EBCM_Osteoarthritis_2024_Harnett-2.pdf

Evidence-based complementary medicines for osteoarthritis pain and disability 2024 Presented by Dr Joanna Harnett, BHSc (Complementary Medicine) MHSc (Complementary Medicine) PhD (Nutritional Pharmacology) Grad Cert Educational Studies (Higher Education) The University of Sydney...

Evidence-based complementary medicines for osteoarthritis pain and disability 2024 Presented by Dr Joanna Harnett, BHSc (Complementary Medicine) MHSc (Complementary Medicine) PhD (Nutritional Pharmacology) Grad Cert Educational Studies (Higher Education) The University of Sydney Page 1 Learning objectives By the end of this lecture, you should be able to: Provide evidence-based information regarding the efficacy and safety of selected CMs in the management of pain and disability associated with osteoarthritis Glucosamine, Chondroitin, Boswellia serrata extract, Curcumin, Maritime Pine bark extract, methylsulfonylmethane (MSM), Omega 3 fatty acids. Describe drug interactions that may occur between specific herbs or nutritional supplements used for osteoarthritis. Respond to requests for Complementary Medicines (CMs) for the management of osteoarthritis. The University of Sydney Page 2  APC Learning Domains Australian Pharmacy Councils Learning Domains for Degree Programs 2020 domain 2: Pharmacists have a unique role within the health care team as medicines experts and must therefore have a sound understanding of the sources, properties and actions of medicinal substances Medicines – the drug substance and drug action: ‘Evidence-based complementary and alternative therapies, and their interactions with medicines’ The University of Sydney Page 3  Introduction - Osteoarthritis (OA) OA is the most common muscular-skeletal disorder affecting Australians – projected to 3.1 million by 2030. Health care costs for OA were estimated to be over $2.1 billion in 2015; by the year 2030, these are forecast to exceed $2.9 billion ($970 for every person with the condition). (Ackerman 2018) The disabling effects of OA include substantial costs associated with healthcare and work loss due to OA‐related pain and disability (Laires 2018) There is no proven cure Goals of treatment are to: Reduce pain Improve function Prevent disability The University of Sydney Page 4  Case 2023 Mrs Bryant is a 65 year old female with pain in both her knees that impacts her mobility. She does not met the criteria for ‘knee replacement’ and is unable to continue NSAIDs due to gastritis and a history of PUD Takes no other medications Allergic to shellfish Has a preference to use CMs to manage her pain and disability Her doctor said to ask you if there is any evidence to support the efficacy of CMs commonly used to treat OA associated pain and disability? The University of Sydney Page 5 What CMs are consumers taking? (Basedow, Runciman, March, & Esterman, 2014) Objectives: To investigate complementary and alternative medicine (CAM) use amongst a cohort of osteoarthritis (OA) sufferers and to explore reasons for use. Results: Conclusion: As CAM use is a key 69% percent of respondents reported that component of the self- they had tried CAM, with little difference management strategies for a between age groups and genders. Patients who substantial proportion of had a better knowledge of their condition and Australians with OA, users need excellent self-rated health were more likely to to be more fully informed use CAM. An aversion to the side effects of about evidence of efficacy. conventional medicine, failure to engage in exercise, and a belief in the efficacy of CAM were the principal factors underlying use. The University of Sydney Page 6  What are Australians taking for osteoarthritis? Journal of Nutrition Health and Ageing 2016 Of the 10,638 women in the Australian Longitudinal Women's Health Study, 26.8% reported use of omega-3 FA and 15.9% glucosamine mainly taken for joint pain, osteoarthritis and other arthritis The University of Sydney Page 7  What you need to know – what consumers need to know What does a pharmacist need to know about CM and Osteoarthritis? Where to access reliable information on CM quickly in a Pharmacy The evidence for efficacy The evidence for safety Adverse effects Precautions and Contraindications Significant drug-nutrient-herb interactions Pregnancy and Lactation What are some of the professional considerations when communicating to people about complementary medicine product use? (refer to year 2 communications and CM lecture) The University of Sydney Page 8 8  Glucosamine – what is it? Glucosamine sulfate is a naturally occurring substance found in synovial fluid that is required for the production of proteoglycans, mucopolysaccharides and hyaluronic acid which are substances that make up joint tissue, such as articular cartilage, tendons and synovial fluid Chemical components 2-amino-2-deoxy-D-glucose Dietary sources of glucosamine are from chitin in the shells of prawns and other crustaceans. As supplements glucosamine is derived from marine exoskeletons or is produced synthetically and available in salt forms glucosamine sulfate glucosamine hydrochloride N-acetyl-glucosamine The University of Sydney Page 9  What are the ‘proposed’ actions? – The molecular mode of action is not fully understood: – Symptomatic relief and disease-modifying effects have been attributed to Glucosamine sulphate through: – Preliminary animal studies that suggest that glucosamine inhibits protein N-glycosylation and cytokine stimulated production of mediators of inflammation and cartilage degradation. (Reginster, Deroisy et al. 2001)(Bruyère, Altman, & Reginster, 2016) The University of Sydney Page 10  Is it effective in the management of osteoarthritis? Cochrane Review - updated 2009 – 25 studies with 4963 patients. – non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function. – Rotta preparations show that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA. – Glucosamine was as safe as placebo. Towheed, T. E. et al. (2005). Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev(2) (updated 2009) The University of Sydney Page 11  Glucosamine use continues to be supported by – The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends chronic symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) including glucosamine sulfate (GS) and chondroitin sulfate (CS) as first-line therapy for knee osteoarthritis (OA). – Glucosamine sulphate (patented crystalline form) prescription only – Bruyère, O., Cooper, C., Pelletier, J.-P., Maheu, E., Rannou, F., Branco, J.,... Reginster, J.-Y. (2016). A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—From evidence-based medicine to the real-life setting. Seminars in Arthritis and Rheumatism, 45(4, Supplement), S3-S11. The University of Sydney Page 12  Not supported in other countries – NIH USA – “The preponderance of evidence indicates little or no meaningful effect on pain or function.” – The American College of Rheumatology (2012) (2021) – The American Academy of Orthopaedic surgeons (2010) – Arthritis Australia and Australian Rheumatology Association comment: – “This information highlights growing evidence that glucosamine does not help people with osteoarthritis and is a reminder that people with shellfish allergy should not take glucosamine (which is commonly derived from shellfish). It does not identify any new safety concerns and should not cause undue alarm in people already taking glucosamine.” https://arthritisaustralia.com.au/australian-rheumatology- association-and-arthritis-australia-statement-regarding-the-use-of- glucosamine-for-the-treatment-of-osteoarthritis/ (accessed 9th August 2022) The University of Sydney Page 13  Drug Interactions DO not combine with Warfarin (anti-thrombotic and anticoagulants) – increases risk of bleeding Avoid concurrent use with antimitotic therapy- theoretically may reduce drugs’ inhibition of topoisomerase II, an enzyme required for DNA replication Caution with anti-diabetic medications may reduce efficacy of BSL control (check IM gateway and NMD for multiple interactions with this supplement) The University of Sydney Page 14  Glucosamine safety Renally excreted – renal impairment Common mild side effects including nausea, heartburn, diarrhoea, and constipation. Rare side effects include drowsiness, skin reactions, and headache Pregnancy or breast-feeding: Insufficient evidence to recommend Asthma: Glucosamine supplements have also been implicated in worsening underlying asthma. *** Diabetics – whether it raises blood glucose levels in people with or without diabetes is unclear *** Hyperlipidaemia: Animal studies cautioned cholesterol levels may rise however this has not been found in humans **** Hypertension: monitor blood pressure*** Shellfish or sulphur allergy: Because some glucosamine sulfate products are made from the shells of shrimp, lobsters or crabs, there is concern that glucosamine products might cause allergic reactions in people who are allergic to shellfish. Surgery: Discontinue glucosamine sulfate at least 2 weeks before a scheduled surgery. *** for discussion in lecture The University of Sydney Page 15  Chondroitin (Cochrane Review 2017) Chondroitin is a complex sugar derived from the cartilage of animals; it is considered a food supplement. glycosaminoglycan produced naturally in the body. It is formed by the 1-3 linkage of D-glucuronic acid to N-acetylgalactosamine. shark and bovine cartilage, or produced synthetically 9,000 patients, majority of trials are for knee OA, for 3 months minimum. significantly reduces pain by an average