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Original Investigation
December 25, 2018

Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Unit of Biostatistics, Epidemiology, and Public Health, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova, Padova, Italy
  • 2Department of Biostatistics, Rottapharm Biotech, Monza, Italy
  • 3Scientific Information and Library Services, Rottapharm Biotech, Monza, Italy
  • 4Department of Clinical Research, Rottapharm Biotech, Monza, Italy
  • 5School of Medicine and Surgery, University of Milano – Bicocca, Monza, Italy
JAMA. 2018;320(24):2564-2579. doi:10.1001/jama.2018.19319
Key Points

Question  What is the association of available medications with long-term pain control in knee osteoarthritis?

Findings  In this systematic review and network meta-analysis of 33 pharmacological interventions that included 22 037 patients with knee osteoarthritis in 47 randomized clinical trials lasting at least 12 months, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo, including the 2 medications that were associated with improved pain (celecoxib and glucosamine sulfate).

Meaning  Larger randomized clinical trials are needed to resolve the uncertainty around the long-term efficacy of medications for knee osteoarthritis.


Importance  Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management.

Objective  To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis.

Data Sources and Study Selection  The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer.

Data Extraction and Synthesis  Data at baseline and at the longest available treatment and follow-up of 12 months’ duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed.

Main Outcomes and Measures  The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value.

Results  Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, −0.18 [95% CrI, −0.35 to −0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, −0.29 [95% CrI, −0.49 to −0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, −0.42 [95% CrI, −0.65 to −0.19]), chondroitin sulfate (SMD, −0.20 [95% CrI, −0.31 to −0.07]), and strontium ranelate (SMD, −0.20 [95% CrI, −0.36 to −0.05]).

Conclusions and Relevance  In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis.