Clinical guidelines

Osteoarthritis clinical guidelines

Recent guideline updates have downgraded the use of paracetamol and opioids for osteoarthritis (OA)-associated pain and highlighted the importance of individual patient management^1–4. Find out the key points of the updated treatment guidelines in the following infographic.

Clinical guidelines to inform OA patient management

This Learning Zone focuses on global guidelines available but country-specific guidelines may also be available to you.

Osteoarthritis Research Society International (OARSI)

OARSI is a scientific organisation to promote and advance research for the prevention and treatment of osteoarthritis. They regularly update and expand upon prior guidelines and the most recent update has developed patient-focused treatment recommendations for individuals with knee, hip, and polyarticular osteoarthritis (OA) using expert consensus and based on objective review of high-quality meta-analytic data¹.

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)

ESCEO is an organisation dedicated to a close interaction between clinical scientists, the pharmaceutical industry, regulators and health policymakers, with the goal of integrating the management of osteoporosis and osteoarthritis. They provide HCPs with the latest clinical information from an evidence-based perspective, a recent example being a 2019 updated algorithm recommendation for the management of knee osteoarthritis².

American College of Rheumatology (ACR)

ACR is an organisation of and for HCPs and scientists that advances rheumatology through programmes of education, research, advocacy and practice support relating to the care of people with arthritis and rheumatic and musculoskeletal diseases. The ACR published a 2019 guideline for the management of osteoarthritis of the hand, hip, and knee³.

The European League Against Rheumatism (EULAR)

EULAR is an organisation that represents patients with arthritis/rheumatism, HCPs and scientific rheumatology societies across Europe. EULAR published updated recommendations for the management of hand osteoarthritis in 2018⁴. The recommendations complement their 2018 recommendations for the health professional's approach to pain management and recommendations for physical activity in inflammatory arthritis and osteoarthritis^5,6.

Clinical guidelines strongly recommend use of NSAIDs for osteoarthritis-associated pain

NSAIDs

“All NSAIDs should be used at the lowest effective dose for the shortest period of time necessary to control pain, i.e. intermittently or in longer cycles rather than in chronic use”²

NSAIDs are widely used for analgesia in osteoarthritis (OA). Topical NSAIDs are preferred to oral NSAIDs for knee and hand OA as they have similar efficacy to the oral medications in reducing pain but with a reduced risk of systemic adverse reactions^2,3. This makes topical NSAIDs more suitable for patients >75 years and those with comorbidities or at an increased risk of gastrointestinal (GI), cardiovascular (CV) or renal side effects². Mild local skin reactions are sometimes observed with topical NSAIDs, particularly with diclofenac⁷.

Oral NSAIDs are widely recommended for hip OA and knee or hand OA if topical NSAIDs are ineffective^1–3. Oral NSAIDs have been associated with wide-ranging side effects mainly in the GI, CV and renal systems.

• GI toxicity is found with all NSAIDs and while GI adverse reactions associated with non-selective (ns) NSAIDs may be reduced by co-medication with a gastroprotective agent (proton pump inhibitor), intestinal symptoms are not ameliorated⁸.
• CV risk is present for both nsNSAIDs and COX-2 inhibitors. A safety meta-analysis of COX-2 inhibitors (celecoxib, rofecoxib, etoricoxib and valdecoxib) found a significant increase in hypertension, congestive heart failure, and peripheral and generalised oedema⁹, which is consistent with other findings for nsNSAIDs¹⁰. Indeed, the risk of hospitalisation due to heart failure is roughly doubled by all NSAID regimens¹¹.
• Patients taking NSAIDs have a threefold increased risk of developing clinical acute kidney injury, and patients with OA and comorbid conditions such as hypertension, heart failure and diabetes are at further risk¹². Oral NSAIDs may be partly responsible for the excess mortality seen in patients with OA and should be used judiciously in OA because of safety considerations¹³.

Intra-articular injections

What are the potential advantages of intra-articular injection? Access directly to the pain source, increased bioavailability and lower systemic toxicity are some attractive features¹⁴. Intra-articular (IA) treatment may be considered for patients with OA for whom NSAIDs are contraindicated, or if a patient remains symptomatic despite use of NSAIDs. IA hyaluronic acid (IAHA) may be a suitable alternative to NSAIDs for knee OA, given its more favourable safety profile, especially for elderly patients or those at greater risk for NSAID-induced adverse reactions^1,2. The American College of Rheumatology (ACR), however, do not recommend IAHA for knee OA due to a risk of bias in the relevant studies and strongly recommend against IAHA for hip OA due to a lack of benefit in relevant studies³.

Intra-articular corticosteroids are more widely recommended for all types of OA^1–3. However, short-term treatment is recommended given meta-analyses have shown less evidence of long-term benefits (post-4 weeks after injection)¹⁴.

Duloxetine

Duloxetine is the only centrally acting agent with enough evidence to recommend it for use in patients with OA³. OARSI recommends duloxetine in patients with widespread pain and/or depression¹ and ESCEO recommends it as an alternative to weak opioids as third-line treatment accompanied with the caveat that it may cause a high rate of adverse reactions, including dizziness and risk of falls².

Topical capsaicin

Capsaicin, the chemical in chilli peppers that makes them spicy, acts by binding to transient receptor potential vanilloid-1 (TRPV1) receptors, causing a decrease in membrane resistance, depolarisation and activation of neurotransmitter release. This results in desensitisation and depletion of neurotransmitters, which produces an analgesic effect¹⁵. However, the ACR only conditionally recommends capsaicin because of the small effect sizes and wide confidence intervals in the available literature³. Capsaicin is conditionally recommended against in hand OA because of a lack of direct evidence to support use, and the potential risk of contamination of the eye, which would be severe, given that capsaicin commonly causes burning and irritation³. Capsaicin is not considered for hip OA, given the depth of the joint below the skin surface³.

The use of paracetamol has been downgraded for osteoarthritis pain in recent pain management guidelines

“When analgesic benefit is uncertain and with increasing safety issues, more careful consideration of paracetamol use is required”¹³

Paracetamol (acetaminophen) is commonly used as first-line analgesia for osteoarthritis (OA), despite having only a minimal effect on pain and increasing evidence of gastrointestinal (GI), cardiovascular (CV) and renal adverse reactions, along with increased mortality risk¹³.

A systematic literature review of observational studies showed a considerable degree of paracetamol toxicity, particularly at higher doses (up to 4 g/day)¹⁶. Two of the studies included in the review reported on mortality. The first reported a dose-response increase in all-cause mortality and rate of GI adverse reactions or bleeding based upon increasing medication possession ratio (measured by repeat prescription frequency)¹⁷. The second reported an increase in standardised mortality ratio for patients prescribed paracetamol, compared with those not prescribed paracetamol, regardless of specific cause of death, with a nearly doubled overall death rate¹⁸. Other studies included in the analysis showed a paracetamol dose-dependent risk of CV adverse reactions and increased risk of renal adverse reactions¹⁶. This type of evidence, along with reports of hepatotoxicity and acute liver failure following chronic paracetamol dosing, explains the general downgrading of paracetamol for use in patients with chronic pain caused by OA². However, there are differences in the guideline recommendations. OARSI strongly recommend against paracetamol for any OA phenotype or comorbidity subgroup¹; paracetamol is only weakly recommended for short-term analgesia up to 3 g/day by ESCEO² and by the ACR only when NSAIDs are contraindicated³.

The use of opioids has been downgraded in recent pain management guidelines

“Use of the lowest possible doses for the shortest possible length of time is prudent”³

Did you know that opioids have been shown to cause similar levels of pain relief as oral NSAIDs? Two meta-analyses have shown similar pain relief to oral NSAIDs in osteoarthritis (OA)^19,20. Given the risk of chemical dependence, they are either strongly recommended against for all OA phenotypes (OARSI)¹ or weakly recommended as a last resort or when joint replacement is contraindicated (ESCEO)². The ACR differentiates between tramadol and non-tramadol opioids, conditionally recommending tramadol for OA phenotypes when NSAIDs are contraindicated but recommending against non-tramadol opioids, given the higher risk of toxicity and dependence³. However, tramadol use has been reported to be associated with increased all-cause mortality among OA patients²¹. Given that systematic review and meta-analysis have shown that less pain relief occurs during longer trials in the treatment of non-cancer chronic pain²², the American College of Rheumatology (ACR) states that tramadol is conditionally recommended when:

• NSAIDs are contraindicated
• other therapies are ineffective
• no surgical options are available