of 9% to 10% compared to placebo. WOMAC scale, taking chondroitin for 6 months reduced pain scores by 20% in significantly more patients than placebo. In this analysis, 16 patients would need to be treated for one additional patient to experience a 20% reduction in pain. The typical dose of chondroitin sulfate is 200-400 mg two to three times daily or 1000-1200 mg as a single daily dose Adverse events were generally mild. – Singh JA et al. Chondroitin for osteoarthritis. Cochrane Database of Systematic Reviews 2015, Issue 1. The University of Sydney Page 16  Chondroitin - safety Chondroitin sulfate is LIKELY SAFE when taken by mouth at recommended doses. It has been used safely in research for up to 3 years. Chondroitin sulfate from animal sources ? Products from diseased animal tissue, there are no reports of chondroitin causing disease in humans, and the risk is thought to be low. It can cause some mild stomach pain and nausea. Other side effects that have been reported are diarrhoea, constipation, swollen eyelids, leg swelling, hair loss, and irregular heartbeat. Some chondroitin products contain excess amounts of manganese. Pregnancy and breast-feeding: Not enough is known about the safety of chondroitin sulfate use during pregnancy and breast-feeding. Asthma: May exacerbate asthmatic symptoms in some patients May increase bleeding in patients taking anti-coagulant medications The University of Sydney Page 17  Indian frankincense (Boswellia serrata) Indian frankincense (Boswellia serrata) is a tree. Under the bark is a gummy oleo-resin. The resin contains up to 16% of essential oil and beta-boswellic acid (BA) is the major triterpene constituent. BAs from the gum resin block the synthesis of 5-lipoxygenase products in vitro, including 5- hydroxyeicosatetraenoic acid and leukotriene B4 (pro-inflammatory) The University of Sydney Page 18  Evidence – standardised Boswellia serrata extract (BSE) – DB - RCT n=30 - improved pain, flexion, walking distance after 8 wk in the BSE group (p < 0.001) Kimmatkar, Thawani, Hingorani, & Khiyani, 2003 – Bioequivalence open label study n=66 BSE plus NSAIDs compared to NSAIDs alone were superior at 2 months, 7 months and 1 month after discontinuation Sontakke et al., 2007 – DB-RCT n=90 BSE improved pain, stiffness and functional ability scores vs placebo (p < 0.0001). Concentration of the proteolytic enzyme MMP-3 in synovial fluid pain scores were significantly lower with higher doses 250mg/d vs the low-dose 100mg/d group at day 7 Sengupta et al., 2008 – Collectively these studies support large and clinically important treatment effects for pain and disability improvement Liu 2018 – Small studies, overall low quality evidence The University of Sydney Page 19  Safety- Boswellia serrata Safety: Standardised extracts have been demonstarted to be safe and well tolerated however safety data is limited Major adverse events have not been reported in clinical trials Minor adverse events reported, include nausea, headache, abdominal pain, diarrhoea, fever and general weakness. Liu 2018 Contraindications and cautions Caution in autoimmune conditions (based on theoretical concerns) Pregnancy and Lactation Not recommended for use in pregnancy and lactation due to lack of data Interactions In vitro evidence shows that Boswellia serrata inhibits cytochrome P450 3A4,1A2, 2C19, 2C9, 2D6, 3A4. Frank 2006 There are no human studies on drug interactions with Boswellia serrata at this time. The University of Sydney Page 20  Turmeric – Curcumin (curcuma longa) Rhizome is used in curry and medicinally Turmeric rhizome contains 5% phenolic curcuminoids, which give turmeric its yellow colour. The most significant curcuminoid is curcumin Turmeric rhizome also contain polysaccharides, including acid glucans known as ukonan A, Anti-inflammatory (Chainani-Wu, 2003)(Khedr & Khedr, 2014) Curcumin inhibits 5-lipooxygenase (5LOX) and COX-2 in the arachidonic acid metabolic cycle, Anti-oxidant (Khedr & Khedr, 2014), Immuno-modulatory, wound healing, anti-proliferative (Du et al., 2013), anti- microbial activities Issues related to bioavailability of active constituents resulting in sub-optimal plasma levels to exert a biological effect Bioavailability of curcumin improved in a phosphotidylcholin phytosome complex (lecithinized delivery system) or the addition of piperine to curcumin formulation The University of Sydney Page 21  Is there any evidence for curcumin in the management of pain associated with OA of the knee? Aim: To critically appraise and evaluate the evidence for effectiveness of curcuminoids in the treatment of osteoarthritis (OA) in adults by assessing RCTs that investigated the effectiveness of orally-administered curcuminoids in OA. Results: total of 797 participants with primarily knee OA. All