppressive effect of dissolucytotic gold ions. J Inflamm (Lond). 2012 Nov 9;9(1):43. doi: 10.1186/1476-9255-9-43. — View Citation

Stürmer T, Brenner H, Koenig W, Günther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis. 2004 Feb;63(2):200-5. — View Citation

Turk DC, Dworkin RH, Allen RR, Bellamy N, Brandenburg N, Carr DB, Cleeland C, Dionne R, Farrar JT, Galer BS, Hewitt DJ, Jadad AR, Katz NP, Kramer LD, Manning DC, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robinson JP, Royal MA, Simon L, Stauffer JW, Stein W, Tollett J, Witter J. Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain. 2003 Dec;106(3):337-345. doi: 10.1016/j.pain.2003.08.001. Review. — View Citation

Williams HJ. Comparisons of sulfasalazine to gold and placebo in the treatment of rheumatoid arthritis. J Rheumatol Suppl. 1988 Sep;16:9-13. Review. — View Citation

Wylde V, Sayers A, Lenguerrand E, Gooberman-Hill R, Pyke M, Beswick AD, Dieppe P, Blom AW. Preoperative widespread pain sensitization and chronic pain after hip and knee replacement: a cohort analysis. Pain. 2015 Jan;156(1):47-54. doi: 10.1016/j.pain.0000 — View Citation

* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	WOMAC	The WOMAC[6] is a subject-rated instrument that measures Osteoarthritis (OA)	8 weeks, 2 years
Secondary	Quantitative sensory testing	Pressure Pain Sensitivity Cuff Pressure Algometry	8 weeks
Secondary	Weekly pain diary	Subjects rated their pain intensity on a VAS scale every day at home. On the VAS scale ''0" indicates ''no pain", and ''10" indicates ''maximal pain".; Subjects rated the pain severity for: Average Pain Score (APS) for the last 24 hours Worst pain for the last 24 hours Pain severity at night.	8 weeks
Secondary	Inflammatory markers	Proteomic analysis of blood and synovial fluid	8 weeks
Secondary	PainDetect questionnaire (PD-Q	The PD-Q is a validated, easy to use screening tool that predicts the likelihood of a neuropathic pain component in chronic pain disorders[14]. It shows higher sensitivity and specificity in comparison with other neuropathic pain screening questionnaires. The questionnaire is comprised of 3 major components: gradation of pain, pain course pattern and radiating pain. There are 7 questions evaluating gradation of pain. Each question is scored by the patient using a 0 to 5 score with 0 = never, 1 = hardly notice, 2 = slightly, 3 = moderately, 4 = strongly and 5 = very strongly. There is one question evaluating pain course pattern. Patients select from one of four pictures to indicate which pattern of pain best describes their course of pain. Each picture is associated with a unique score of 0, -1, or +1 (2 pictures have this score possible). There is one question evaluating radiating pain with a yes (score of +2) or no (score of 0) response option.	8 weeks, 2 years
Secondary	Global Rating of Change Scale	we asked the question, "Concerning your knee, how will you describe yourself compared to immediately before injection of gold into your knee" and evaluated the answer at an 11-point scale from very much worse (-5) to complete recovered (5).	2 years