Personalised approach for osteoarthritis management

Recent guidelines recommend a personalised approach, particularly in OA patients with comorbidities

Common osteoarthritis comorbidities

The prevalence of comorbidities among patients with osteoarthritis (OA) is high. In a large retrospective cohort study in Canada (n = 207,610 patients), 67 % of those with OA (14% of study population) had at least one comorbidity (after adjustment for age and sex), which included²³:

• hypertension (prevalence ratio [PR] 1.17, 95% confidence interval 1.15–1.19)
• depression (PR 1.26, 95% confidence interval 1.22–1.30)
• chronic obstructive pulmonary disease (COPD) (PR 1.16, 95% confidence interval 1.11–1.21)
• epilepsy (PR 1.27, 95% confidence interval 1.13-1.13)

Depression and anxiety are common comorbidities among people experiencing pain. In a meta-analysis of 49 studies, people with OA were 35% and 17% more likely to experience anxiety and depression, respectively, when compared with healthy controls²⁴. Obesity and smoking have also been more commonly recorded among patients with OA than among those without OA²³. Diabetes is also a relatively common comorbidity (~15%) among OA patients²⁵. A recent systematic review and meta-analysis of observational studies identified the key comorbidities associated with OA²⁶ as:

• stroke (PR 2.61, 95%CI 2.13–3.21)
• peptic ulcers (PR 2.36, 95%CI 1.71–3.27)
• metabolic syndrome (PR 1.94, 95%CI 1.21–3.12)

The prevalence of cardiovascular (CV) disease among patients with OA is also high. A meta-analysis including over 32 million patients with OA found that they were twice as likely to have CV disease²⁷. In terms of mortality, studies have also suggested that OA is associated with excess mortality risk due to CV disease, diabetes, obesity, cognitive disorders and disability^28,29.

Certainly a greater comorbidity burden with CV disease, diabetes or back pain has been shown to contribute to worse pain and reduced physical function in patients with knee and/or hip OA³⁰.

Personalised approach to osteoarthritis management

The presence of comorbidities in patients with OA will influence pharmacological treatment choices for pain. Oral NSAID use is often limited because of the increased risk of adverse reactions, many of which would be harmful in patients with some of the common comorbidities listed above.

Otherwise, the same general management principles of OA still apply, in that all patients should engage in non-pharmacological measures, such as weight management and exercise, and psychological interventions, as appropriate. Indeed the beneficial effects of exercise and weight loss will improve several other comorbidities as well as OA².

The ESCEO proposed treatment algorithm for OA is an example of combining evidence-based medicine and patient-centric care, with the ultimate aim of greater HCP and patient satisfaction¹³.

Multidisciplinary team approach to managing osteoarthritis pain

Although osteoarthritis (OA) treatment guidelines provide information about recommended therapies, they do not provide guidance about when specific treatments are appropriate and how various therapies may best fit together in a comprehensive treatment approach. Therefore, models of care that attempt to combine evidence-based treatments have been developed. These encompass various combinations of supervised exercise, physiotherapy, occupational therapy, psychological support (especially cognitive behavioural therapy [CBT]), dietary management and medical management³¹. A multidisciplinary team of professionals can best deliver these programs.

For example, a clinical psychologist can help the patient understand how pain is perceived, and work with them to reduce anxiety and depression, and increase their self-efficacy and ability to manage their OA. In addition, an exercise physiologist and/or physiotherapist can help tailor an exercise program for their needs, and a dietician can work with them on healthy eating and weight loss. These core treatments can be combined with judicious use of pain medications prescribed by primary or specialist HCPs in accordance with the guidelines³¹.

A multidisciplinary team can also assist primary care practitioners develop skills and confidence in treating OA. For example, practitioners such as rheumatology nurses, physiotherapists, community pharmacists, dieticians and rheumatologists can help GPs to reduce overuse of X-rays in diagnosing OA, and inappropriate surgical referrals, as well as increase the uptake of core therapies such as exercise³². In addition, primary healthcare nurses can perform a vital coordination role, helping connect patients with a range of allied health providers³³.

Despite the many recommended treatments for managing OA pain offered by a range of disciplines, researchers acknowledge there are significant evidence-to-practice gaps in OA care³². Moreover, little evidence exists on the and cost-effectiveness of a multidisciplinary approach to management³¹.