studies were conducted in Asia. The overall risk of bias was moderate. Improvements in WOMAC Index total scores, with significant reductions in the use of rescue medication were also observed with curcuminoids. No serious adverse events were reported. Conclusions: Curcuminoids may have some beneficial effects on knee pain and quality of life in patients with knee OA. However, they are less effective at relieving pain compared with ibuprofen. Curcuminoids appear safe on the short-term, and may reduce the need for rescue medication. Published RCTs vary in reporting quality, are characterized by small sample sizes The University of Sydney Page 22  Is there any evidence for curcumin in the management of pain associated with OA of the knee? Pain Medicine 2016 Aim: To provide the highest level of evidence on the efficacy of curcuminoids in patients with painful conditions through meta-analysis of data from randomized controlled trials (RCTs). Methods. A systematic review and meta-analysis was conducted using data reported by RCTs. The primary efficacy measure was pain intensity or algofunctional status. Results. 8 RCTs met inclusion criteria that included 606 randomized patients. Curcuminoids were found to significantly reduce pain. This pain-relieving effect was found to be independent of administered dose and duration of treatment with Conclusion: curcuminoids,Curcuminoids and was freesupplements maybias. from publication be aCurcuminoids safe and effective werestrategy safe andtowell improve tolerated pain in allseverity, by warranting evaluated RCTs. further rigorously conducted studies to define the The University of Sydney Page 23 long-term efficacy and safety.  Safety – Turmeric/Curcumin (Exercise time – log into Natural Medicine Database) Contraindications and Cautions? Pregnancy and Lactation ? Toxicity - ?? Adverse reactions ?? The University of Sydney Page 24  Adverse events – hepatotoxicity Updated 2023 https://consultations.tga.gov.au/medicines-regulation-division/low-neg-risk-2023- 2024/user_uploads/tga---low-negligible-risk-annual-consultation-2023-2024---final.pdf – In July 2019, the TGA became aware of a cluster of 28 hepatotoxicity cases in Italy following consumption of C. longa/curcumin supplements. 61% (17/28) received a WHO causality assessment of probable, 36% (10/28) were assessed as possible. Of note, 33% (9/28) of cases did not involve piperine-containing medicines. – An additional 64 international AE reports of drug related hepatic disorders (reported in VigiBase1 as of 02 July 2023) of which 15 reported C. longa/curcumin as the only suspected ingredient. – Only 2 cases also involved piperine or black pepper, which were reported as ‘suspect’ along with multiple other suspected ingredients. – Of the 15 cases that reported C. longa/curcumin as the only suspected ingredient, 9 were reported as ‘serious’. The University of Sydney Page 25  Adverse events continued https://consultations.tga.gov.au/medicines-regulation-division/low-neg-risk-2023-2024/user_uploads/tga--- low-negligible-risk-annual-consultation-2023-2024---final.pdf – Between 2002 and June 2023, the TGA received 18 liver-related AE reports associated with C. longa/curcumin containing products. – Across several countries and regulatory agencies, changes to labelling and maximum doses have been implemented. – In Australia a consultation paper regarding doses and labelling of Curcuma longa and other species containing curcumin have been published – As of 22 June 2023, there were 536 oral listed medicines included in the ARTG that contained at least one Curcuma species (the majority being C. longa), 56 of which included C. longa as part of a proprietary ingredient The University of Sydney Page 26  Drug Herb Interactions (IM gateway 2020) – A study has found that curcumin causes a large increase in the blood concentrations of sulfasalazine. This may increase the risk of adverse events, and patients taking sulfasalazine should avoid taking curcumin or turmeric. IM Gateway 2020 – Based on the available details of a case report, Curcumin may have the potential to interact with warfarin resulting in elevated INR with an increased risk of bleeding. This combination should be avoided until further evidence becomes available. – Although the effect of curcumin on chemotherapy has not been studied directly in humans, the current evidence suggests that patients taking cyclophosphamide should avoid taking curcumin. The University of Sydney Page 27  Pycnogenol (bark extract of maritime pine) Pinus pinaster – a concentrate of plant polyphenols, composed of several phenolic acids, catechin, taxifolin and procyanidins Maimoona A et al 2011 – anti-inflammatory effects through the inhibition of matrix metalloproteinases. – Three studies have evaluated the effects