• Bruno R da Costa, Eveline Nüesch, Rahel Kasteler, Elaine Husni, Vivian Welch, Anne W S Rutjes, and Peter Jüni.
• Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, Bern, Bern, Switzerland, 3012.
• Cochrane Db Syst Rev. 2014 Sep 17; 2014 (9): CD003115CD003115.

BackgroundOsteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in older people. Opioids may be a viable treatment option if people have severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. This is an update of a Cochrane review first published in 2009.ObjectivesTo determine the effects on pain, function, safety, and addiction of oral or transdermal opioids compared with placebo or no intervention in people with knee or hip osteoarthritis.Search MethodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL (up to 28 July 2008, with an update performed on 15 August 2012), checked conference proceedings, reference lists, and contacted authors.Selection CriteriaWe included randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in people with knee or hip osteoarthritis. We excluded studies of tramadol. We applied no language restrictions.Data Collection And AnalysisWe extracted data in duplicate. We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain and function, and risk ratios for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis.Main ResultsWe identified 12 additional trials and included 22 trials with 8275 participants in this update. Oral oxycodone was studied in 10 trials, transdermal buprenorphine and oral tapentadol in four, oral codeine in three, oral morphine and oral oxymorphone in two, and transdermal fentanyl and oral hydromorphone in one trial each. All trials were described as double-blind, but the risk of bias for other domains was unclear in several trials due to incomplete reporting. Opioids were more beneficial in pain reduction than control interventions (SMD -0.28, 95% CI -0.35 to -0.20), which corresponds to a difference in pain scores of 0.7 cm on a 10-cm visual analogue scale (VAS) between opioids and placebo. This corresponds to a difference in improvement of 12% (95% CI 9% to 15%) between opioids (41% mean improvement from baseline) and placebo (29% mean improvement from baseline), which translates into a number needed to treat (NNTB) to cause one additional treatment response on pain of 10 (95% CI 8 to 14). Improvement of function was larger in opioid-treated participants compared with control groups (SMD -0.26, 95% CI -0.35 to -0.17), which corresponds to a difference in function scores of 0.6 units between opioids and placebo on a standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10. This corresponds to a difference in improvement of 11% (95% CI 7% to 14%) between opioids (32% mean improvement from baseline) and placebo (21% mean improvement from baseline), which translates into an NNTB to cause one additional treatment response on function of 11 (95% CI 7 to 14). We did not find substantial differences in effects according to type of opioid, analgesic potency, route of administration, daily dose, methodological quality of trials, and type of funding. Trials with treatment durations of four weeks or less showed larger pain relief than trials with longer treatment duration (P value for interaction = 0.001) and there was evidence for funnel plot asymmetry (P value = 0.054 for pain and P value = 0.011 for function). Adverse events were more frequent in participants receiving opioids compared with control. The pooled risk ratio was 1.49 (95% CI 1.35 to 1.63) for any adverse event (9 trials; 22% of participants in opioid and 15% of participants in control treatment experienced side effects), 3.76 (95% CI 2.93 to 4.82) for drop-outs due to adverse events (19 trials; 6.4% of participants in opioid and 1.7% of participants in control treatment dropped out due to adverse events), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials; 1.3% of participants in opioid and 0.4% of participants in control treatment experienced serious adverse events). Withdrawal symptoms occurred more often in opioid compared with control treatment (odds ratio (OR) 2.76, 95% CI 2.02 to 3.77; 3 trials; 2.4% of participants in opioid and 0.9% of participants control treatment experienced withdrawal symptoms).Authors' ConclusionsThe small mean benefit of non-tramadol opioids are contrasted by significant increases in the risk of adverse events. For the pain outcome in particular, observed effects were of questionable clinical relevance since the 95% CI did not include the minimal clinically important difference of 0.37 SMDs, which corresponds to 0.9 cm on a 10-cm VAS.

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