A EULAR task force conducted a systematic literature review of systematic reviews to evaluate evidence regarding effects on pain of multiple treatment modalities. The task force concluded: “multidisciplinary treatment is cautiously recommended considering the absence of studies examining the added effect on pain of multidisciplinary treatment to monodisciplinary therapies and considering that meta-analyses on multimodal treatment did not observe effects on pain”⁵. An example given of a possible scenario for multidisciplinary treatment was treating psychological distress in combination with a sedentary lifestyle, if monotherapy had failed⁵. Combinations of exercise, weight management and CBT have shown benefits, but more evidence is needed³¹.

Marie's treatment

Once you have read through this section you will have the option to complete a short quiz based on Marie's treatment programme.

Pharmacological treatment options

• Marie was initially started on 325 mg of paracetamol four times a day and the dose was increased to 1 g four times a day after two weeks but it did not alleviate her pain.

Guidelines no longer recommend regular paracetamol because it has a minimal effect on pain and there is increasing evidence of gastrointestinal, cardiovascular and renal adverse reactions, along with increased mortality risk¹³.

• After six weeks, Marie was switched to 500 mg of naproxen twice a day, which improved her symptoms by about 50%. Her physician also prescribed a proton pump inhibitor to prevent gastric discomfort, and tramadol, one to two 50-mg tablets every 6 hours as needed for breakthrough pain.

Naproxen is an oral, non-selective non-steroidal anti-inflammatory drug (nsNSAID). Topical NSAIDs are preferred to oral NSAIDs in current guidelines for knee and hand OA as they have similar efficacy to the oral medications in reducing pain but with a reduced risk of systemic adverse reactions^2,3.

Guidelines no longer recommend tramadol or opioids for treatment of OA as these agents have only moderate effects in relieving OA pain and improving function, but an increased risk of adverse reactions³⁴.

Marie’s symptoms also improved with physiotherapy, and she lost 4 kg which she maintained.

However, over the next several years Marie’s symptoms worsened, and after experiencing a severe effusion to her right knee with an inflammatory component, Marie opted to have intra-articular glucocorticoid injections.

Marie received 3 injections spaced about 3 months apart and, each time, this provided about 3 months of relief. When the pain returned following the third injection, Marie elected to have hyaluronic acid injections.

The first intra-articular hyaluronic acid treatment was given in a series of 3 injections and provided 18 months of relief and Marie opted to repeat the hyaluronic acid injections when the symptoms returned.

Although surgical interventions including a tibial osteotomy and a total knee replacement were options when Marie’s condition worsened, she elected to pursue the more conservative course with intra-articular hyaluronic acid, which may postpone the need for surgical intervention. Marie continues to take NSAIDs with a PPI only for exacerbations but also takes tramadol intermittently for breakthrough pain.

ACR and ESCEO guidelines only recommend tramadol for knee OA only in cases where NSAIDs or surgery are contraindicated, or as a last resort^2,3.

Although surgical procedures remain an option for Marie should her condition deteriorate, by postponing or avoiding surgery in a relatively young patient such as Marie, the need for multiple knee replacements may be averted.

Given that two of the analgesic medications that Marie was prescribed are no longer recommended by clinical guidelines, it is important that new analgesic therapies are developed to give patients more options.