of Pycnogenol - 50mg twice or three times daily in people living with OA (n=182) Belcaro 2008, Cisar 2008, Farid 2007 – The overall evidence indicates large and clinically meaningful effects for both pain and disability – The overall evidence is considered of moderate quality Liu 2018 – No side effects or serious adverse events were reported in the 3 clinical studies cited – While generally recognised as safe for use there is insufficient safety data for use in pregnancy and lactation The University of Sydney Page 28  Safety – theoretical drug interactions (NM database 2022) – Maritime pine bark extract inhibits platelet aggregation and therefore might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs. – Clinical studies report that maritime pine bark extract decreases blood sugar in diabetic patients being treated pharmacologically – diabetic patients BSL should be monitored if they commence pine bark extract – Maritime pine bark extract may interfere with immunosuppressant therapy because of its immune stimulating activity (no animal or clinical studies to support this theoretical interaction) The University of Sydney Page 29  Methylsulfonylmethane (MSM) – What is it? – MSM is a naturally occurring organosulfur compound. – How does it work? – In vitro data indicates MSM downregulates the expression of inflammatory cytokines such as Interleukin-1and 6, and Tumour necrosis-alpha thus exerting and anti-inflammatory effect – Does it work clinically? – A 2018 review including three studies (n=148) evaluated the evidence for MSM over 12 weeks in patients with OA of the knee – Overall a modest to large treatment effects for pain relief and mobility were demonstrated (though the quality of evidence was low and very low). – No optimal dose could be established due to dose regimen variations – No major adverse events were reported in any of the three studies included. Liu X et al. 2018 Brit J Sports Med 2018;52:167 – Generally recognised as safe with no known interactions Natural Medicine Database 2020 The University of Sydney Page 30  Pharmacological plausibility - How might omega-3 fatty acids work in inflammatory conditions? Basic Biochemical Pathways of Omega-3 and Omega 6 Fatty Acids The University of Sydney Page 31  The evidence for efficacy and safety confirmed for RA but not good for OA (2017) The objective was to evaluate whether marine oil supplements reduce pain and/or improve other clinical outcomes in patients with arthritis included randomized trials of oral supplements of all marine oils compared with a control in arthritis Results:patients. Forty-two trials were included; 30 trials reported complete data on pain. A significant effect was found in patients with rheumatoid arthritis (22 trials) and other or mixed diagnoses (3 trials) but not in osteoarthritis patients (5 trials). Conclusion - The evidence for using marine oil to alleviate pain in arthritis patients was overall of low quality, but of moderate quality in rheumatoid arthritis patient The University of Sydney Page 32  Summary of omega-3 fatty acids (marine sources) for RA and OA Pain relief Evidence Rheumatoid arthritis Possibly effective in reducing morning joint modest benefits stiffness and tenderness for up to 3 months. obtained from Effects beyond three months of treatment are moderate quality unclear. evidence (Goldberg & Katz, 2007) 2.7 g/day (EPA/DHA) for 3 months possibly effective in reducing NSAID consumption by RA patients (Lee, Bae, & Song, 2012) Reductions in leukotriene B4 production (Jiang et al., 2016) 1-3 fish meals per week may lower disease activity (Senflteleber 2017) Osteoarthritis Possibly ineffective poor studies or negative outcomes for the efficacy of fish oil supplements for pain and/or functional improvements in osteoarthritis The University of Sydney Page 33  Case 2024 Mrs Bryant is a 65 year old female with pain in both her knees that impacts her mobility. She does not met the criteria for ‘knee replacement’ and is unable to continue NSAIDs due to gastritis and a history of PUD Takes no other medications Allergic to shellfish Has a preference to use CMs to manage her pain and disability Mrs Bryants doctor said to ask you if there is any evidence to support the efficacy of CMs commonly used to treat OA associated pain and disability? The University of Sydney Page 34  Recommendations for the use of supplements in OA by outcomes ASU: avocado/soybean unsaponifiables; BSE: Boswellia serrata extract; CH: collagen hydrolysate; MSM: methylsulfonylmethane; WBE: willow bark extract. Rheumatology (Oxford), Volume 57, Issue suppl_4, May 2018, Pages iv75–iv87, https://doi.org/10.1093/rheumatology/key005 The content of this slide may be subject to copyright: please see the slide notes for details. The University of Sydney Page 35