Relative analgesic effectiveness of pharmacological interventions in knee osteoarthritis: a component network meta-analysis

Abstract Introduction Knee osteoarthritis (KNOA) is a chronic, burdensome, highly prevalent degenerative disease1. As there is no current cure for KNOA, treatments are primarily focused on pain management. While pharmacological interventions typically demonstrate superiority to placebo for pain relief, evidence regarding their relative effectiveness is lacking. Component Network Meta-Analysis (CNMA) is a relatively new technique that uses all available evidence to estimate effects of each treatment against all other treatments via its performance relative to a common comparator such as placebo. Aim To evaluate relative analgesic effectiveness of pharmacotherapies for KNOA using CNMA to provide comprehensive, evidence-based information for clinical decisions and inform future guidelines. Methods We performed a comprehensive search of major electronic databases (MEDLINE, EMBASE and CENTRAL) and trial registries from inception to January 2021 without language restriction for RCTs that compared treatment for adults with KNOA with another treatment or control listed in NICE guidelines: paracetamol, NSAIDs (with and without gastroprotection), COX2-inhibitors, opioids, duloxetine, capsaicin, hyaluronic acid (HA) and corticosteroids (CS), administered via oral, topical, transdermal or intra-articular (IA) routes2. Assessment at the following time windows: immediate (up to two weeks), short (closest to 3 months), medium (closest to 6 months) and long (closest to 12 months). A random-effects CNMA was used to estimate relative treatment effects; mean differences (MD) for a primary outcome of pain (0-10) within a frequentist framework3. Certainty of evidence was evaluated using the Confidence in Network Meta-Analysis (CINeMA) with risk of bias (RoB) assessed using the revised Cochrane RoB2 tool. This study does not require ethical approval as it is a systematic review and CNMA of already approved trials and is registered with PROSPERO, CRD42020184192. Results Screening initially identified 33298 citations, reduced to 202 studies after a full-text review. In the immediate-term relative effectiveness ranged between -1.41 (95% confidence interval [CI] -2.23, -0.60) for transdermal NSAIDs and -0.25 (-0.48, -0.02) for IAHA. In the short term, we found evidence of significant effects for all interventions except topical capsaicin and transdermal opioids; effects ranged from -2.09 (-3.69, -0.49) for transdermal NSAIDs to -0.31 (-0.57, -0.04) for IACS. In the medium term, we only found a significant effect for IAHA with MD -0.36 (-0.62, -0.10). We did not find evidence of a significant effect in the long term. 137 (67.8%) of 202 studies included were rated at high risk of bias, 50 (24.7%) at some concerns, and 15 (7.5%) at low, and the certainty of evidence ranged from moderate to very low. Discussion/Conclusion This large-scale and first CNMA provides comprehensive evidence for KNOA pain management. We found evidence of significant effects for several single and multicomponent interventions for immediate and short-term effectiveness. However, their effect diminished over time. While we employed ranking metrics, we could not declare a clear winner among competing interventions due to the between-study heterogeneity, strength of evidence, and the complex nature of KNOA pain. Findings from this study should serve as a tool to inform future guideline developments and clinical decisions, emphasising a holistic approach towards managing KNOA pain with considerations to routes of administration, comorbidities, polypharmacy, and patient needs. References 1. Steinmetz JD, Culbreth GT, Haile LM, Rafferty Q, Lo J, Fukutaki KG, et al. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Rheumatology [Internet]. 2023 Sep 1 [cited 2024 Feb 5];5(9):e508–22. Available from: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00163-7/fulltext 2. NICE. Osteoarthritis in over 16s: diagnosis and management [Internet]. London: National Institute for Health and Care Excellence (NICE); 2022 [cited 2024 Jun 4]. (National Institute for Health and Care Excellence: Guidelines). Available from: http://www.ncbi.nlm.nih.gov/books/NBK588843/ 3. Rücker G, Petropoulou M, Schwarzer G. Network meta-analysis of multicomponent interventions. Biometrical Journal [Internet]. 2020 [cited 2024 Jun 6];62(3):808–21. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/bimj.201800167