References

1. Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil. 2019;27(11):1578–1589.
2. Bruyere O, Honvo G, Veronese N, Arden NK, Branco J, Curtis EM, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019;49(3):337–350.
3. Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220–233.
4. Kloppenburg M, Kroon FP, Blanco FJ, Doherty M, Dziedzic KS, Greibrokk E, et al. 2018 update of the EULAR recommendations for the management of hand osteoarthritis. Ann Rheum Dis. 2019;78:16–24.
5. Honvo G, Leclercq V, Geerinck A, Thomas T, Veronese N, Charles A, et al. Safety of topical non-steroidal anti-inflammatory drugs in osteoarthritis: Outcomes of a systematic review and meta-analysis. Drugs and Aging. 2019;36(1):45–64.
6. Wang X, Tian HJ, Yang HK, Wanyan P, Peng YJ. Meta-analysis: Cyclooxygenase-2 inhibitors are no better than nonselective nonsteroidal anti-inflammatory drugs with proton pump inhibitors in regard to gastrointestinal adverse events in osteoarthritis and rheumatoid arthritis. Eur J Gastroenterol Hepatol. 2011;23(10):876–880.
7. Curtis E, Fuggle N, Shaw S, Spooner L, Ntani G, Parsons C, et al. Safety of cyclooxygenase-2 inhibitors in osteoarthritis: Outcomes of a systematic review and meta-analysis. Drugs and Aging. 2019;36(Suppl 1):25–44.
8. Ungprasert P, Srivali N, Thongprayoon C. Nonsteroidal anti-inflammatory drugs and risk of incident heart failure: A systematic review and meta-analysis of observational studies. Clin Cardiol. 2016;39(2):111–118.
9. Baigent C, Bhala N, Emberson J, Merhi A, Abramson S, Arber N, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779.
10. Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015;26(4):285–291.
11. Kucharz EJ, Szántó S, Ivanova Goycheva M, Petronijević M, Šimnovec K, Domżalski M, et al. Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis. 2019;39:1117–1123.
12. Wehling P, Evans C, Wehling J, Maixner W. Effectiveness of intra-articular therapies in osteoarthritis: a literature review. Therapeutic Advances in Musculoskeletal Disease. 2017;9(8):183–196.
13. Cameron M, Chrubasik S. Topical herbal therapies for treating osteoarthritis. Cochrane Database Syst Rev. 2013;5(5):1–91.
14. Roberts E, Nunes VD, Buckner S, Latchem S, Constanti M, Miller P, et al. Paracetamol: Not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552–559.
15. De Vries F, Setakis E, Van Staa T-P. Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes. Br J Clin Pharmacol. 2010;70(3):429–438.
16. Lipworth L, Friis S, Mellemkjær L, Signorello LB, Johnsen SP, Nielsen GL, et al. A population-based cohort study of mortality among adults prescribed paracetamol in Denmark. J Clin Epidemiol. 2003;56(8):796–801.
17. Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E. Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: Systematic analytic review. Osteoarthritis and Cartilage. 2016;24(6):962–972.
18. Stewart M, Cibere J, Sayre EC, Kopec JA. Efficacy of commonly prescribed analgesics in the management of osteoarthritis: a systematic review and meta-analysis. Rheumatology International. 2018;38(11):1985–1997.
19. Zeng C, Dubreuil M, Larochelle MR, Lu N, Wei J, Choi HK, et al. Association of Tramadol with All-Cause Mortality among Patients with Osteoarthritis. JAMA. 2019;321(10):969–982.
20. Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, et al. Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA. 2018;320(23):2448–2460.
21. Birtwhistle R, Morkem R, Peat G, Williamson T, Green ME, Khan S, et al. Prevalence and management of osteoarthritis in primary care: an epidemiologic cohort study from the Canadian Primary Care Sentinel Surveillance Network. C Open. 2015;3(3):E270–E275.
22. Stubbs B, Aluko Y, Myint PK, Smith TO. Prevalence of depressive symptoms and anxiety in osteoarthritis: a systematic review and meta-analysis. Age Ageing. 2016;45(2):228–35.
23. Louati K, Vidal C, Berenbaum F, Sellam J. Association between diabetes mellitus and osteoarthritis: Systematic literature review and meta-analysis. RMD Open. 2015;1(1):e000077.
24. Swain S, Sarmanova A, Coupland C, Doherty M, Zhang W. Comorbidities in osteoarthritis: A systematic review and meta‐analysis of observational studies. Arthritis Care Res (Hoboken). 2019;acr.24008.
25. Hall AJ, Stubbs B, Mamas MA, Myint PK, Smith TO. Association between osteoarthritis and cardiovascular disease: Systematic review and meta-analysis. European Journal of Preventive Cardiology. 2015;23(9):938–946.
26. Nüesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Jüni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: Population based cohort study. Br Med J. 2011;342:d1165.
27. Hawker GA, Croxford R, Bierman AS, Harvey PJ, Ravi B, Stanaitis I, et al. All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: A population based cohort study. PLoS One. 2014;9(3):e91286.
28. Calders P, Van Ginckel A. Presence of comorbidities and prognosis of clinical symptoms in knee and/or hip osteoarthritis: A systematic review and meta-analysis. Seminars in Arthritis and Rheumatism. 2018;47(6):805–813.
29. da Costa BR, Nüesch E, Kasteler R, Husni E, Welch V, Rutjes AWS, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews. 2014;2014(9). doi:10.1002/14651858.CD003115.pub4.