Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis.

Objective: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
Design: Systematic review and network meta-analysis of randomised trials.
Data Sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
Eligibility Criteria for Selecting Studies: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
Outcomes and Measures: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
Review Methods: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
Results: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
Conclusions: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
Systematic Review Registration: PROSPERO number CRD42020213656.
Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Arthritis Society, Canada Research Chairs Programme, National Institute for Health Research, Chevening Scholarship Program for the submitted work. PJ serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Abbot Vascular, and Terumo; he has received research grants to the institution from Appili Therapeutics, and honorariums to the institution for participation in advisory boards or consulting from Amgen, Ava and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. AJS has been a paid consultant by Janssen-Cilag and GlaxoSmithKline. PT has received royalty payments as contributing author and editor for journals, textbooks and articles published by Elsevier, Little Brown, Wolters Kluwer, and John Wiley and Sons; PT has been an independent paid consultant to CHEOR Solutions (Canada), Innovative Science Solutions LLC and Reformulary Group; he serves as unpaid chair of the management subcommittee, of the executive committee of OMERACT; OMERACT receives unrestricted educational grants from the American College of Rheumatology, European League of Rheumatology, Amgen, Astra Zeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Horizon Pharma, Merck, Novartis, Pfizer, PPD, Quintiles, Regeneron, Savient, Takeda Pharmaceutical, UCB Group, Vertex, Forest and Bioiberica; PT serves as an independent committee member in Data Safety Monitoring Boards of FDA approved trials being conducted by UCB Biopharma GmbH and SPRL, Parexel International and Prahealth Sciences. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work.
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